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Huo J, Xiao J, Zhang Y, Qiu X, Huang X, Wang G, Wang J, Liu K, Xu J. Salicylamide derivatives as potent HBV inhibitors: insights into structure-activity relationships. RSC Med Chem 2025:d5md00222b. [PMID: 40352669 PMCID: PMC12059771 DOI: 10.1039/d5md00222b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2025] [Accepted: 04/07/2025] [Indexed: 05/14/2025] Open
Abstract
Current HBV treatment with nucleos(t)ide analogs requires lifelong administration and is associated with the risk of drug resistance, underscoring the urgent need for novel antivirals with alternative targets. Herein, we reported the design, synthesis, and biological evaluation of a series of salicylamide derivatives as potent anti-HBV agents. The nine selected compounds exhibited dose-dependent inhibitory effects on HBV replication, as evidenced by significant reductions in both virion DNA and the secretion levels of HBsAg and HBeAg. Among them, compounds 50 and 56 exhibited the highest anti-HBV activity (IC50 = 0.52 and 0.47 μM, respectively) and selectivity (SI = 20.1 and 17.6, respectively). Mechanistic studies revealed that compounds 27, 31, and 47 impaired HBV core protein (HBc) expression, while compound 50 disrupted capsid formation without significantly affecting HBc expression. These findings highlight the therapeutic potential of salicylamide derivatives as promising anti-HBV agents and provide a foundation for further structural optimization and mechanistic exploration.
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Affiliation(s)
- Jingwen Huo
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University Shenzhen 518107 China
| | - Jizhen Xiao
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University Shenzhen 518107 China
| | - Yushi Zhang
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University Shenzhen 518107 China
| | - Xinhui Qiu
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University Shenzhen 518107 China
| | - Xuechen Huang
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University Shenzhen 518107 China
| | - Ge Wang
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University Shenzhen 518107 China
| | - Jianhao Wang
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University Shenzhen 518107 China
| | - Kuancheng Liu
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University Shenzhen 518107 China
- School of Public Health (Shenzhen), Sun Yat-sen University Guangzhou 510275 China
- Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety, Shenzhen Campus of Sun Yat-sen University Shenzhen 518107 China
| | - Jimin Xu
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University Shenzhen 518107 China
- School of Public Health (Shenzhen), Sun Yat-sen University Guangzhou 510275 China
- Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety, Shenzhen Campus of Sun Yat-sen University Shenzhen 518107 China
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2
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Coomar S, Gasser JA, Słabicki M, Donovan KA, Fischer ES, Ebert BL, Gillingham D, Thomä NH. Niclosamide: CRL4 AMBRA1 mediated degradation of cyclin D1 following mitochondrial membrane depolarization. RSC Med Chem 2025:d5md00054h. [PMID: 40337304 PMCID: PMC12054360 DOI: 10.1039/d5md00054h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Accepted: 04/19/2025] [Indexed: 05/09/2025] Open
Abstract
Targeted protein degradation has emerged as a promising approach in drug discovery, utilizing small molecules like molecular glue degraders to harness the ubiquitin-proteasome pathway for selective degradation of disease-driving proteins. Based on results from proteomics screens we investigated the potential of niclosamide, an FDA-approved anthelmintic drug with a 50 year history in treating tapeworm infections, as a molecular glue degrader targeting the proto-oncogene cyclin D1. Proteomics screens in HCT116 colon carcinoma and KELLY neuroblastoma cells, found that niclosamide induces rapid cyclin D1 degradation through a mechanism involving the ubiquitin-proteasome pathway. A genetic CRISPR screen identified the E3 ligase CRL4AMBRA1 as a key player in this process. Structure-activity relationship studies highlighted critical features of niclosamide necessary for cyclin D1 degradation, demonstrating a correlation between mitochondrial membrane potential (MMP) disruption and cyclin D1 downregulation. Notably, various mitochondrial uncouplers and other compounds with similar drug sensitivity profiles share this correlation suggesting that MMP disruption can trigger cyclin D1 degradation, and that the cellular signal driving the degradation differs from previously described mechanism involving CRL4AMBRA1. Our findings underscore the complexities of proteostatic mechanisms and the multitude of mechanisms that contribute to degrader drug action.
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Affiliation(s)
- Seemon Coomar
- Friedrich Miescher Institute for Biomedical Research Fabrikstrasse 24 Basel 4056 Switzerland
| | | | - Mikołaj Słabicki
- Broad Institute of MIT and Harvard Cambridge MA 02142 USA
- Department of Medical Oncology, Dana-Farber Cancer Institute Boston MA 02115 USA
- Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center Charlestown MA 02129 USA
| | - Katherine A Donovan
- Department of Cancer Biology, Dana-Farber Cancer Institute 450 Brookline Ave. Boston MA 02215 USA
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School 240 Longwood Ave. Boston MA 02215 USA
| | - Eric S Fischer
- Department of Cancer Biology, Dana-Farber Cancer Institute 450 Brookline Ave. Boston MA 02215 USA
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School 240 Longwood Ave. Boston MA 02215 USA
| | | | | | - Nicolas H Thomä
- Friedrich Miescher Institute for Biomedical Research Fabrikstrasse 24 Basel 4056 Switzerland
- Swiss Institute for Experimental Cancer Research (ISREC) EPFL, Station 19 Lausanne 1015 Switzerland
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3
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Neale DA, Morris JC, Verrills NM, Ammit AJ. Understanding the regulatory landscape of protein phosphatase 2A (PP2A): Pharmacological modulators and potential therapeutics. Pharmacol Ther 2025; 269:108834. [PMID: 40023321 DOI: 10.1016/j.pharmthera.2025.108834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 01/20/2025] [Accepted: 02/20/2025] [Indexed: 03/04/2025]
Abstract
Protein phosphatase 2A (PP2A) is a ubiquitously expressed serine/threonine phosphatase with a diverse and integral role in cellular signalling pathways. Consequently, its dysfunction is frequently observed in disease states such as cancer, inflammation and Alzheimer's disease. A growing understanding of both PP2A and its endogenous regulatory proteins has presented numerous targets for therapeutic intervention. This provides important context for the dynamic control and dysregulation of PP2A function in disease states. Understanding the intricate regulation of PP2A signalling in disease has resulted in the development of novel pharmacological agents aimed at restoring cellular homeostasis. Herein we review the structure and function of PP2A together with pharmacological modulators, both endogenous (proteins) and exogenous (small molecules and peptides), with relevance to targeting PP2A as a future pharmacotherapeutic strategy.
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Affiliation(s)
- David A Neale
- School of Chemistry, UNSW Sydney, NSW 2052, Australia
| | | | - Nicole M Verrills
- School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, NSW 2308, Australia; Precision Medicine Program, Hunter Medical Research Institute, New Lambton, NSW 2305, Australia
| | - Alaina J Ammit
- Woolcock Emphysema Centre, Woolcock Institute of Medical Research, Macquarie University, NSW, Australia; School of Life Sciences, Faculty of Science, University of Technology Sydney, NSW, Australia.
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4
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Lu Y, Liang X, Song J, Guan Y, Yang L, Shen R, Niu Y, Guo Z, Zhu N. Niclosamide modulates phenotypic switch and inflammatory responses in human pulmonary arterial smooth muscle cells. Mol Cell Biochem 2025; 480:1583-1593. [PMID: 38980591 DOI: 10.1007/s11010-024-05061-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 06/29/2024] [Indexed: 07/10/2024]
Abstract
Excessive proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) represent key steps of pulmonary vascular remodeling, leading to the development of pulmonary arterial hypertension (PAH) and right ventricular failure. Niclosamide (NCL), an FDA-approved anthelmintic, has been shown to regulate cell proliferation, migration, invasion, and apoptosis through a variety of signaling pathways. However, its role on modulating the phenotypic switch and inflammatory responses in PASMCs remains unclear. In this study, cell proliferation assay showed that NCL inhibited PDGF-BB induced proliferation of human PASMCs in a dose-dependent manner. Western blot analysis further confirmed a notable reduction in the expression of cyclin D1 and PCNA proteins. Subsequently, flow cytometry analysis demonstrated that NCL induced an increased percentage of cells in the G1 phase while promoting apoptosis in PASMCs. Moreover, both scratch wound assay and transwell assay confirmed that NCL decreased PDGF-BB-induced migration of PASMCs. Mechanistically, western blot revealed that pretreatment of PASMCs with NCL markedly restored the protein levels of SMA, SM22, and calponin, while reducing phosphorylation of P38/STAT3 signaling in the presence of PDGF-BB. Interestingly, macrophages adhesion assay showed that NCL markedly reduced recruitment of Calcein-AM labeled RAW264.7 by TNFα-stimulated PASMCs. Western blot revealed that NCL suppressed TNFα-induced expression of both of VCAM-1 and ICAM-1 proteins. Furthermore, pretreatment of PASMCs with NCL significantly inhibited NLRP3 inflammasome activity through reducing NLRP3, AIM2, mature interleukin-1β (IL-β), and cleaved Caspase-1 proteins expression. Together, these results suggested versatile effects of NCL on controlling of proliferation, migration, and inflammatory responses in PASMCs through modulating different pathways, indicating that repurposing of NCL may emerge as a highly effective drug for PAH treatment.
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Affiliation(s)
- Yuwen Lu
- Department of Cardiology, Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Xiaogan Liang
- Department of Cardiology, Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Jingwen Song
- Department of Cardiology, Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Yugen Guan
- Department of Cardiology, Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Liang Yang
- Department of Cardiology, Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Rongrong Shen
- Department of Cardiology, Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Yunpu Niu
- Department of Cardiology, Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Zhifu Guo
- Department of Cardiology, Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China.
| | - Ni Zhu
- Department of Cardiology, Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China.
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Liu S, Luo R, Li D, Tang A, Qiu Y, Sherrier RP, Aube J, Wu X, Xu L, Huang Y. RNA-binding protein HuR regulates the transition of septic AKI to CKD by modulating CD147. Clin Sci (Lond) 2025; 139:69-84. [PMID: 39716463 PMCID: PMC11948685 DOI: 10.1042/cs20241756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 12/20/2024] [Accepted: 12/23/2024] [Indexed: 12/25/2024]
Abstract
Septic acute kidney injury (AKI) is an important risk factor for developing chronic kidney disease (CKD). Hu antigen R (HuR) is recognized as a crucial modulator in inflammation. We hypothesized that elevated HuR contributes to the transition from septic AKI to CKD by promoting persistent inflammation and fibrosis, and inhibition of HuR may reverse septic kidney injury. Mice subjected to lipopolysaccharide (LPS) injections every other day were concurrently treated without or with either KH39 or niclosamide (NCS) for 7 days. Control mice received saline injections. Repeated LPS injections led to a significant increase in HuR expression in the kidneys, which was effectively suppressed by KH39 or NCS treatment. LPS-induced kidney injury was characterized by elevated plasma blood urea nitrogen levels and urinary albuminuria, along with histological signs of inflammatory cell infiltration and fibrosis, as determined by periodic acid-Schiff and Masson's trichrome staining, and immunofluorescent staining for markers such as α-smooth muscle actin, fibronectin, collagen III, and F4/80. Treatment with either KH39 or NCS mitigated these changes observed in LPS-injured kidneys. Additionally, increased expression of CD147, a molecule implicated in inflammatory cell recruitment and tubular injury, was inhibited by KH39 or NCS treatment. These effects on HuR and CD147 expression were further validated in vitro in cultured macrophages and tubular cells. This study suggests that HuR elevation in LPS-stimulated macrophages and kidney cells contributes to the progression of septic kidney injury, possibly through HuR-CD147 interactions, underscoring the therapeutic potential of HuR inhibitors for this condition.
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Affiliation(s)
- Simeng Liu
- Division of Nephrology & Hypertension, Department of Internal Medicine, University of Utah Health Science, Salt Lake City, UT, USA
- Division of Nephrology, Department of Internal Medicine, Nanjing Medical University Jiangsu Province Hospital, Nanjing, China
| | - Renfei Luo
- Division of Nephrology & Hypertension, Department of Internal Medicine, University of Utah Health Science, Salt Lake City, UT, USA
| | - Davey Li
- Division of Nephrology & Hypertension, Department of Internal Medicine, University of Utah Health Science, Salt Lake City, UT, USA
| | - Anna Tang
- Division of Nephrology & Hypertension, Department of Internal Medicine, University of Utah Health Science, Salt Lake City, UT, USA
| | - Yuli Qiu
- Division of Nephrology, Department of Internal Medicine, Nanjing Medical University Jiangsu Province Hospital, Nanjing, China
| | - Ryan P. Sherrier
- Department of Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA
| | - Jeffrey Aube
- Department of Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA
- Department of Chemical Biology and Medical Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA
| | - Xiaoqing Wu
- Department of Molecular Biosciences, University of Kansas, Lawrence, KS, USA
| | - Liang Xu
- Department of Molecular Biosciences, University of Kansas, Lawrence, KS, USA
| | - Yufeng Huang
- Division of Nephrology & Hypertension, Department of Internal Medicine, University of Utah Health Science, Salt Lake City, UT, USA
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Zhang H, Guo R, Li Z, Ma R, Xu S, Yin L, Zhu H, Huang Z, Xing C, Yang Y, Pu Y, Cheng Z, Liu J, Peng H, Sheng Y. MSI2 mediates WNT/β-Catenin pathway function in hematopoietic stem cells. Leukemia 2025; 39:265-270. [PMID: 39438589 DOI: 10.1038/s41375-024-02447-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Revised: 10/14/2024] [Accepted: 10/17/2024] [Indexed: 10/25/2024]
Affiliation(s)
- Huifang Zhang
- Department of Hematology, The Second Xiangya Hospital, Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha, Hunan, PR China.
- Hunan Engineering Research Center of Targeted therapy for Hematopoietic Malignancies, Changsha, 410011, Hunan, PR China.
| | - Ruixue Guo
- Department of Hematology, The Second Xiangya Hospital, Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha, Hunan, PR China
- Hunan Engineering Research Center of Targeted therapy for Hematopoietic Malignancies, Changsha, 410011, Hunan, PR China
| | - Zhenfen Li
- Department of Hematology, The Second Xiangya Hospital, Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha, Hunan, PR China
- Hunan Engineering Research Center of Targeted therapy for Hematopoietic Malignancies, Changsha, 410011, Hunan, PR China
| | - Rui Ma
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, PR China
| | - Shina Xu
- Department of Hematology, The Second Xiangya Hospital, Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha, Hunan, PR China
- Hunan Engineering Research Center of Targeted therapy for Hematopoietic Malignancies, Changsha, 410011, Hunan, PR China
| | - Le Yin
- Department of Hematology, The Second Xiangya Hospital, Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha, Hunan, PR China
- Hunan Engineering Research Center of Targeted therapy for Hematopoietic Malignancies, Changsha, 410011, Hunan, PR China
| | - Hongkai Zhu
- Department of Hematology, The Second Xiangya Hospital, Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha, Hunan, PR China
- Hunan Engineering Research Center of Targeted therapy for Hematopoietic Malignancies, Changsha, 410011, Hunan, PR China
| | - Zineng Huang
- Department of Hematology, The Second Xiangya Hospital, Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha, Hunan, PR China
- Hunan Engineering Research Center of Targeted therapy for Hematopoietic Malignancies, Changsha, 410011, Hunan, PR China
| | - Cheng Xing
- Department of Hematology, The Second Xiangya Hospital, Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha, Hunan, PR China
- Hunan Engineering Research Center of Targeted therapy for Hematopoietic Malignancies, Changsha, 410011, Hunan, PR China
| | - Yunlong Yang
- Department of Hematology, The Second Xiangya Hospital, Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha, Hunan, PR China
- Hunan Engineering Research Center of Targeted therapy for Hematopoietic Malignancies, Changsha, 410011, Hunan, PR China
| | - Yulin Pu
- Department of Hematology, The Second Xiangya Hospital, Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha, Hunan, PR China
| | - Zhao Cheng
- Department of Hematology, The Second Xiangya Hospital, Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha, Hunan, PR China
- Hunan Engineering Research Center of Targeted therapy for Hematopoietic Malignancies, Changsha, 410011, Hunan, PR China
| | - Jing Liu
- Department of Hematology, The Second Xiangya Hospital, Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha, Hunan, PR China
- Hunan Engineering Research Center of Targeted therapy for Hematopoietic Malignancies, Changsha, 410011, Hunan, PR China
| | - Hongling Peng
- Department of Hematology, The Second Xiangya Hospital, Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha, Hunan, PR China.
- Hunan Engineering Research Center of Targeted therapy for Hematopoietic Malignancies, Changsha, 410011, Hunan, PR China.
| | - Yue Sheng
- Department of Hematology, The Second Xiangya Hospital, Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha, Hunan, PR China.
- Hunan Engineering Research Center of Targeted therapy for Hematopoietic Malignancies, Changsha, 410011, Hunan, PR China.
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7
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Baek K, Woo MR, ud Din F, Choi YS, Kang MJ, Kim JO, Choi HG, Jin SG. Comparison of Solid Self-Nanoemulsifying Systems and Surface-Coated Microspheres: Improving Oral Bioavailability of Niclosamide. Int J Nanomedicine 2024; 19:13857-13874. [PMID: 39735329 PMCID: PMC11681811 DOI: 10.2147/ijn.s494083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Accepted: 11/26/2024] [Indexed: 12/31/2024] Open
Abstract
Purpose This study aimed to develop a solid self-nanoemulsifying drug delivery system (SNEDDS) and surface-coated microspheres to improve the oral bioavailability of niclosamide. Methods A solubility screening study showed that liquid SNEDDS, prepared using an optimized volume ratio of corn oil, Cremophor RH40, and Tween 80 (20:24:56), formed nanoemulsions with the smallest droplet size. Niclosamide was incorporated into this liquid SNEDDS and spray-dried with calcium silicate to produce solid SNEDDS. Surface-coated microspheres were prepared using sodium alginate and poloxamer 407 and optimized through solubility and dissolution tests. Scanning electron microscopy, differential scanning calorimetry, and X-ray diffraction were used to evaluate the physicochemical properties of the prepared solid SNEDDS, surface-coated microspheres, and the drug alone. The solubility, dissolution, and oral bioavailability were also assessed. Results Physicochemical evaluation demonstrated that niclosamide was converted to an amorphous state in the Solid SNEDDS formulation, with enhanced solubility and oral bioavailability. In comparison to niclosamide alone, solid SNEDDS exhibited an increase in drug solubility (approximately 2500-fold vs 158-fold) and oral bioavailability (approximately 10-fold vs 1.65-fold), significantly outperforming surface-coated microspheres. Conclusion This solid SNEDDS formulation may be an excellent candidate for niclosamide with improved oral bioavailability for repurposing.
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Affiliation(s)
- Kyungho Baek
- Department of Pharmaceutical Engineering, Dankook University, Cheonan, South Korea
| | - Mi Ran Woo
- College of Pharmacy, Hanyang University, Ansan, South Korea
| | - Fakhar ud Din
- Department of Pharmacy, Quaid-I-Azam University, Islamabad, Pakistan
| | - Yong Seok Choi
- College of Pharmacy, Dankook University, Cheonan, South Korea
| | - Myung Joo Kang
- College of Pharmacy, Dankook University, Cheonan, South Korea
| | - Jong Oh Kim
- College of Pharmacy, Yeungnam University, Gyeongsan, South Korea
| | - Han-Gon Choi
- College of Pharmacy, Hanyang University, Ansan, South Korea
| | - Sung Giu Jin
- Department of Pharmaceutical Engineering, Dankook University, Cheonan, South Korea
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Schmitt L, Krings KS, Wolsing A, Buque X, Zimmermann M, Flores-Romero H, Lenz T, Lechtenberg I, Peter C, Stork B, Teusch N, Proksch P, Stühler K, García-Sáez AJ, Reichert AS, Aspichueta P, Bhatia S, Wesselborg S. Targeting mitochondrial metabolism by the mitotoxin bromoxib in leukemia and lymphoma cells. Cell Commun Signal 2024; 22:541. [PMID: 39533399 PMCID: PMC11558866 DOI: 10.1186/s12964-024-01913-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 10/28/2024] [Indexed: 11/16/2024] Open
Abstract
Targeting mitochondrial metabolism represents a promising approach for cancer treatment. Here, we investigated the mitotoxic potential of the polybrominated diphenyl ether bromoxib, a natural compound isolated from the marine sponge Dysidea family. We could show that bromoxib comprised strong cytotoxicity in different leukemia and lymphoma cell lines (such as HL60, HPBALL, Jurkat, K562, KOPTK1, MOLT4, SUPB15 and Ramos), but also in solid tumor cell lines (such as glioblastoma cell lines SJ-GBM2 and TP365MG). Bromoxib activated the mitochondrial death pathway as evidenced by the rapid translocation of Bax to the mitochondria and the subsequent mitochondrial release of Smac. Accordingly, bromoxib-induced apoptosis was blocked in caspase 9 deficient Jurkat cells and Jurkat cells overexpressing the antiapoptotic protein Bcl-2. In addition, we could show that bromoxib functioned as an uncoupler of the electron transport chain with similar rapid kinetics as CCCP in terms of dissipation of the mitochondrial membrane potential (ΔΨm), processing of the dynamin-like GTPase OPA1 and subsequent fragmentation of mitochondria. Beyond that, bromoxib strongly abrogated ATP production via glycolysis as well as oxidative phosphorylation (OXPHOS) by targeting electron transport chain complexes II, III, and V (ATP-synthase) in Ramos lymphoma cells. Thus, bromoxib's potential to act on both cytosolic glycolysis and mitochondrial respiration renders it a promising agent for the treatment of leukemia and lymphoma.
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Affiliation(s)
- Laura Schmitt
- Institute for Molecular Medicine I, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Karina S Krings
- Institute for Molecular Medicine I, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Andre Wolsing
- Institute of Biochemistry and Molecular Biology I, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Xabier Buque
- Department of Physiology, Faculty of Medicine and Nursing, Universidad del País Vasco, Vitoria-gasteiz, Spain
| | - Marcel Zimmermann
- Institute of Biochemistry and Molecular Biology I, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Hector Flores-Romero
- Institute for Genetics, Faculty of Mathematics and Natural Sciences, University of Cologne, 50931, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931, Cologne, Germany
- Ikerbasque, Basque Foundation for Science, Bilbao, 48013, Spain
- Achucarro Basque Center for Neuroscience, Leioa, Spain
| | - Thomas Lenz
- Molecular Proteomics Laboratory, Biological-Medical-Research Centre (BMFZ), Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Ilka Lechtenberg
- Institute for Molecular Medicine I, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Christoph Peter
- Institute for Molecular Medicine I, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Björn Stork
- Institute for Molecular Medicine I, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Nicole Teusch
- Institute of Pharmaceutical Biology and Biotechnology, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Peter Proksch
- Institute of Pharmaceutical Biology and Biotechnology, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Kai Stühler
- Molecular Proteomics Laboratory, Biological-Medical-Research Centre (BMFZ), Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Ana J García-Sáez
- Institute for Genetics, Faculty of Mathematics and Natural Sciences, University of Cologne, 50931, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931, Cologne, Germany
| | - Andreas S Reichert
- Institute of Biochemistry and Molecular Biology I, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany
| | - Patricia Aspichueta
- Department of Physiology, Faculty of Medicine and Nursing, Universidad del País Vasco, Vitoria-gasteiz, Spain
- Biobizkia Health Research Institute, Barakaldo, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Sanil Bhatia
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany
| | - Sebastian Wesselborg
- Institute for Molecular Medicine I, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany.
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Wiggins R, Woo J, Mito S. Optimizing Niclosamide for Cancer Therapy: Improving Bioavailability via Structural Modification and Nanotechnology. Cancers (Basel) 2024; 16:3548. [PMID: 39456642 PMCID: PMC11506536 DOI: 10.3390/cancers16203548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Revised: 10/15/2024] [Accepted: 10/16/2024] [Indexed: 10/28/2024] Open
Abstract
Inhibition of multiple cancer-related pathways has made niclosamide a promising candidate for the treatment of various cancers. However, its clinical application has been significantly limited by poor bioavailability. This review will discuss current findings on improving niclosamide bioavailability through modification of its chemical structure and utilization of novel nanotechnologies, like electrospraying and supercritical fluids, to improve drug delivery. For example, niclosamide derivatives, such as o-alkylamino-tethered niclosamide derivates, niclosamide ethanolamine salt, and niclosamide piperazine salt, have demonstrated increased water solubility without compromising anticancer activity in vitro. Additionally, this review briefly discusses recent findings on the first pass metabolism of niclosamide in vivo, the role of cytochrome P450-mediated hydroxylation, UDP-glucuronosyltransferase mediated glucuronidation, and how enzymatic inhibition could enhance niclosamide bioavailability. Ultimately, there is a need for researchers to synthesize, evaluate, and improve upon niclosamide derivatives while experimenting with the employment of nanotechnologies, such as targeted delivery and nanoparticle modification, as a way to improve drug administration. Researchers should strive to improve drug-target accuracy, its therapeutic index, and increase the drug's efficacy as an anti-neoplastic agent.
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Affiliation(s)
| | | | - Shizue Mito
- Department of Medical Education, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX 78541, USA; (R.W.); (J.W.)
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10
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Huang Z, Iqbal Z, Zhao Z, Chen X, Mahmmod A, Liu J, Li W, Deng Z. TMEM16 proteins: Ca 2+‑activated chloride channels and phospholipid scramblases as potential drug targets (Review). Int J Mol Med 2024; 54:81. [PMID: 39092585 PMCID: PMC11315658 DOI: 10.3892/ijmm.2024.5405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 06/06/2024] [Indexed: 08/04/2024] Open
Abstract
TMEM16 proteins, which function as Ca2+‑activated Cl‑ channels are involved in regulating a wide variety of cellular pathways and functions. The modulators of Cl‑ channels can be used for the molecule‑based treatment of respiratory diseases, cystic fibrosis, tumors, cancer, osteoporosis and coronavirus disease 2019. The TMEM16 proteins link Ca2+ signaling, cellular electrical activity and lipid transport. Thus, deciphering these complex regulatory mechanisms may enable a more comprehensive understanding of the physiological functions of the TMEM16 proteins and assist in ascertaining the applicability of these proteins as potential pharmacological targets for the treatment of a range of diseases. The present review examined the structures, functions and characteristics of the different types of TMEM16 proteins, their association with the pathogenesis of various diseases and the applicability of TMEM16 modulator‑based treatment methods.
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Affiliation(s)
- Zeqi Huang
- Department of Hand and Foot Surgery, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University), Shenzhen, Guangdong 518000, P.R. China
| | - Zoya Iqbal
- Department of Orthopaedics, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University), Shenzhen, Guangdong 518000, P.R. China
| | - Zhe Zhao
- Department of Hand and Foot Surgery, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University), Shenzhen, Guangdong 518000, P.R. China
| | - Xiaoqiang Chen
- Department of Hand and Foot Surgery, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University), Shenzhen, Guangdong 518000, P.R. China
| | - Ayesha Mahmmod
- Faculty of Pharmacy, The University of Lahore, Lahore, Punjab 58240, Pakistan
| | - Jianquan Liu
- Department of Hand and Foot Surgery, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University), Shenzhen, Guangdong 518000, P.R. China
| | - Wencui Li
- Department of Hand and Foot Surgery, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University), Shenzhen, Guangdong 518000, P.R. China
| | - Zhiqin Deng
- Department of Hand and Foot Surgery, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University), Shenzhen, Guangdong 518000, P.R. China
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Torres Quintas S, Canha-Borges A, Oliveira MJ, Sarmento B, Castro F. Special Issue: Nanotherapeutics in Women's Health Emerging Nanotechnologies for Triple-Negative Breast Cancer Treatment. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2300666. [PMID: 36978237 DOI: 10.1002/smll.202300666] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 03/03/2023] [Indexed: 06/18/2023]
Abstract
Breast cancer appears as the major cause of cancer-related deaths in women, with more than 2 260 000 cases reported worldwide in 2020, resulting in 684 996 deaths. Triple-negative breast cancer (TNBC), characterized by the absence of estrogen, progesterone, and human epidermal growth factor type 2 receptors, represents ≈20% of all breast cancers. TNBC has a highly aggressive clinical course and is more prevalent in younger women. The standard therapy for advanced TNBC is chemotherapy, but responses are often short-lived, with high rate of relapse. The lack of therapeutic targets and the limited therapeutic options confer to individuals suffering from TNBC the poorest prognosis among breast cancer patients, remaining a major clinical challenge. In recent years, advances in cancer nanomedicine provided innovative therapeutic options, as nanoformulations play an important role in overcoming the shortcomings left by conventional therapies: payload degradation and its low solubility, stability, and circulating half-life, and difficulties regarding biodistribution due to physiological and biological barriers. In this integrative review, the recent advances in the nanomedicine field for TNBC treatment, including the novel nanoparticle-, exosome-, and hybrid-based therapeutic formulations are summarized and their drawbacks and challenges are discussed for future clinical applications.
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Affiliation(s)
- Sofia Torres Quintas
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
- INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
- ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Rua Jorge de Viterbo Ferreira 228, Porto, 4050-313, Portugal
| | - Ana Canha-Borges
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
- INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
- ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Rua Jorge de Viterbo Ferreira 228, Porto, 4050-313, Portugal
| | - Maria José Oliveira
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
- INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
- ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Rua Jorge de Viterbo Ferreira 228, Porto, 4050-313, Portugal
| | - Bruno Sarmento
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
- INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
- IUCS-CESPU - Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Rua Central de Gandra 1317, 4585-116, Gandra, Portugal
| | - Flávia Castro
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
- INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
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12
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Zhuang L, Liu W, Tsai XQ, Outtrim C, Tang A, Wang Z, Huang Y. Repurposing Niclosamide to Modulate Renal RNA-Binding Protein HuR for the Treatment of Diabetic Nephropathy in db/db Mice. Int J Mol Sci 2024; 25:9651. [PMID: 39273597 PMCID: PMC11394915 DOI: 10.3390/ijms25179651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 08/31/2024] [Accepted: 09/05/2024] [Indexed: 09/15/2024] Open
Abstract
Hu antigen R (HuR) plays a key role in regulating genes critical to the pathogenesis of diabetic nephropathy (DN). This study investigates the therapeutic potential of niclosamide (NCS) as an HuR inhibitor in DN. Uninephrectomized mice were assigned to four groups: normal control; untreated db/db mice terminated at 14 and 22 weeks, respectively; and db/db mice treated with NCS (20 mg/kg daily via i.p.) from weeks 18 to 22. Increased HuR expression was observed in diabetic kidneys from db/db mice, which was mitigated by NCS treatment. Untreated db/db mice exhibited obesity, progressive hyperglycemia, albuminuria, kidney hypertrophy and glomerular mesangial matrix expansion, increased renal production of fibronectin and a-smooth muscle actin, and decreased glomerular WT-1+-podocytes and nephrin expression. NCS treatment did not affect mouse body weight, but reduced blood glucose and HbA1c levels and halted the DN progression observed in untreated db/db mice. Renal production of inflammatory and oxidative stress markers (NF-κBp65, TNF-a, MCP-1) and urine MDA levels increased during disease progression in db/db mice but were halted by NCS treatment. Additionally, the Wnt1-signaling-pathway downstream factor, Wisp1, was identified as a key downstream mediator of HuR-dependent action and found to be markedly increased in db/db mouse kidneys, which was normalized by NCS treatment. These findings suggest that inhibition of HuR with NCS is therapeutic for DN by improving hyperglycemia, renal inflammation, and oxidative stress. The reduction in renal Wisp1 expression also contributes to its renoprotective effects. This study supports the potential of repurposing HuR inhibitors as a novel therapy for DN.
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Affiliation(s)
| | | | | | | | | | | | - Yufeng Huang
- Division of Nephrology & Hypertension, Department of Internal Medicine, University of Utah Health, Salt Lake City, UT 84132, USA; (L.Z.); (W.L.); (X.-Q.T.); (C.O.); (A.T.); (Z.W.)
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13
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Yang Z, Li H, Yang B, Liu Y. Albumin-Based Microneedles for Spatiotemporal Delivery of Temozolomide and Niclosamide to Resistant Glioblastoma. ACS APPLIED MATERIALS & INTERFACES 2024; 16:44518-44527. [PMID: 39145481 DOI: 10.1021/acsami.4c09394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/16/2024]
Abstract
Glioblastoma (GBM) is the most common and aggressive malignant brain tumor. Standard therapy includes maximal surgical resection, radiotherapy, and adjuvant temozolomide (TMZ) administration. However, the rapid development of TMZ resistance and the impermeability of the blood-brain barrier (BBB) significantly hinder the therapeutic efficacy. Herein, we developed spatiotemporally controlled microneedle patches (BMNs) loaded with TMZ and niclosamide (NIC) to overcome GBM resistance. We found that hyaluronic acid (HA) increased the viscosity of bovine serum albumin (BSA) and evidenced that concentrations of BSA/HA exert an impact degradation rates exposure to high-temperature treatment, showing that the higher BSA/HA concentrations result in slower drug release. To optimize drug release rates and ensure synergistic antitumor effects, a 15% BSA/HA solution constituting the bottoms of BMNs was chosen to load TMZ, showing sustained drug release for over 28 days, guaranteeing long-term DNA damage in TMZ-resistant cells (U251-TR). Needle tips made from 10% BSA/HA solution loaded with NIC released the drug within 14 days, enhancing TMZ's efficacy by inhibiting the activity of O6-methylguanine-DNA methyltransferase (MGMT). BMNs exhibit superior mechanical properties, bypass the BBB, and gradually release the drug into the tumor periphery, thus significantly inhibiting tumor proliferation and expanding median survival in mice. The on-demand delivery of BMNs patches shows a strong translational potential for clinical applications, particularly in synergistic GBM treatment.
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Affiliation(s)
- Zhipeng Yang
- Institute of Biomedical Engineering and Technology, Academy for Engineering & Technology, Fudan University, Shanghai 200433, China
| | - Haoyuan Li
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
| | - Biao Yang
- Shanghai Medical College, Fudan University, Shanghai 200040, China
| | - Yanjie Liu
- Henan University of Chinese Medicine, Zhengzhou, Henan 450046, China
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14
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Omran MM, Kamal MM, Ammar YA, Abusaif MS, Ismail MMF, Mansour HH. Pharmacological investigation of new niclosamide-based isatin hybrids as antiproliferative, antioxidant, and apoptosis inducers. Sci Rep 2024; 14:19818. [PMID: 39191850 DOI: 10.1038/s41598-024-69250-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Accepted: 08/02/2024] [Indexed: 08/29/2024] Open
Abstract
A group of Niclosamide-linked isatin hybrids (Xo, X1, and X2) was created and examined using IR, 1HNMR, 13C NMR, and mass spectrometry. These hybrids' cytotoxicity, antioxidant, cell cycle analysis, and apoptosis-inducing capabilities were identified. Using the SRB assay, their cytotoxicity against the human HCT-116, MCF-7, and HEPG-2 cancer cell lines, as well as VERO (African Green Monkey Kidney), was evaluated. Compound X1 was the most effective compound. In HCT-116 cells, compound X1 produced cell cycle arrest in the G1 phase, promoted cell death, and induced apoptosis through mitochondrial membrane potential breakdown in comparison to niclosamide and the control. Niclosamide and compound X1 reduced reactive oxygen species generation and modulated the gene expression of BAX, Bcl-2, Bcl-xL, and PAR-4 in comparison to the control. Docking modeling indicated their probable binding modalities with the XIAP BIR2 domain, which selectively binds caspase-3/7, and highlighted their structural drivers of activity for further optimization investigations. Computational in silico modeling of the new hybrids revealed that they presented acceptable physicochemical values as well as drug-like characteristics, which may introduce them as drug-like candidates. The study proved that compound X1 might be a novel candidate for the development of anticancer agents as it presents antiproliferative activity mediated by apoptosis.
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Affiliation(s)
- Mervat M Omran
- Pharmacology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Mona M Kamal
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Yousry A Ammar
- Department of Chemistry, Faculty of Science (Boys), Al-Azhar University, Nasr City, Cairo, 11884, Egypt
| | - Moustafa S Abusaif
- Department of Chemistry, Faculty of Science (Boys), Al-Azhar University, Nasr City, Cairo, 11884, Egypt
| | - Magda M F Ismail
- Department of Medicinal Pharmaceutical Chemistry and Drug Design, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo, 11754, Egypt
| | - Heba H Mansour
- Health Radiation Research Department, National Centre for Radiation Research and Technology, Egyptian Atomic Energy Authority, P.O. Box 29, Nasr City Cairo, Egypt.
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15
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Jitobaom K, Boonarkart C, Thongon S, Sirihongthong T, Sornwong A, Auewarakul P, Suptawiwat O. In vitro synergistic antiviral activity of repurposed drugs against enterovirus 71. Arch Virol 2024; 169:169. [PMID: 39078431 DOI: 10.1007/s00705-024-06097-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 06/13/2024] [Indexed: 07/31/2024]
Abstract
Enteroviruses cause viral diseases that are harmful to children. Hand, foot, and mouth disease (HFMD) with neurological complications is mainly caused by enterovirus 71 (EV71). Despite its clinical importance, there is no effective antiviral drug against EV71. However, several repurposed drugs have been shown to have antiviral activity against related viruses. Treatments with single drugs and two-drug combinations were performed in vitro to assess anti-EV71 activity. Three repurposed drug candidates with broad-spectrum antiviral activity were found to demonstrate potent anti-EV71 activity: prochlorperazine, niclosamide, and itraconazole. To improve antiviral activity, combinations of two drugs were tested. Niclosamide and itraconazole showed synergistic antiviral activity in Vero cells, whereas combinations of niclosamide-prochlorperazine and itraconazole-prochlorperazine showed only additive effects. Furthermore, the combination of itraconazole and prochlorperazine showed an additive effect in neuroblastoma cells. Itraconazole and prochlorperazine exert their antiviral activities by inhibiting Akt phosphorylation. Repurposing of drugs can provide a treatment solution for HFMD, and our data suggest that combining these drugs can enhance that efficacy.
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Affiliation(s)
- Kunlakanya Jitobaom
- Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Chompunuch Boonarkart
- Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Songkran Thongon
- Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Thanyaporn Sirihongthong
- Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Arpakorn Sornwong
- Department of Central instrument and Research Laboratory, Virology and Immunology Laboratory, Chulabhorn Royal Academy, Bangkok, 10210, Thailand
| | - Prasert Auewarakul
- Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Ornpreya Suptawiwat
- Department of Central instrument and Research Laboratory, Virology and Immunology Laboratory, Chulabhorn Royal Academy, Bangkok, 10210, Thailand.
- Princess Srisavangavadhana College of Medicine, Chulabhorn Royal Academy, Bangkok, 10210, Thailand.
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16
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Song P, Gao Z, Bao Y, Chen L, Huang Y, Liu Y, Dong Q, Wei X. Wnt/β-catenin signaling pathway in carcinogenesis and cancer therapy. J Hematol Oncol 2024; 17:46. [PMID: 38886806 PMCID: PMC11184729 DOI: 10.1186/s13045-024-01563-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Accepted: 05/31/2024] [Indexed: 06/20/2024] Open
Abstract
The Wnt/β-catenin signaling pathway plays a crucial role in various physiological processes, encompassing development, tissue homeostasis, and cell proliferation. Under normal physiological conditions, the Wnt/β-catenin signaling pathway is meticulously regulated. However, aberrant activation of this pathway and downstream target genes can occur due to mutations in key components of the Wnt/β-catenin pathway, epigenetic modifications, and crosstalk with other signaling pathways. Consequently, these dysregulations contribute significantly to tumor initiation and progression. Therapies targeting the Wnt/β-catenin signaling transduction have exhibited promising prospects and potential for tumor treatment. An increasing number of medications targeting this pathway are continuously being developed and validated. This comprehensive review aims to summarize the latest advances in our understanding of the role played by the Wnt/β-catenin signaling pathway in carcinogenesis and targeted therapy, providing valuable insights into acknowledging current opportunities and challenges associated with targeting this signaling pathway in cancer research and treatment.
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Affiliation(s)
- Pan Song
- Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu, Sichuan Province, 610041, China
| | - Zirui Gao
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Yige Bao
- Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu, Sichuan Province, 610041, China
| | - Li Chen
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Yuhe Huang
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Yanyan Liu
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Qiang Dong
- Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu, Sichuan Province, 610041, China.
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China.
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17
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Xue W, Zhu B, Zhao K, Huang Q, Luo H, Shou Y, Huang Z, Guo H. Targeting LRP6: A new strategy for cancer therapy. Pharmacol Res 2024; 204:107200. [PMID: 38710241 DOI: 10.1016/j.phrs.2024.107200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 04/19/2024] [Accepted: 04/28/2024] [Indexed: 05/08/2024]
Abstract
Targeting specific molecular drivers of tumor growth is a key approach in cancer therapy. Among these targets, the low-density lipoprotein receptor-related protein 6 (LRP6), a vital component of the Wnt signaling pathway, has emerged as an intriguing candidate. As a cell-surface receptor and vital co-receptor, LRP6 is frequently overexpressed in various cancer types, implicating its pivotal role in driving tumor progression. The pursuit of LRP6 as a target for cancer treatment has gained substantial traction, offering a promising avenue for therapeutic intervention. Here, this comprehensive review explores recent breakthroughs in our understanding of LRP6's functions and underlying molecular mechanisms, providing a profound discussion of its involvement in cancer pathogenesis and drug resistance. Importantly, we go beyond discussing LRP6's role in cancer by discussing diverse potential therapeutic approaches targeting this enigmatic protein. These approaches encompass a wide spectrum, including pharmacological agents, natural compounds, non-coding RNAs, epigenetic factors, proteins, and peptides that modulate LRP6 expression or disrupt its interactions. In addition, also discussed the challenges associated with developing LRP6 inhibitors and their advantages over Wnt inhibitors, as well as the drugs that have entered phase II clinical trials. By shedding light on these innovative strategies, we aim to underscore LRP6's significance as a valuable and multifaceted target for cancer treatment, igniting enthusiasm for further research and facilitating translation into clinical applications.
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Affiliation(s)
- Wei Xue
- Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Guangxi Key Laboratory of Research and Evaluation of Bioactive Molecules&College of Pharmacy, Guangxi Medical University, Nanning 530021, China; Department of Pharmacy, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning 530011, China
| | - Bo Zhu
- Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed by the Province and Ministry Guangxi Collaborative Innovation Center for Biomedicine, Guangxi Medical University, Nanning 530021, China
| | - Kaili Zhao
- Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Guangxi Key Laboratory of Research and Evaluation of Bioactive Molecules&College of Pharmacy, Guangxi Medical University, Nanning 530021, China
| | - Qiuju Huang
- Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Guangxi Key Laboratory of Research and Evaluation of Bioactive Molecules&College of Pharmacy, Guangxi Medical University, Nanning 530021, China
| | - Hua Luo
- Macau Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau Special Administrative Region of China
| | - Yiwen Shou
- Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Guangxi Key Laboratory of Research and Evaluation of Bioactive Molecules&College of Pharmacy, Guangxi Medical University, Nanning 530021, China
| | - Zhaoquan Huang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China.
| | - Hongwei Guo
- Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Guangxi Key Laboratory of Research and Evaluation of Bioactive Molecules&College of Pharmacy, Guangxi Medical University, Nanning 530021, China.
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18
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Ramos MLM, Almeida-Silva F, de Souza Rabello VB, Nahal J, Figueiredo-Carvalho MHG, Bernardes-Engemann AR, Poester VR, Xavier MO, Meyer W, Zancopé-Oliveira RM, Frases S, Almeida-Paes R. In vitro activity of the anthelmintic drug niclosamide against Sporothrix spp. strains with distinct genetic and antifungal susceptibility backgrounds. Braz J Microbiol 2024; 55:1359-1368. [PMID: 38466550 PMCID: PMC11153390 DOI: 10.1007/s42770-024-01301-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 03/07/2024] [Indexed: 03/13/2024] Open
Abstract
The drugs available to treat sporotrichosis, an important yet neglected fungal infection, are limited. Some Sporothrix spp. strains present reduced susceptibility to these antifungals. Furthermore, some patients may not be indicated to use these drugs, while others may not respond to the therapy. The anthelmintic drug niclosamide is fungicidal against the Sporothrix brasiliensis type strain. This study aimed to evaluate whether niclosamide also has antifungal activity against Sporothrix globosa, Sporothrix schenckii and other S. brasiliensis strains with distinct genotypes and antifungal susceptibility status. Minimal inhibitory and fungicidal concentrations (MIC and MFC, respectively) were determined using the microdilution method according to the CLSI protocol. The checkerboard method was employed to evaluate niclosamide synergism with drugs used in sporotrichosis treatment. Metabolic activity of the strains under niclosamide treatment was evaluated using the resazurin dye. Niclosamide was active against all S. brasiliensis strains (n = 17), but it was ineffective (MIC > 20 µM) for some strains (n = 4) of other pathogenic Sporothrix species. Niclosamide MIC values for Sporothrix spp. were similar for mycelial and yeast-like forms of the strains (P = 0.6604). Niclosamide was fungicidal (MFC/MIC ratio ≤ 2) for most strains studied (89%). Niclosamide activity against S. brasiliensis is independent of the fungal genotype or non-wild-type phenotypes for amphotericin B, itraconazole, or terbinafine. These antifungal drugs presented indifferent interactions with niclosamide. Niclosamide has demonstrated potential for repurposing as a treatment for sporotrichosis, particularly in S. brasiliensis cases, instigating in vivo studies to validate the in vitro findings.
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Affiliation(s)
- Mariana Lucy Mesquita Ramos
- Laboratório de Biofísica de Fungos, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Fernando Almeida-Silva
- Laboratório de Micologia, Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - Vanessa Brito de Souza Rabello
- Laboratório de Micologia, Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - Juliana Nahal
- Laboratório de Micologia, Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | | | - Andrea Reis Bernardes-Engemann
- Laboratório de Micologia, Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - Vanice Rodrigues Poester
- Laboratório de Micologia, Faculdade de Medicina, Universidade Federal Do Rio Grande, Rio Grande, RS, Brazil
| | - Melissa Orzechowski Xavier
- Laboratório de Micologia, Faculdade de Medicina, Universidade Federal Do Rio Grande, Rio Grande, RS, Brazil
| | - Wieland Meyer
- Westerdijk Fungal Biodiversity Institute of the KNAW, Utrecht, The Netherlands
| | - Rosely Maria Zancopé-Oliveira
- Laboratório de Micologia, Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - Susana Frases
- Laboratório de Biofísica de Fungos, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
- Rede Micologia - FAPERJ, Rio de Janeiro, RJ, Brazil.
| | - Rodrigo Almeida-Paes
- Laboratório de Micologia, Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
- Rede Micologia - FAPERJ, Rio de Janeiro, RJ, Brazil.
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Nguyen NT, Sennoune SR, Dharmalingam-Nandagopal G, Sivaprakasam S, Bhutia YD, Ganapathy V. Impact of Oncogenic Changes in p53 and KRAS on Macropinocytosis and Ferroptosis in Colon Cancer Cells and Anticancer Efficacy of Niclosamide with Differential Effects on These Two Processes. Cells 2024; 13:951. [PMID: 38891084 PMCID: PMC11171492 DOI: 10.3390/cells13110951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 05/25/2024] [Accepted: 05/29/2024] [Indexed: 06/21/2024] Open
Abstract
Mutations in p53 and KRAS are seen in most cases of colon cancer. The impact of these mutations on signaling pathways related to cancer growth has been studied in depth, but relatively less is known on their effects on amino acid transporters in cancer cells. This represents a significant knowledge gap because amino acid nutrition in cancer cells profoundly influences macropinocytosis and ferroptosis, two processes with opposing effects on tumor growth. Here, we used isogenic colon cancer cell lines to investigate the effects of p53 deletion and KRAS activation on two amino acid transporters relevant to macropinocytosis (SLC38A5) and ferroptosis (SLC7A11). Our studies show that the predominant effect of p53 deletion is to induce SLC7A11 with the resultant potentiation of antioxidant machinery and protection of cancer cells from ferroptosis, whereas KRAS activation induces not only SLC7A11 but also SLC38A5, thus offering protection from ferroptosis as well as improving amino acid nutrition in cancer cells via accelerated macropinocytosis. Niclosamide, an FDA-approved anti-helminthic, blocks the functions of SLC7A11 and SLC38A5, thus inducing ferroptosis and suppressing macropinocytosis, with the resultant effective reversal of tumor-promoting actions of oncogenic changes in p53 and KRAS. These findings underscore the potential of this drug in colon cancer treatment.
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Affiliation(s)
| | | | | | | | | | - Vadivel Ganapathy
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; (N.T.N.); (S.R.S.); (G.D.-N.); (S.S.); (Y.D.B.)
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20
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Kim T, Jung W, Cho S, Kim G, Yun H, Chae J. Predicting lung exposure of intramuscular niclosamide as an antiviral agent: Power-law based pharmacokinetic modeling. Clin Transl Sci 2024; 17:e13833. [PMID: 38797873 PMCID: PMC11128490 DOI: 10.1111/cts.13833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 04/28/2024] [Accepted: 04/30/2024] [Indexed: 05/29/2024] Open
Abstract
Niclosamide, a potent anthelmintic agent, has emerged as a candidate against COVID-19 in recent studies. Its formulation has been investigated extensively to address challenges related to systemic exposure. In this study, niclosamide was formulated as a long-acting intramuscular injection to achieve systemic exposure in the lungs for combating the virus. To establish the dose-exposure relationship, a hamster model was selected, given its utility in previous COVID-19 infection studies. Pharmacokinetic (PK) analysis was performed using NONMEM and PsN. Hamsters were administered doses of 55, 96, 128, and 240 mg/kg with each group comprising five animals. Two types of PK models were developed, linear models incorporating partition coefficients and power-law distributed models, to characterize the relationship between drug concentrations in the plasma and lungs of the hamsters. Numerical and visual diagnostics, including basic goodness-of-fit and visual predictive checks, were employed to assess the models. The power-law-based PK model not only demonstrated superior numerical performance compared with the linear model but also exhibited better agreement in visual diagnostic evaluations. This phenomenon was attributed to the nonlinear relationship between drug concentrations in the plasma and lungs, reflecting kinetic heterogeneity. Dose optimization, based on predicting lung exposure, was conducted iteratively across different drug doses, with the minimum effective dose estimated to be ~1115 mg/kg. The development of a power-law-based PK model proved successful and effectively captured the nonlinearities observed in this study. This method is expected to be applicable for investigating the drug disposition of specific formulations in the lungs.
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Affiliation(s)
- Taeheon Kim
- Life Science Institute, Daewoong PharmaceuticalYonginSouth Korea
| | - Woojin Jung
- College of PharmacyChungnam National UniversityDaejeonSouth Korea
| | - Sangeun Cho
- Life Science Institute, Daewoong PharmaceuticalYonginSouth Korea
| | - Gwanyoung Kim
- Life Science Institute, Daewoong PharmaceuticalYonginSouth Korea
| | - Hwi‐yeol Yun
- College of PharmacyChungnam National UniversityDaejeonSouth Korea
- Department of Bio‐AI ConvergenceChungnam National UniversityDaejeonSouth Korea
| | - Jung‐woo Chae
- College of PharmacyChungnam National UniversityDaejeonSouth Korea
- Department of Bio‐AI ConvergenceChungnam National UniversityDaejeonSouth Korea
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21
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Needham D. Niclosamide: A career builder. J Control Release 2024; 369:786-856. [PMID: 37544514 DOI: 10.1016/j.jconrel.2023.07.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 06/24/2023] [Accepted: 07/08/2023] [Indexed: 08/08/2023]
Abstract
My contribution to honoring Professor Kinam Park celebrates and resonates with his scholarly career in drug delivery, his commitment to encouraging the next generation(s), and his efforts to keep us focused on clinically effective formulations. To do this I take as my example, niclosamide, a small molecule protonophore that, uniquely, can "target" all cell membranes, both plasma and organelle. As such, it acts upstream of many cell pathways and so has the potential to affect many of the essential events that a cell, and particularly a diseased cell or other entities like a virus, use to stay alive and prosper. Literature shows that it has so far been discovered to positively influence (at least): cancer, bacterial and viral infection, metabolic diseases such as Type II diabetes, NASH and NAFLD, artery constriction, endometriosis, neuropathic pain, rheumatoid arthritis, sclerodermatous graft-versus-host disease, systemic sclerosis, Parkinson's, and COPD. With such a fundamental action and broad-spectrum activity, I believe that studying niclosamide in all its manifestations, discovering if and to what extent it can contribute positively to disease control (and also where it can't), formulating it as effective therapeutics, and testing them in preclinical and clinical trials is a career builder for our next generation(s). The article is divided into two parts: Part I introduces niclosamide and other proton shunts mainly in cancer and viral infections and reviews an exponentially growing literature with some concepts and physicochemical properties that lead to its proton shunt mechanism. Part II focuses on repurposing by reformulation of niclosamide. I give two examples of "carrier-free formulations", - one for cancer (as a prodrug therapeutic of niclosamide stearate for i.v. and other administration routes, exemplified by our recent work on Osteosarcoma in mice and canine patients), and the other as a niclosamide solution formulation (that could provide the basis for a preventative nasal spray and early treatment option for COVID19 and other respiratory virus infections). My goal is to excite and enthuse, encourage, and motivate all involved in the drug development and testing process in academia, institutes, and industry, to learn more about this interesting molecule and others like it. To enable such endeavors, I give many proposed ideas throughout the document, that have been stimulated and inspired by gaps in the literature, urgent needs in disease, and new studies arising from our own work. The hope is that, by reading through this document and studying the suggested topics and references, the drug delivery and development community will continue our lineage and benefit from our legacy to achieve niclosamide's potential as an effective contributor to the treatment and control of many diseases and conditions.
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Affiliation(s)
- David Needham
- Department of Mechanical Engineering and Material Science, Duke University, Durham, NC 27708, USA; Translational Therapeutics, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK.
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22
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Horváth L, Biri-Kovács B, Baranyai Z, Stipsicz B, Méhes E, Jezsó B, Krátký M, Vinšová J, Bősze S. New Salicylanilide Derivatives and Their Peptide Conjugates as Anticancer Compounds: Synthesis, Characterization, and In Vitro Effect on Glioblastoma. ACS OMEGA 2024; 9:16927-16948. [PMID: 38645331 PMCID: PMC11024950 DOI: 10.1021/acsomega.3c05727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 12/28/2023] [Accepted: 01/03/2024] [Indexed: 04/23/2024]
Abstract
Pharmacologically active salicylanilides (2-hydroxy-N-phenylbenzamides) have been a promising area of interest in medicinal chemistry-related research for quite some time. This group of compounds has shown a wide spectrum of biological activities, including but not limited to anticancer effects. In this study, substituted salicylanilides were chosen to evaluate the in vitro activity on U87 human glioblastoma (GBM) cells. The parent salicylanilide, salicylanilide 5-chloropyrazinoates, a 4-aminosalicylic acid derivative, and the new salicylanilide 4-formylbenzoates were chemically and in vitro characterized. To enhance the internalization of the compounds, they were conjugated to delivery peptides with the formation of oxime bonds. Oligotuftsins ([TKPKG]n, n = 1-4), the ligands of neuropilin receptors, were used as GBM-targeting carrier peptides. The in vitro cellular uptake, intracellular localization, and penetration ability on tissue-mimicking models of the fluorescent peptide derivatives were determined. The compounds and their peptide conjugates significantly decreased the viability of U87 glioma cells. Salicylanilide compound-induced GBM cell death was associated with activation of autophagy, as characterized by immunodetection of autophagy-related processing of light chain 3 protein.
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Affiliation(s)
- Lilla Horváth
- ELKH-ELTE
Research Group of Peptide Chemistry, Eötvös Loránd
Research Network, Eötvös Loránd
University, Budapest 1117, Hungary
| | - Beáta Biri-Kovács
- ELKH-ELTE
Research Group of Peptide Chemistry, Eötvös Loránd
Research Network, Eötvös Loránd
University, Budapest 1117, Hungary
| | - Zsuzsa Baranyai
- ELKH-ELTE
Research Group of Peptide Chemistry, Eötvös Loránd
Research Network, Eötvös Loránd
University, Budapest 1117, Hungary
| | - Bence Stipsicz
- ELKH-ELTE
Research Group of Peptide Chemistry, Eötvös Loránd
Research Network, Eötvös Loránd
University, Budapest 1117, Hungary
- Institute
of Biology, Doctoral School of Biology, Eötvös Loránd University, Budapest 1117, Hungary
| | - Előd Méhes
- Institute
of Physics, Department of Biological Physics, Eötvös Loránd University, Budapest 1117, Hungary
| | - Bálint Jezsó
- Research
Centre for Natural Sciences, Institute of
Enzymology, Budapest 1053, Hungary
- ELTE-MTA
“Momentum” Motor Enzymology Research Group, Department
of Biochemistry, Eötvös Loránd
University, Budapest 1117, Hungary
| | - Martin Krátký
- Department
of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec
Králové, Charles University, 500 03 Hradec Králové, Czech Republic
| | - Jarmila Vinšová
- Department
of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec
Králové, Charles University, 500 03 Hradec Králové, Czech Republic
| | - Szilvia Bősze
- ELKH-ELTE
Research Group of Peptide Chemistry, Eötvös Loránd
Research Network, Eötvös Loránd
University, Budapest 1117, Hungary
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23
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Li J, Han N, Li Y, Zhao F, Xiong W, Zeng Z. The synergistic antibacterial activity and mechanism of colistin-oxethazaine combination against gram-negative pathogens. Front Pharmacol 2024; 15:1363441. [PMID: 38576480 PMCID: PMC10991713 DOI: 10.3389/fphar.2024.1363441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Accepted: 03/01/2024] [Indexed: 04/06/2024] Open
Abstract
Background The rapid spread of bacteria with plasmid-mediated resistance to antibiotics poses a serious threat to public health. The search for potential compounds that can increase the antibacterial activity of existing antibiotics is a promising strategy for addressing this issue. Methods Synergistic activity of the FDA-approved agent oxethazine combined with colistin was investigated in vitro using checkerboard assays and time-kill curves. The synergistic mechanisms of their combination of oxethazine and colistin was explored by fluorescent dye, scanning electron microscopy (SEM) and LC-MS/MS. The synergistic efficacy was evaluated in vivo by the Galleria mellonella and mouse sepsis models. Results In this study, we found that oxethazine could effectively enhance the antibacterial activity of colistin against both mcr-positive and -negative pathogens, and mechanistic assays revealed that oxethazine could improve the ability of colistin to destruct bacterial outer membrane and cytoplasmic membrane permeability. In addition, their combination triggered the accumulation of reactive oxygen species causing additional damage to the membrane structure resulting in cell death. Furthermore, oxethazine significantly enhanced the therapeutic efficacy of colistin in two animal models. Conclusion These results suggested that oxethazine, as a promising antibiotic adjuvant, can effectively enhance colistin activity, providing a potential strategy for treating multidrug-resistant bacteria.
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Affiliation(s)
- Jie Li
- Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- National Laboratory of Safety Evaluation (Environmental Assessment) of Veterinary Drugs, South China Agricultural University, Guangzhou, China
- National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou, China
| | - Ning Han
- Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- National Laboratory of Safety Evaluation (Environmental Assessment) of Veterinary Drugs, South China Agricultural University, Guangzhou, China
- National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou, China
| | - Yangyang Li
- Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- National Laboratory of Safety Evaluation (Environmental Assessment) of Veterinary Drugs, South China Agricultural University, Guangzhou, China
- National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou, China
| | - Feifei Zhao
- Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- National Laboratory of Safety Evaluation (Environmental Assessment) of Veterinary Drugs, South China Agricultural University, Guangzhou, China
- National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou, China
| | - Wenguang Xiong
- Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- National Laboratory of Safety Evaluation (Environmental Assessment) of Veterinary Drugs, South China Agricultural University, Guangzhou, China
- National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou, China
| | - Zhenling Zeng
- Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- National Laboratory of Safety Evaluation (Environmental Assessment) of Veterinary Drugs, South China Agricultural University, Guangzhou, China
- National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou, China
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24
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Liu Y, Guerrero DQ, Lechuga-Ballesteros D, Tan M, Ahmad F, Aleiwi B, Ellsworth EL, Chen B, Chua MS, So S. Lipid-Based Self-Microemulsion of Niclosamide Achieved Enhanced Oral Delivery and Anti-Tumor Efficacy in Orthotopic Patient-Derived Xenograft of Hepatocellular Carcinoma in Mice. Int J Nanomedicine 2024; 19:2639-2653. [PMID: 38500681 PMCID: PMC10946447 DOI: 10.2147/ijn.s442143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 02/20/2024] [Indexed: 03/20/2024] Open
Abstract
Introduction We previously identified niclosamide as a promising repurposed drug candidate for hepatocellular carcinoma (HCC) treatment. However, it is poorly water soluble, limiting its tissue bioavailability and clinical application. To overcome these challenges, we developed an orally bioavailable self-microemulsifying drug delivery system encapsulating niclosamide (Nic-SMEDDS). Methods Nic-SMEDDS was synthesized and characterized for its physicochemical properties, in vivo pharmacokinetics and absorption mechanisms, and in vivo therapeutic efficacy in an orthotopic patient-derived xenograft (PDX)-HCC mouse model. Niclosamide ethanolamine salt (NEN), with superior water solubility, was used as a positive control. Results Nic-SMEDDS (5.6% drug load) displayed favorable physicochemical properties and drug release profiles in vitro. In vivo, Nic-SMEDDS displayed prolonged retention time and plasma release profile compared to niclosamide or NEN. Oral administration of Nic-SMEDDS to non-tumor bearing mice improved niclosamide bioavailability and Cmax by 4.1- and 1.8-fold, respectively, compared to oral niclosamide. Cycloheximide pre-treatment blocked niclosamide absorption from orally administered Nic-SMEDDS, suggesting that its absorption was facilitated through the chylomicron pathway. Nic-SMEDDS (100 mg/kg, bid) showed greater anti-tumor efficacy compared to NEN (200 mg/kg, qd); this correlated with higher levels (p < 0.01) of niclosamide, increased caspase-3, and decreased Ki-67 in the harvested PDX tissues when Nic-SMEDDS was given. Biochemical analysis at the treatment end-point indicated that Nic-SMEDDS elevated lipid levels in treated mice. Conclusion We successfully developed an orally bioavailable formulation of niclosamide, which significantly enhanced oral bioavailability and anti-tumor efficacy in an HCC PDX mouse model. Our data support its clinical translation for the treatment of solid tumors.
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Affiliation(s)
- Yi Liu
- Department of Surgery, School of Medicine, Stanford University, Stanford, CA, USA
| | - David Quintanar Guerrero
- Laboratorio de Investigación y Posgrado en Tecnologías Farmacéuticas, Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México, Cuautitlán Izcalli, CP, 54745, Mexico
| | | | - Mingdian Tan
- Department of Surgery, School of Medicine, Stanford University, Stanford, CA, USA
| | - Faiz Ahmad
- Department of Surgery, School of Medicine, Stanford University, Stanford, CA, USA
| | - Bilal Aleiwi
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
| | - Edmund Lee Ellsworth
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
| | - Bin Chen
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
| | - Mei-Sze Chua
- Department of Surgery, School of Medicine, Stanford University, Stanford, CA, USA
| | - Samuel So
- Department of Surgery, School of Medicine, Stanford University, Stanford, CA, USA
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25
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Mathew M, Sivaprakasam S, Dharmalingam-Nandagopal G, Sennoune SR, Nguyen NT, Jaramillo-Martinez V, Bhutia YD, Ganapathy V. Induction of Oxidative Stress and Ferroptosis in Triple-Negative Breast Cancer Cells by Niclosamide via Blockade of the Function and Expression of SLC38A5 and SLC7A11. Antioxidants (Basel) 2024; 13:291. [PMID: 38539825 PMCID: PMC10967572 DOI: 10.3390/antiox13030291] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Revised: 02/21/2024] [Accepted: 02/24/2024] [Indexed: 03/08/2025] Open
Abstract
The amino acid transporters SLC38A5 and SLC7A11 are upregulated in triple-negative breast cancer (TNBC). SLC38A5 transports glutamine, methionine, glycine and serine, and therefore activates mTOR signaling and induces epigenetic modifications. SLC7A11 transports cystine and increases the cellular levels of glutathione, which protects against oxidative stress and lipid peroxidation via glutathione peroxidase, a seleno (Se)-enzyme. The primary source of Se is dietary Se-methionine (Se-Met). Since SLC38A5 transports methionine, we examined its role in Se-Met uptake in TNBC cells. We found that SLC38A5 interacts with methionine and Se-Met with comparable affinity. We also examined the influence of Se-Met on Nrf2 in TNBC cells. Se-Met activated Nrf2 and induced the expression of Nrf2-target genes, including SLC7A11. Our previous work discovered niclosamide, an antiparasitic drug, as a potent inhibitor of SLC38A5. Here, we found SLC7A11 to be inhibited by niclosamide with an IC50 value in the range of 0.1-0.2 μM. In addition to the direct inhibition of SLC38A5 and SLC7A11, the pretreatment of TNBC cells with niclosamide reduced the expression of both transporters. Niclosamide decreased the glutathione levels, inhibited proliferation, suppressed GPX4 expression, increased lipid peroxidation, and induced ferroptosis in TNBC cells. It also significantly reduced the growth of the TNBC cell line MB231 in mouse xenografts.
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Affiliation(s)
| | | | | | | | | | | | | | - Vadivel Ganapathy
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; (M.M.); (S.S.); (G.D.-N.); (S.R.S.); (N.T.N.); (V.J.-M.); (Y.D.B.)
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26
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Liu C, Li S, Zhang C, Jin CH. Recent Advances in Research on Active Compounds Against Hepatic Fibrosis. Curr Med Chem 2024; 31:2571-2628. [PMID: 37497688 DOI: 10.2174/0929867331666230727102016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 05/14/2023] [Accepted: 06/26/2023] [Indexed: 07/28/2023]
Abstract
BACKGROUND Almost all chronic liver diseases cause fibrosis, which can lead to cirrhosis and eventually liver cancer. Liver fibrosis is now considered to be a reversible pathophysiological process and suppression of fibrosis is necessary to prevent liver cancer. At present, no specific drugs have been found that have hepatic anti-fibrotic activity. OBJECTIVE The research progress of anti-hepatic fibrosis compounds in recent ten years was reviewed to provide a reference for the design and development of anti-hepatic fibrosis drugs. METHODS According to the structure of the compounds, they are divided into monocyclic compounds, fused-heterocyclic compounds, and acyclic compounds. RESULTS In this article, the natural products and synthetic compounds with anti-fibrotic activity in recent ten years were reviewed, with emphasis on their pharmacological activity and structure-activity relationship (SAR). CONCLUSION Most of these compounds are natural active products and their derivatives, and there are few researches on synthetic compounds and SAR studies on natural product.
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Affiliation(s)
- Chuang Liu
- Key Laboratory of Natural Resources of Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, Jilin, 133002, China
| | - Siqi Li
- Key Laboratory of Natural Resources of Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, Jilin, 133002, China
| | - Changhao Zhang
- Key Laboratory of Natural Resources of Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, Jilin, 133002, China
| | - Cheng-Hua Jin
- Key Laboratory of Natural Resources of Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, Jilin, 133002, China
- Interdisciplinary of Biological Functional Molecules, College of Integration Science, Yanbian University, Yanji, Jilin, 133002, China
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27
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Ajmeera D, Ajumeera R. Drug repurposing: A novel strategy to target cancer stem cells and therapeutic resistance. Genes Dis 2024; 11:148-175. [PMID: 37588226 PMCID: PMC10425757 DOI: 10.1016/j.gendis.2022.12.013] [Citation(s) in RCA: 22] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 11/21/2022] [Accepted: 12/08/2022] [Indexed: 01/21/2023] Open
Abstract
Chemotherapy is an effortless and frequently used approach in cancer therapy. However, in most cases, it can only prolong life expectancy and does not guarantee a complete cure. Furthermore, chemotherapy is associated with severe adverse effects, one of the major complications of effective cancer therapy. In addition, newly published research outputs show that cancer stem cells are involved in cancer disease progression, drug resistance, metastasis, and recurrence and that they are functional in the trans-differentiation capacity of cancer stem cells to cancer cells in response to treatments. Novel strategies are therefore required for better management of cancer therapy. The prime approach would be to synthesize and develop novel drugs that need extensive resources, time, and endurance to be brought into therapeutic use. The subsequent approach would be to screen the anti-cancer activity of available non-cancerous drugs. This concept of repurposing non-cancer drugs as an alternative to current cancer therapy has become popular in recent years because using existing anticancer drugs has several adverse effects. Micronutrients have also been investigated for cancer therapy due to their significant anti-cancer effects with negligible or no side effects and availability in food sources. In this paper, we discuss an ideal hypothesis for screening available non-cancerous drugs with anticancer activity, with a focus on cancer stem cells and their clinical application for cancer treatment. Further, drug repurposing and the combination of micronutrients that can target both cancers and cancer stem cells may result in a better therapeutic approach leading to maximum tumor growth control.
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Affiliation(s)
- Divya Ajmeera
- Cell Biology Department, ICMR-National Institute of Nutrition (NIN), Hyderabad, Telangana 500007, India
| | - Rajanna Ajumeera
- Cell Biology Department, ICMR-National Institute of Nutrition (NIN), Hyderabad, Telangana 500007, India
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28
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Kang HW, Kim JH, Lee DE, Lee YS, Kim MJ, Kim HS, Fang S, Lee BE, Lee KJ, Yoo J, Kim HJ, Park JS. Combination therapy of niclosamide with gemcitabine inhibited cell proliferation and apoptosis via Wnt/β-catenin/c-Myc signaling pathway by inducing β-catenin ubiquitination in pancreatic cancer. Cancer Biol Ther 2023; 24:2272334. [PMID: 37917550 PMCID: PMC10623893 DOI: 10.1080/15384047.2023.2272334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 10/10/2023] [Indexed: 11/04/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a type of cancer with high morbidity and mortality rates worldwide. Owing to a lack of therapeutic options, the overall survival rate of patients with pancreatic cancer is low. Gemcitabine has been mainly used to treat patients with pancreatic cancer, but its efficacy is limited by chemoresistance. Therefore, a novel therapeutic agent for PDAC therapy is urgently needed. An anthelminthic drug, niclosamide, has already been researched in breast, lung, colon, and pancreatic cancer as an anti-cancer purpose by re-positioning its original purpose. However, combination therapy of gemcitabine and niclosamide was not informed yet. Here, we found that niclosamide co-administered with gemcitabine significantly inhibited tumorigenesis of pancreatic cancer compared to gemcitabine alone. Further, combining niclosamide and gemcitabine inhibited cell proliferation and induced apoptosis. Niclosamide induced cell cycle arrest at the G1 phase, and the levels of CDK4/6 and cyclin D1 were lowered after gemcitabine treatment. In addition, the combination of these chemical compounds more effectively increased the binding level of activated β-catenin destruction complex and β-catenin to enable phosphorylation, compared to gemcitabine alone. After phosphorylation, niclosamide - gemcitabine upregulated the ubiquitin level, which caused phosphorylated β-catenin to undergo proteasomal degradation; the combination was more potent than gemcitabine alone. Finally, the combination more effectively suppressed tumor growth in vivo, compared to gemcitabine alone. Altogether, our results indicate that niclosamide synergistically enhances the antitumor effect of gemcitabine in pancreatic cancer, by inducing the degradation of β-catenin with ubiquitination. Therefore, this drug combination can potentially be used in PDAC therapy.
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Affiliation(s)
- Hyeon Woong Kang
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Republic of Korea
| | - Ju Hyun Kim
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Da Eun Lee
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yun Sun Lee
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Myeong Jin Kim
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Republic of Korea
| | - Hyung Sun Kim
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - SungSoon Fang
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Republic of Korea
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Bo Eun Lee
- CHA Organoid Research Center, School of Medicine, CHA University, Seoul, Republic of Korea
- ORGANOIDSCIENCES, Ltd, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Kyung Jin Lee
- CHA Organoid Research Center, School of Medicine, CHA University, Seoul, Republic of Korea
- ORGANOIDSCIENCES, Ltd, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Jongman Yoo
- CHA Organoid Research Center, School of Medicine, CHA University, Seoul, Republic of Korea
- ORGANOIDSCIENCES, Ltd, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Hyo Jung Kim
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Joon Seong Park
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
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Rahman M, Afzal O, Ullah SNM, Alshahrani MY, Alkhathami AG, Altamimi ASA, Almujri SS, Almalki WH, Shorog EM, Alossaimi MA, Mandal AK, abdulrahman A, Sahoo A. Nanomedicine-Based Drug-Targeting in Breast Cancer: Pharmacokinetics, Clinical Progress, and Challenges. ACS OMEGA 2023; 8:48625-48649. [PMID: 38162753 PMCID: PMC10753706 DOI: 10.1021/acsomega.3c07345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Revised: 11/08/2023] [Accepted: 11/16/2023] [Indexed: 01/03/2024]
Abstract
Breast cancer (BC) is a malignant neoplasm that begins in the breast tissue. After skin cancer, BC is the second most common type of cancer in women. At the end of 2040, the number of newly diagnosed BC cases is projected to increase by over 40%, reaching approximately 3 million worldwide annually. The hormonal and chemotherapeutic approaches based on conventional formulations have inappropriate therapeutic effects and suboptimal pharmacokinetic responses with nonspecific targeting actions. To overcome such issues, the use of nanomedicines, including liposomes, nanoparticles, micelles, hybrid nanoparticles, etc., has gained wider attention in the treatment of BC. Smaller dimensional nanomedicine (especially 50-200 nm) exhibited improved in vivo effectiveness, such as better tissue penetration and more effective tumor suppression through enhanced retention and permeation, as well as active targeting of the drug. Additionally, nanotechnology, which further extended and developed theranostic nanomedicine by incorporating diagnostic and imaging agents in one platform, has been applied to BC. Furthermore, hybrid and theranostic nanomedicine has also been explored for gene delivery as anticancer therapeutics in BC. Moreover, the nanocarriers' size, shape, surface charge, chemical compositions, and surface area play an important role in the nanocarriers' stability, cellular absorption, cytotoxicity, cellular uptake, and toxicity. Additionally, nanomedicine clinical translation for managing BC remains a slow process. However, a few cases are being used clinically, and their progress with the current challenges is addressed in this Review. Therefore, this Review extensively discusses recent advancements in nanomedicine and its clinical challenges in BC.
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Affiliation(s)
- Mahfoozur Rahman
- Department
of Pharmaceutical Sciences, Shalom Institute of Health and Allied
Sciences, Sam Higginbottom University of
Agriculture, Technology & Sciences, Allahabad, Uttar Pradesh 211007, India
| | - Obaid Afzal
- Department
of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Shehla Nasar Mir
Najib Ullah
- Phyto
Pharmaceuticals Research Lab, Department of Pharmacognosy and Phytochemistry, School of Pharmaceutical Sciences and Research, Jamia
Hamdard University, Hamdard Nagar, New Delhi, Delhi 110062, India
| | - Mohammad Y. Alshahrani
- Department
of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, P.O. Box 61413, Abha 9088, Saudi Arabia
| | - Ali G. Alkhathami
- Department
of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, P.O. Box 61413, Abha 9088, Saudi Arabia
| | | | - Salem Salman Almujri
- Department
of Pharmacology, College of Pharmacy, King
Khalid University, Asir-Abha 61421, Saudi Arabia
| | - Waleed H Almalki
- Department
of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia
| | - Eman M. Shorog
- Department
of Clinical Pharmacy, Faculty of Pharmacy, King Khalid University, Abha 61421, Saudi Arabia
| | - Manal A Alossaimi
- Department
of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Ashok Kumar Mandal
- Department
of Pharmacology, Faculty of Medicine, University
Malaya, Kuala Lumpur 50603, Malaysia
| | - Alhamyani abdulrahman
- Pharmaceuticals
Chemistry Department, Faculty of Clinical Pharmacy, Al Baha University, Al Baha 65779, Saudi Arabia
| | - Ankit Sahoo
- Department
of Pharmaceutical Sciences, Shalom Institute of Health and Allied
Sciences, Sam Higginbottom University of
Agriculture, Technology & Sciences, Allahabad, Uttar Pradesh 211007, India
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30
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Menezes CA, Montresor LC, Jangola STG, de Mattos AC, Domingues ALC, Júnior AM, Silva CCM, Barbosa CS, de Mendonça CLF, Massara CL, Fonseca CT, de Oliveira EJ, Gomes ECDS, da Silva EF, Bezerra FSDM, Silva-Jr FP, de Siqueira IC, Silva JRME, Heller L, Farias LP, Beck LCNH, Santos MCS, Lima MG, Mourão MDM, Enk MJ, Fernandez MA, Katz N, Carvalho ODS, Parreiras PM, Neves RH, Gava SG, de Oliveira SA, Thiengo SC, Favre TC, Graeff-Teixeira C, Pieri OS, Caldeira RL, da Silva-Pereira RA, Rocha RS, Oliveira RR. FioSchisto's expert perspective on implementing WHO guidelines for schistosomiasis control and transmission elimination in Brazil. Front Immunol 2023; 14:1268998. [PMID: 38143743 PMCID: PMC10739458 DOI: 10.3389/fimmu.2023.1268998] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 11/17/2023] [Indexed: 12/26/2023] Open
Abstract
The World Health Organization (WHO) recognizes schistosomiasis as one of the Neglected Tropical Diseases targeted for global elimination in the 2030 Agenda of the Sustainable Development Goals. In Brazil, schistosomiasis mansoni is considered a public health problem, particularly prevalent among vulnerable populations living in areas with poor environmental and sanitary conditions. In 2022, the WHO published a Guideline encompassing recommendations to assist national programs in endemic countries in achieving morbidity control, eliminating schistosomiasis as a public health problem, and advancing towards interrupting transmission. The perspectives presented here, collectively prepared by members of the Oswaldo Cruz Foundation's (Fiocruz) Schistosomiasis Translational Program (FioSchisto), along with invited experts, examine the feasibility of the WHO recommendations for the Brazilian settings, providing appropriate recommendations for public health policies applicable to the epidemiological reality of Brazil, and suggests future research to address relevant issues. In Brazil, the provision of safe water and sanitation should be the key action to achieve schistosomiasis elimination goals. The agencies involved in measures implementation should act together with the Primary Care teams for planning, executing, monitoring, and evaluating actions in priority municipalities based on their epidemiological indicators. Host snails control should prioritize judicious ecological interventions at breeding sites. The Information, Education, and Communication (IEC) strategy should be associated with water and sanitation and other control actions, actively involving school community. To identify infected carriers, FioSchisto recommends a two-stage approach of immunological and molecular tests to verify transmission interruption during the intervention and beyond. Praziquantel administration should be done under medical supervision at the Primary Care level. MDA should be considered in exceptional settings, as a measure of initial attack strategy in locations presenting high endemicity, always integrated with water and sanitation, IEC, and snail control. To assist decision-making, as well as the monitoring and evaluation of strategic actions, there is a need for an Information System. FioSchisto considers this systematization essential to make investments in strategic research to support the improvement of schistosomiasis control actions. Efforts toward schistosomiasis elimination in Brazil will succeed with a paradigm shift from the vertical prescriptive framework to a community-centered approach involving intersectoral and interdisciplinary collaboration.
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Affiliation(s)
| | | | | | | | - Ana Lúcia Coutinho Domingues
- Centro de Ciências da Saúde, Departamento de Medicina Clínica, Universidade Federal de Pernambuco, Recife, Brazil
| | | | | | | | | | | | | | | | | | | | | | | | | | | | - Leo Heller
- Instituto René Rachou, Fundação Oswaldo Cruz - FIOCRUZ, Belo Horizonte, Brazil
| | | | | | | | - Mariana Gomes Lima
- Instituto Oswaldo Cruz, Fundação Oswaldo Cruz - FIOCRUZ, Rio de Janeiro, Brazil
| | | | | | | | - Naftale Katz
- Instituto René Rachou, Fundação Oswaldo Cruz - FIOCRUZ, Belo Horizonte, Brazil
| | | | | | - Renata Heisler Neves
- Faculdade de Ciências Médicas, Universidade Estatual do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Sandra Grossi Gava
- Instituto René Rachou, Fundação Oswaldo Cruz - FIOCRUZ, Belo Horizonte, Brazil
| | | | | | | | - Carlos Graeff-Teixeira
- Centro de Ciências da Saúde, Núcleo de Doenças Infecciosas, Universidade Federal do Espírito Santo, Vitória, Brazil
| | | | | | | | - Roberto Sena Rocha
- Instituto René Rachou, Fundação Oswaldo Cruz - FIOCRUZ, Belo Horizonte, Brazil
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Kulthawatsiri T, Kittirat Y, Phetcharaburanin J, Tomacha J, Promraksa B, Wangwiwatsin A, Klanrit P, Titapun A, Loilome W, Namwat N. Metabolomic analyses uncover an inhibitory effect of niclosamide on mitochondrial membrane potential in cholangiocarcinoma cells. PeerJ 2023; 11:e16512. [PMID: 38025687 PMCID: PMC10676079 DOI: 10.7717/peerj.16512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 11/02/2023] [Indexed: 12/01/2023] Open
Abstract
Background Niclosamide is an oral anthelminthic drug that has been used for treating tapeworm infections. Its mechanism involves the disturbance of mitochondrial membrane potential that in turn inhibits oxidative phosphorylation leading to ATP depletion. To date, niclosamide has been validated as the potent anti-cancer agent against several cancers. However, the molecular mechanisms underlying the effects of niclosamide on the liver fluke Opisthorchis viverrini (Ov)-associated cholangiocarcinoma (CCA) cell functions remain to be elucidated. The aims of this study were to investigate the effects of niclosamide on CCA cell proliferation and on metabolic phenoconversion through the alteration of metabolites associated with mitochondrial function in CCA cell lines. Materials and Methods The inhibitory effect of niclosamide on CCA cells was determined using SRB assay. A mitochondrial membrane potential using tetramethylrhodamine, ethyl ester-mitochondrial membrane potential (TMRE-MMP) assay was conducted. Liquid chromatography-mass spectrometry-based metabolomics was employed to investigate the global metabolic changes upon niclosamide treatment. ATP levels were measured using CellTiter-Glo® luminescent cell viability assay. NAD metabolism was examined by the NAD+/NADH ratio. Results Niclosamide strongly inhibited CCA cell growth and reduced the MMP of CCA cells. An orthogonal partial-least square regression analysis revealed that the effects of niclosamide on suppressing cell viability and MMP of CCA cells were significantly associated with an increase in niacinamide, a precursor in NAD synthesis that may disrupt the electron transport system leading to suppression of NAD+/NADH ratio and ATP depletion. Conclusion Our findings unravel the mode of action of niclosamide in the energy depletion that could potentially serve as the promising therapeutic strategy for CCA treatment.
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Affiliation(s)
- Thanaporn Kulthawatsiri
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Khon Kaen, Thailand
- Khon Kaen University Phenome Centre, Khon Kaen University, Khon Kaen, Khon Kaen, Thailand
| | - Yingpinyapat Kittirat
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Khon Kaen, Thailand
- Department of Medical Sciences/Regional Medical Sciences Center 2, Ministry of Public Health, Phitsanulok, Phitsanulok, Thailand
| | - Jutarop Phetcharaburanin
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Khon Kaen, Thailand
- Khon Kaen University Phenome Centre, Khon Kaen University, Khon Kaen, Khon Kaen, Thailand
- Department of Systems Biosciences and Computational Medicine/Faculty of Medicine, Khon Kaen University, Khon Kaen, Khon Kaen, Thailand
| | - Jittima Tomacha
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Khon Kaen, Thailand
| | - Bundit Promraksa
- Department of Medical Sciences/Regional Medical Sciences Center 2, Ministry of Public Health, Phitsanulok, Phitsanulok, Thailand
| | - Arporn Wangwiwatsin
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Khon Kaen, Thailand
- Khon Kaen University Phenome Centre, Khon Kaen University, Khon Kaen, Khon Kaen, Thailand
- Department of Systems Biosciences and Computational Medicine/Faculty of Medicine, Khon Kaen University, Khon Kaen, Khon Kaen, Thailand
| | - Poramate Klanrit
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Khon Kaen, Thailand
- Khon Kaen University Phenome Centre, Khon Kaen University, Khon Kaen, Khon Kaen, Thailand
- Department of Systems Biosciences and Computational Medicine/Faculty of Medicine, Khon Kaen University, Khon Kaen, Khon Kaen, Thailand
| | - Attapol Titapun
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Khon Kaen, Thailand
- Khon Kaen University Phenome Centre, Khon Kaen University, Khon Kaen, Khon Kaen, Thailand
- Department of Surgery/Faculty of Medicine, Khon Kaen University, Khon Kaen, Khon Kaen, Thailand
| | - Watcharin Loilome
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Khon Kaen, Thailand
- Khon Kaen University Phenome Centre, Khon Kaen University, Khon Kaen, Khon Kaen, Thailand
- Department of Systems Biosciences and Computational Medicine/Faculty of Medicine, Khon Kaen University, Khon Kaen, Khon Kaen, Thailand
| | - Nisana Namwat
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Khon Kaen, Thailand
- Khon Kaen University Phenome Centre, Khon Kaen University, Khon Kaen, Khon Kaen, Thailand
- Department of Systems Biosciences and Computational Medicine/Faculty of Medicine, Khon Kaen University, Khon Kaen, Khon Kaen, Thailand
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Pal C. Small-molecule redox modulators with anticancer activity: A comprehensive mechanistic update. Free Radic Biol Med 2023; 209:211-227. [PMID: 37898387 DOI: 10.1016/j.freeradbiomed.2023.10.406] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 09/27/2023] [Accepted: 10/25/2023] [Indexed: 10/30/2023]
Abstract
The pursuit of effective anticancer therapies has led to a burgeoning interest in the realm of redox modulation. This review provides a comprehensive exploration of the intricate mechanisms by which diverse anticancer molecules leverage redox pathways for therapeutic intervention. Redox modulation, encompassing the fine balance of oxidation-reduction processes within cells, has emerged as a pivotal player in cancer treatment. This review delves into the multifaceted mechanisms of action employed by various anticancer compounds, including small molecules and natural products, to disrupt cancer cell proliferation and survival. Beginning with an examination of the role of redox signaling in cancer development and resistance, the review highlights how aberrant redox dynamics can fuel tumorigenesis. It then meticulously dissects the strategies employed by anticancer agents to induce oxidative stress, perturb redox equilibrium, and trigger apoptosis within cancer cells. Furthermore, the review explores the challenges and potential side effects associated with redox-based treatments, along with the development of novel redox-targeted agents. In summary, this review offers a profound understanding of the dynamic interplay between redox modulation and anticancer molecules, presenting promising avenues to revolutionize cancer therapy and enhance patient outcomes.
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Affiliation(s)
- Chinmay Pal
- Department of Chemistry, Gobardanga Hindu College, North 24 Parganas, West Bengal, 743273, India.
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Mito S, Cheng B, Garcia BA, Yee Ooi X, Gonzalez D, Ruiz TC, Elisarraras FX, Tsin A. SAR study of niclosamide derivatives for neuroprotective function in SH-SY5Y neuroblastoma. Bioorg Med Chem Lett 2023; 96:129498. [PMID: 37804994 DOI: 10.1016/j.bmcl.2023.129498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 08/06/2023] [Accepted: 10/04/2023] [Indexed: 10/09/2023]
Abstract
Neurodegenerative disease is a debilitating and incurable condition that affects millions of people around the world. The loss of functions or malfunctions of neural cells are the causes of mortality. A proteosome inhibitor, MG132, is well known to cause neurodegeneration in vitro when model neuronal-derived cell lines are exposed to it. Niclosamide, an anthelmintic drug, which has been used to treat tapeworm infections for more than 50 years, has recently attracted renewed attention in drug repurposing because it has been found to be a good candidate in many drug development screenings. We recently found that all markers of MG132-induced neuronal cell toxicity, including the accumulation of ubiquitinated proteins, were prevented by the presence of niclosamide. In addition, niclosamide was shown to enhance autophagy induced by MG132. There results suggested that niclosamide could act as a neuroprotective agent. In the present study, niclosamide derivatives were synthesized, and the structure-activity relationship (SAR) were determined with respect to protein ubiquitination induced by MG132 and effect on cell survival signaling pathways for neuroprotective function. Our results indicate that phenol OH plays a significant role in neuroprotective activity while the niclosamide derivatives without Cl (5- or 2'-Cl) showed almost the same neuroprotective effect. 4'-NO2 can be replaced by N3 or CF3 whereas NH2 significantly decreased activity. These findings provide guidance for the development of new niclosamide analogues against neurodegenerative diseases including Parkinson's disease.
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Affiliation(s)
- Shizue Mito
- Department of Chemistry, The University of Texas Rio Grande Valley, Edinburg, TX 78539, USA; Department of Medical Education, School of Medicine, The University of Texas Rio Grande Valley, Edinburg 78541, USA.
| | - Benxu Cheng
- Department of Neuroscience, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Benjamin A Garcia
- Department of Chemistry, The University of Texas Rio Grande Valley, Edinburg, TX 78539, USA
| | - Xin Yee Ooi
- Department of Neuroscience, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Daniela Gonzalez
- Department of Neuroscience, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Tess C Ruiz
- Department of Chemistry, The University of Texas Rio Grande Valley, Edinburg, TX 78539, USA
| | - Francisco X Elisarraras
- Department of Neuroscience, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Andrew Tsin
- Department of Neuroscience, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA
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Zhang Q, Yang Z, Hao X, Dandreo LJ, He L, Zhang Y, Wang F, Wu X, Xu L. Niclosamide improves cancer immunotherapy by modulating RNA-binding protein HuR-mediated PD-L1 signaling. Cell Biosci 2023; 13:192. [PMID: 37848943 PMCID: PMC10583380 DOI: 10.1186/s13578-023-01137-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 09/21/2023] [Indexed: 10/19/2023] Open
Abstract
BACKGROUND Immune checkpoint blockade (ICB) represents a revolutionary advance in cancer treatment but remains limited success in triple-negative breast cancer (TNBC). Here we aim to explore the mechanism of RNA-binding protein (RBP) HuR in cancer immune evasion by post-transcriptionally regulating PD-L1 and evaluate the potential of HuR inhibition to improve immune response. METHODS The binding between HuR and PD-L1 mRNA was determined by ribonucleoprotein immunoprecipitation and RNA pull-down assays. The HuR knockout clones were established by CRISPR/Cas9 technology. The protein levels were assessed by Western blot, immunohistochemistry, and immunocytochemistry. The function and molecular mechanism of HuR-PD-L1 were determined by in vitro T cell activation and killing assay and in vivo efficacy assay. RESULTS We found that HuR directly bound to and stabilized PD-L1 mRNA. Knocking out HuR reduced PD-L1 levels and promoted T cell activation. We discovered that niclosamide reduced PD-L1 by inhibiting HuR cytoplasmic translocation, and diminished glycosylation of PD-L1. Niclosamide enhanced T cell-mediated killing of cancer cells and significantly improved the efficacy of anti-PD-1 immunotherapy in two syngeneic animal tumor models. CONCLUSION We identified HuR as a novel posttranscriptional regulator of PD-L1, which plays an important role in tumor immune evasion. Niclosamide might be a promising repurposed drug to improve the patient response to immunotherapy by targeting HuR-PD-L1 axis. Our study demonstrates a novel strategy for targeting HuR/PD-L1 and provides the first proof-of-principle for repurposing niclosamide as a HuR inhibitor to overcome cancer immune evasion and improve response to ICB immunotherapy.
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Affiliation(s)
- Qi Zhang
- Department of Molecular Biosciences, The University of Kansas, 1567 Irving Hill Rd, Lawrence, KS, 66045-7534, USA
| | - Zhe Yang
- Department of Molecular Biosciences, The University of Kansas, 1567 Irving Hill Rd, Lawrence, KS, 66045-7534, USA
| | - Xinbao Hao
- Department of Molecular Biosciences, The University of Kansas, 1567 Irving Hill Rd, Lawrence, KS, 66045-7534, USA
| | - Lauren J Dandreo
- Department of Molecular Biosciences, The University of Kansas, 1567 Irving Hill Rd, Lawrence, KS, 66045-7534, USA
| | - Lily He
- Department of Pharmacology, Toxicology & Therapeutics, The University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Yuxia Zhang
- Department of Pharmacology, Toxicology & Therapeutics, The University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Fen Wang
- Department of Radiation Oncology, The University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Xiaoqing Wu
- Department of Molecular Biosciences, The University of Kansas, 1567 Irving Hill Rd, Lawrence, KS, 66045-7534, USA.
- The University of Kansas Cancer Center, The University of Kansas Medical Center, Kansas City, KS, 66160, USA.
| | - Liang Xu
- Department of Molecular Biosciences, The University of Kansas, 1567 Irving Hill Rd, Lawrence, KS, 66045-7534, USA.
- Department of Radiation Oncology, The University of Kansas Medical Center, Kansas City, KS, 66160, USA.
- The University of Kansas Cancer Center, The University of Kansas Medical Center, Kansas City, KS, 66160, USA.
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Tai Y, Tian M, Chen Y, You P, Song X, Xu B, Duan C, Jin D. Preparation of PLGA microspheres loaded with niclosamide via microfluidic technology and their inhibition of Caco-2 cell activity in vitro. Front Chem 2023; 11:1249293. [PMID: 37780982 PMCID: PMC10537947 DOI: 10.3389/fchem.2023.1249293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 09/04/2023] [Indexed: 10/03/2023] Open
Abstract
Niclosamide (NIC) is a multifunctional drug that regulates various signaling pathways and biological processes. It is widely used for the treatment of cancer, viral infections, and metabolic disorders. However, its low water solubility limits its efficacy. In this study, poly(lactic-co-glycolic acid) (PLGA) and hyaluronic acid (HA), which exhibit good biocompatibility, biodegradability, and non-immunogenicity, were conjugated with niclosamide to prepare PLGA-HA-niclosamide polymeric nanoparticles (NIC@PLGA-HA) using microfluidic technology. The obtained microspheres had a uniform size distribution, with an average mean size of 442.0 ± 18.8 nm and zeta potential of -25.4 ± 0.41 mV, indicating their stable dispersion in water. The drug-loading efficiency was 8.70%. The drug-loaded microspheres showed sustained release behavior at pH 7.4 and 5.0, but not at pH 2.0, and the drug release kinetics were described by a quasi-first-order kinetic equation. The effect of the drug-loaded microspheres on the proliferation of Caco-2 cells was detected using the MTT assay. Hydrophilic HA-modified NIC@PLGA-HA microspheres prepared via microfluidic technology increased the cellular uptake by Caco-2 cells. Compared to the same concentration of NIC, the NIC@PLGA-HA microspheres demonstrated a stronger inhibitory effect on Caco-2 cells owing to the combined effect of PLGA, HA, and NIC. Therefore, the pH-responsive NIC@PLGA-HA microspheres synthesized using microfluid technology increased the solubility of NIC and improved its biological activity, thus contributing to the demand for intestinal drug carriers.
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Affiliation(s)
- Yulei Tai
- School Laboratory of Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, China
- Laboratory of Biomarkers and In Vitro Diagnosis Translation of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Menglun Tian
- School Laboratory of Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, China
- Laboratory of Biomarkers and In Vitro Diagnosis Translation of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Yu Chen
- School Laboratory of Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, China
- Laboratory of Biomarkers and In Vitro Diagnosis Translation of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Peijun You
- School Laboratory of Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, China
- Laboratory of Biomarkers and In Vitro Diagnosis Translation of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Xiaojun Song
- School Laboratory of Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, China
- Laboratory of Biomarkers and In Vitro Diagnosis Translation of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Bangting Xu
- School Laboratory of Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Cidong Duan
- School Laboratory of Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, China
- Laboratory of Biomarkers and In Vitro Diagnosis Translation of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Dazhi Jin
- School Laboratory of Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, China
- Laboratory of Biomarkers and In Vitro Diagnosis Translation of Zhejiang Province, Hangzhou, Zhejiang, China
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36
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Alazemi AM, Dawood KM, Al-Matar HM, Tohamy WM. Microwave-assisted chemoselective synthesis and photophysical properties of 2-arylazo-biphenyl-4-carboxamides from hydrazonals. RSC Adv 2023; 13:25054-25068. [PMID: 37614785 PMCID: PMC10442861 DOI: 10.1039/d3ra04558g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Accepted: 08/07/2023] [Indexed: 08/25/2023] Open
Abstract
The reaction of 3-oxo-2-arylhydrazonopropanals with acetoacetanilide in an equimolar ratio, under DBU/1,4-dioxane/microwave irradiation reaction conditions, resulted in chemoselective formation of 4-arylazo-5-hydroxy-benzamide derivatives. The structures of the obtained biphenyl-4-carboxamides were characterized by several spectroscopic techniques including IR, 1H- and 13C-NMR, MS and HRMS, and X-ray single crystals of three examples. The photophysical properties of the new products were also evaluated, with a particular focus on their absorption and emission spectra, which provided valuable information regarding their optical properties. The new compounds emitted 513-549 nm green fluorescence in acetone solution under UV irradiation.
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Affiliation(s)
- Abdulrahman M Alazemi
- Chemistry Department, Faculty of Science, University of Kuwait P.O. Box 5969 Safat 13060 Kuwait +965 24816482
| | - Kamal M Dawood
- Department of Chemistry, Faculty of Science, Cairo University Giza 12613 Egypt +202 35727556
| | - Hamad M Al-Matar
- Chemistry Department, Faculty of Science, University of Kuwait P.O. Box 5969 Safat 13060 Kuwait +965 24816482
| | - Wael M Tohamy
- Chemistry Department, Faculty of Science, University of Kuwait P.O. Box 5969 Safat 13060 Kuwait +965 24816482
- Organometallic and Organometalloid Chemistry Department, National Research Centre Cairo Egypt
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37
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Erturk E, Onur OE, Aydin I, Akgun O, Coskun D, Ari F. Targeting the epithelial-mesenchymal transition (EMT) pathway with combination of Wnt inhibitor and chalcone complexes in lung cancer cells. J Cell Biochem 2023; 124:1203-1219. [PMID: 37450704 DOI: 10.1002/jcb.30442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 05/31/2023] [Accepted: 07/05/2023] [Indexed: 07/18/2023]
Abstract
Non-small cell lung cancer (NSCLC) is the most common type of the lung cancer. Despite development in treatment options in NSCLC, the overall survival ratios is still poor due to epithelial and mesenchymal transition (EMT) feature and associated metastasis event. Thereby there is a need to develop strategy to increase antitumor response against the NSCLC cells by targeting EMT pathway with combination drugs. Niclosamide and chalcone complexes are both affect cancer cell signaling pathways and therefore inhibit the EMT pathway. In this study, it was aimed to increase antitumor response and suppress EMT pathway in NSCLC cells by combining niclosamide and chalcone complexes. SRB cell viability assay was performed to investigate the anticancer activity of drugs. The drugs were tested on both NSCLC cells (A549 and H1299) and normal lung bronchial cells (BEAS-2B). Then the two drugs were combined and their effects on cancer cells were evaluated. Fluorescence imaging and enzyme-linked immunosorbent assay were performed on treated cells to observe the cell death manner. Wound healing assay, real-time quantitative polymerase chain reaction, and western blot analysis were performed to measure EMT pathway activity. Our results showed that niclosamide and chalcone complexes combination kill cancer cells more than normal lung bronchial cells. Compared to single drug administration, the combination of both drugs killed NSCLC cells more effectively by increasing apoptotic activity. In addition, the combination of niclosamide and chalcone complexes decreased multidrug resistance and EMT activity by lowering their gene expressions and protein levels. These results showed that niclosamide and chalcone complexes combination could be a new drug combination for the treatment of NSCLC.
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Affiliation(s)
- Elif Erturk
- Vocational School of Health Services, Bursa Uludag University, Bursa, Turkey
| | - Omer E Onur
- Department of Biology, Science and Art Faculty, Bursa Uludag University, Bursa, Turkey
| | - Ipek Aydin
- Department of Biology, Science and Art Faculty, Bursa Uludag University, Bursa, Turkey
| | - Oguzhan Akgun
- Department of Biology, Science and Art Faculty, Bursa Uludag University, Bursa, Turkey
| | - Demet Coskun
- Department of Chemistry, Faculty of Science, Firat University, Elazig, Turkey
| | - Ferda Ari
- Department of Biology, Science and Art Faculty, Bursa Uludag University, Bursa, Turkey
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Huang L, Zhang J, Deng Y, Wang H, Zhao P, Zhao G, Zeng W, Wang Y, Chen C, Wagstaff W, Haydon RC, Reid RR, He TC, Shen L, Luu HH, Zhao L. Niclosamide (NA) overcomes cisplatin resistance in human ovarian cancer. Genes Dis 2023; 10:1687-1701. [PMID: 37397523 PMCID: PMC10311098 DOI: 10.1016/j.gendis.2022.12.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Revised: 11/08/2022] [Accepted: 12/04/2022] [Indexed: 01/03/2023] Open
Abstract
Ovarian cancer (OC) is one of the most lethal malignancies of the female reproductive system. OC patients are usually diagnosed at advanced stages due to the lack of early diagnosis. The standard treatment for OC includes a combination of debulking surgery and platinum-taxane chemotherapy, while several targeted therapies have recently been approved for maintenance treatment. The vast majority of OC patients relapse with chemoresistant tumors after an initial response. Thus, there is an unmet clinical need to develop new therapeutic agents to overcome the chemoresistance of OC. The anti-parasite agent niclosamide (NA) has been repurposed as an anti-cancer agent and exerts potent anti-cancer activities in human cancers including OC. Here, we investigated whether NA could be repurposed as a therapeutic agent to overcome cisplatin-resistant (CR) in human OC cells. To this end, we first established two CR lines SKOV3CR and OVCAR8CR that exhibit the essential biological characteristics of cisplatin resistance in human cancer. We showed that NA inhibited cell proliferation, suppressed cell migration, and induced cell apoptosis in both CR lines at a low micromole range. Mechanistically, NA inhibited multiple cancer-related pathways including AP1, ELK/SRF, HIF1, and TCF/LEF, in SKOV3CR and OVCAR8CR cells. NA was further shown to effectively inhibit xenograft tumor growth of SKOV3CR cells. Collectively, our findings strongly suggest that NA may be repurposed as an efficacious agent to combat cisplatin resistance in chemoresistant human OC, and further clinical trials are highly warranted.
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Affiliation(s)
- Linjuan Huang
- Departments of Obstetrics and Gynecology, Orthopaedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400046, China
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Jing Zhang
- Departments of Obstetrics and Gynecology, Orthopaedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400046, China
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Youling Deng
- Departments of Obstetrics and Gynecology, Orthopaedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400046, China
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Hao Wang
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Ministry of Education Key Laboratory of Diagnostic Medicine, and Department of Clinical Biochemistry, The School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Piao Zhao
- Departments of Obstetrics and Gynecology, Orthopaedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400046, China
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Guozhi Zhao
- Departments of Obstetrics and Gynecology, Orthopaedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400046, China
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Wei Zeng
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Neurology, The Second Affiliated Hospital of Jianghan University, Wuhan, Hubei 430050, China
| | - Yonghui Wang
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Clinical Laboratory Medicine, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China
| | - Connie Chen
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - William Wagstaff
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Rex C. Haydon
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Russell R. Reid
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Laboratory of Craniofacial Suture Biology and Development, Department of Surgery Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Tong-Chuan He
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Le Shen
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Hue H. Luu
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Ling Zhao
- Departments of Obstetrics and Gynecology, Orthopaedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400046, China
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
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Vashi Y, Nehru G, Kumar S. Niclosamide inhibits Newcastle disease virus replication in chickens by perturbing the cellular glycolysis. Virology 2023; 585:196-204. [PMID: 37384966 DOI: 10.1016/j.virol.2023.06.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Revised: 06/10/2023] [Accepted: 06/12/2023] [Indexed: 07/01/2023]
Abstract
Newcastle disease virus (NDV), a member of Paramyxoviridae family, is one of the most important pathogens in poultry. To ensure optimal environments for their replication and spread, viruses rely largely on host cellular metabolism. In the present study, we evaluated the small drug molecule niclosamide for its anti-NDV activity. Our study has shown that a sublethal dose of 1 μM niclosamide could drastically reduce NDV replication. The results showed that niclosamide has antiviral activity against NDV infection during in vitro, in ovo and in vivo assays. Pharmacologically inhibiting the glycolytic pathway remarkably reduced NDV RNA synthesis and infectious virion production. Our results suggest that the effect of niclosamide on cellular glycolysis could be the possible reason for the specific anti-NDV effect. This study could help us understand antiviral strategies against similar pathogens and may lead to novel therapeutic approaches through targeted inhibition of specific cellular metabolic pathways.
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Affiliation(s)
- Yoya Vashi
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India
| | - Ganesh Nehru
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India
| | - Sachin Kumar
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India.
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Khedkar HN, Chen LC, Kuo YC, Wu ATH, Huang HS. Multi-Omics Identification of Genetic Alterations in Head and Neck Squamous Cell Carcinoma and Therapeutic Efficacy of HNC018 as a Novel Multi-Target Agent for c-MET/STAT3/AKT Signaling Axis. Int J Mol Sci 2023; 24:10247. [PMID: 37373393 DOI: 10.3390/ijms241210247] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 06/07/2023] [Accepted: 06/12/2023] [Indexed: 06/29/2023] Open
Abstract
Amongst the most prevalent malignancies worldwide, head and neck squamous cell carcinoma (HNSCC) is characterized by high morbidity and mortality. The failure of standard treatment modalities, such as surgery, radiotherapy, and chemotherapy, demands the need for in-depth understanding of the complex signaling networks involved in the development of treatment resistance. A tumor's invasive growth and high levels of intrinsic or acquired treatment resistance are the primary causes of treatment failure. This may be a result of the presence of HNSCC's cancer stem cells, which are known to have self-renewing capabilities that result in therapeutic resistance. Using bioinformatics methods, we discovered that elevated expressions of MET, STAT3, and AKT were associated with poor overall survival in HNSCC patients. We then evaluated the therapeutic potential of our newly synthesized small molecule HNC018 towards its potential as a novel anticancer drug. Our computer-aided structure characterization and target identification study predicted that HNC018 could target these oncogenic markers implicated in HNSCC. Subsequently, the HNC018 has demonstrated its anti-proliferative and anticancer activities towards the head and neck squamous cell carcinoma cell lines, along with displaying the stronger binding affinities towards the MET, STAT3, and AKT than the standard drug cisplatin. Reduction in the clonogenic and tumor-sphere-forming ability displays HNC018's role in decreasing the tumorigenicity. Importantly, an vivo study has shown a significant delay in tumor growth in HNC018 alone or in combination with cisplatin-treated xenograft mice model. Collectively with our findings, HNC018 highlights the desirable properties of a drug-like candidate and could be considered as a novel small molecule for treating head and neck squamous cell carcinoma.
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Affiliation(s)
- Harshita Nivrutti Khedkar
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, and Academia Sinica, Taipei 11031, Taiwan
- Graduate Institute for Cancer Biology & Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
| | - Lung-Ching Chen
- Division of Cardiology, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 11101, Taiwan
- School of Medicine, Fu Jen Catholic University, New Taipei 24205, Taiwan
| | - Yu-Cheng Kuo
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- School of Post-Baccalaureate Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan
| | - Alexander T H Wu
- Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- Taipei Heart Institute (THI), Taipei Medical University, Taipei 11031, Taiwan
- Clinical Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan
- International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- Graduate Institute of Medical Sciences, National Defense Medical Centre, Taipei 11490, Taiwan
| | - Hsu-Shan Huang
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, and Academia Sinica, Taipei 11031, Taiwan
- Graduate Institute for Cancer Biology & Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- Graduate Institute of Medical Sciences, National Defense Medical Centre, Taipei 11490, Taiwan
- School of Pharmacy, National Defense Medical Centre, Taipei 11490, Taiwan
- Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan
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Lawal B, Kuo YC, Wu ATH, Huang HS. Therapeutic potential of EGFR/mTOR/Nf-kb targeting small molecule for the treatment of non-small cell lung cancer. Am J Cancer Res 2023; 13:2598-2616. [PMID: 37424807 PMCID: PMC10326574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 05/28/2023] [Indexed: 07/11/2023] Open
Abstract
Despite the therapeutic advancement with chemotherapy and targeted therapy against non-small-cell lung cancer (NSCLC), most patients ultimately develop resistance to these drugs, exhibiting disease progression, metastasis, and worse prognosis. There is, therefore, a need for the development of novel multi-targeted therapies that can offer a high therapeutic index with lesser chances of drug resistance against NSCLC. In the present study, we evaluated the therapeutic potential of a novel multi-target small molecule NLOC-015A for targeted treatment of NSCLC. Our in vitro studies revealed that NLOC-015A exhibited a broad spectrum of anticancer activities against lung cancer cell line. NLOC-015A decreased the viability of H1975 and H1299 cells with respective IC50 values of 2.07±0.19 and 1.90±0.23 µm. In addition, NLOC-015A attenuated the oncogenic properties (colony formation, migratory ability, and spheroid formation) with concomitant downregulation of expression levels of epidermal growth factor receptor (EGFR)/mammalian target of rapamycin (mTOR)/AKT, nuclear factor (NF)-κB, signaling network. In addition, the stemness inhibitory effect of NLOC0-15A was accompanied by decreased expression levels of aldehyde dehydrogenase (ALDH), MYC Proto-Oncogene (C-Myc), and (sex-determining region Y)-box 2 (SOX2) in both H1975 and H1299 cell lines. Furthermore, NLOC-015A suppressed the tumor burden and increased the body weight and survival of H1975 xenograft-bearing mice. Treatment with NLOC-015A also attenuated biochemical and hematological alterations in the tumor bearing mice. Interestingly, NLOC-015A synergistically enhanced the in vitro efficacy, and therapeutic outcome of osimertinib in vivo. In addition, the toxicity of osimertinib was significantly attenuated by combination with NLOC-015A. Altogether, our findings suggested that combining osimertinib with NLOC-015 appears to be a promising way to improve osimertinib's efficacy and achieve better therapeutic results against NSCLC. We therefore suggest that NLOC-015A might represent a new candidate for treating NSCLC via acting as a multitarget inhibitor of EGFR/mTOR/NF-Κb signaling networks and efficiently compromising the oncogenic phenotype of NSCLC.
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Affiliation(s)
- Bashir Lawal
- UPMC Hillman Cancer Center, University of PittsburghPittsburgh, PA 15260, USA
- Department of Pathology, University of PittsburghPittsburgh, PA 15260, USA
| | - Yu-Cheng Kuo
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical UniversityTaipei 11031, Taiwan
- School of Post-baccalaureate Chinese Medicine, College of Chinese Medicine, China Medical UniversityTaichung 40402, Taiwan
| | - Alexander TH Wu
- The PhD Program of Translational Medicine, College of Medical Science and Technology, Taipei Medical UniversityTaipei 11031, Taiwan
- Clinical Research Center, Taipei Medical University Hospital, Taipei Medical UniversityTaipei 11031, Taiwan
- TMU Research Center of Cancer Translational Medicine, Taipei Medical UniversityTaipei 11031, Taiwan
- Graduate Institute of Medical Sciences, National Defense Medical CenterTaipei 11490, Taiwan
| | - Hsu-Shan Huang
- Graduate Institute of Medical Sciences, National Defense Medical CenterTaipei 11490, Taiwan
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia SinicaTaipei 11031, Taiwan
- Graduate Institute for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical UniversityTaipei 11031, Taiwan
- School of Pharmacy, National Defense Medical CenterTaipei 11490, Taiwan
- PhD Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical UniversityTaipei 11031, Taiwan
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Xiang J, Wu H, Gao J, Jiang W, Tian X, Xie Z, Zhang T, Feng J, Song R. Niclosamide exposure disrupts antioxidant defense, histology, and the liver and gut transcriptome of Chinese soft-shelled turtle (Pelodiscus sinensis). ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 260:115081. [PMID: 37262966 DOI: 10.1016/j.ecoenv.2023.115081] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 05/21/2023] [Accepted: 05/26/2023] [Indexed: 06/03/2023]
Abstract
Niclosamide (NIC) is the only commercially available molluscicide for controlling schistosomiasis, and its negative effects on aquatic animals had been frequently reported in recent years. However, the toxicity mechanism of NIC on the Chinese soft-shelled turtle (Pelodiscus sinensis) have not yet been investigated. Therefore, juvenile turtles were exposed to 0 (control group), 10 (low NIC, L), and 50 (high NIC, H) μg/L NIC for 120 h and our results demonstrated that NIC exposure induced severe pathological changes in the liver of P. sinensis. And the typical symptom included edema, nuclear migration and deformation, and vacuolization. Compared with the liver, the NIC exposure did not cause significant damage in the gut tissue. In addition, the DHE staining demonstrated that the ROS production of liver and gut increased with the increase in concentration of NIC. The activities of antioxidant enzymes including superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) was inhibited with increased malondialdehyde (MDA) content, indicating that the antioxidant defense was significantly perturbed. Further, the transcriptome sequencing and was applied to evaluate the underlying toxicity mechanisms of NIC exposure in liver and gut of P. sinensis. Pathway enrichment showed that the disorder of lipid metabolism and innate immune regulation, including Toll-like receptors (TLRs), tumor necrosis factor (TNF), lectins, and complement and coagulation cascades, were toxicological properties of NIC on P. sinensis. Overall, the current study provides valuable information to understand the toxic effect of NIC on Chinese soft-shelled turtle.
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Affiliation(s)
- Jing Xiang
- Changsha University, Changsha 410022, China
| | - Hao Wu
- Hunan Fisheries Science Institute, Changsha 410153, China
| | - Jinwei Gao
- Hunan Fisheries Science Institute, Changsha 410153, China
| | - Weimin Jiang
- Hunan Institute of Animal and Veterinary Science, Changsha 410125, China
| | - Xing Tian
- Hunan Fisheries Science Institute, Changsha 410153, China
| | - Zhonggui Xie
- Hunan Fisheries Science Institute, Changsha 410153, China
| | - Tao Zhang
- Changsha Animal and Plant Disease Control Center, Changsha 410153, China
| | - Jia Feng
- Changsha Animal and Plant Disease Control Center, Changsha 410153, China
| | - Rui Song
- Hunan Fisheries Science Institute, Changsha 410153, China.
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Kim JH, Park S, Jung E, Shin J, Kim YJ, Kim JY, Sessler JL, Seo JH, Kim JS. A dual-action niclosamide-based prodrug that targets cancer stem cells and inhibits TNBC metastasis. Proc Natl Acad Sci U S A 2023; 120:e2304081120. [PMID: 37186828 PMCID: PMC10214212 DOI: 10.1073/pnas.2304081120] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 04/17/2023] [Indexed: 05/17/2023] Open
Abstract
Chemotherapy typically destroys the tumor mass but rarely eradicates the cancer stem cells (CSCs) that can drive metastatic recurrence. A key current challenge is finding ways to eradicate CSCs and suppress their characteristics. Here, we report a prodrug, Nic-A, created by combining a carbonic anhydrase IX (CAIX) inhibitor, acetazolamide, with a signal transducer and transcriptional activator 3 (STAT3) inhibitor, niclosamide. Nic-A was designed to target triple-negative breast cancer (TNBC) CSCs and was found to inhibit both proliferating TNBC cells and CSCs via STAT3 dysregulation and suppression of CSC-like properties. Its use leads to a decrease in aldehyde dehydrogenase 1 activity, CD44high/CD24low stem-like subpopulations, and tumor spheroid-forming ability. TNBC xenograft tumors treated with Nic-A exhibited decreased angiogenesis and tumor growth, as well as decreased Ki-67 expression and increased apoptosis. In addition, distant metastases were suppressed in TNBC allografts derived from a CSC-enriched population. This study thus highlights a potential strategy for addressing CSC-based cancer recurrence.
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Affiliation(s)
- Ji Hyeon Kim
- Department of Chemistry, Korea University, Seoul02841, Korea
| | - Soeun Park
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul02841, Korea
- Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul02841, Korea
- Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, Seoul08308, Korea
| | - Eunsun Jung
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul02841, Korea
- Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul02841, Korea
- Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, Seoul08308, Korea
| | - Jinwoo Shin
- Department of Chemistry, Korea University, Seoul02841, Korea
| | - Yoon-Jae Kim
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul02841, Korea
- Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul02841, Korea
- Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, Seoul08308, Korea
| | - Ji Young Kim
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul02841, Korea
- Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul02841, Korea
- Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, Seoul08308, Korea
| | - Jonathan L. Sessler
- Department of Chemistry, The University of Texas at Austin, Austin, TX78712-1224
| | - Jae Hong Seo
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul02841, Korea
- Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul02841, Korea
- Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, Seoul08308, Korea
| | - Jong Seung Kim
- Department of Chemistry, Korea University, Seoul02841, Korea
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Li S, Wang D, Zheng X, Li Y, Ding C, Wang M, Ge X, Jiang J, Qiao Y, Wang Y. Combination of niclosamide and quinacrine inactivates Akt/HK2/Cyclin D1 axis mediated by glucose deprivation towards the inhibition of melanoma cell proliferation. Biomed Pharmacother 2023; 163:114865. [PMID: 37187020 DOI: 10.1016/j.biopha.2023.114865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 05/01/2023] [Accepted: 05/08/2023] [Indexed: 05/17/2023] Open
Abstract
Malignant melanoma is one of the most aggressive and lethal skin cancer. At present, the treatment methods for melanoma have shortcomings. Glucose is the primary energy source of cancer cells. However, it is unclear whether glucose deprivation can be used to treat melanoma. Herein, we first found glucose played an essential role in melanoma proliferation. We then further found a drug combination of niclosamide and quinacrine could inhibit melanoma proliferation and glucose intake. Thirdly, we revealed the mechanism of anti-melanoma effect of the drug combination, which suppressed the Akt pathway. In addition, the first-rate limiting enzyme HK2 of glucose metabolism was inhibited. This work also disclosed that the decrease of HK2 inhibited cyclin D1 by reducing the activity of transcription factor E2F3, which further suppressed the proliferation of melanoma cells. The drug combination treatment also resulted in significant tumor regression in the absence of obvious morphologic changes in primary organ in vivo. In summary, our study demonstrated that the drug combination treatment created glucose deprivation to inactive the Akt/HK2/cyclin D1 axis, thereby inhibited the proliferation of melanoma cells, providing a potential anti-melanoma strategy.
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Affiliation(s)
- Shuangting Li
- Shanxi Medical University School and Hospital of Stomatology, Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Taiyuan 030001, China
| | - Diancan Wang
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, No.22, Zhongguancun Avenue South, Haidian District, Beijing 100081, China
| | - Xuan Zheng
- Qingdao Stomatological Hospital Affiliated to Qingdao University, No.17 Dexian Road, Shinan District, Qingdao 266001, Shandong Province, China
| | - Yi Li
- Shanxi Medical University School and Hospital of Stomatology, Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Taiyuan 030001, China
| | - Chong Ding
- Central Laboratory, Peking University School and Hospital of Stomatology, No.22, Zhongguancun Avenue South, Haidian District, Beijing 100081, China
| | - Meng Wang
- Central Laboratory, Peking University School and Hospital of Stomatology, No.22, Zhongguancun Avenue South, Haidian District, Beijing 100081, China
| | - Xuejun Ge
- Shanxi Medical University School and Hospital of Stomatology, Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Taiyuan 030001, China.
| | - Jiuhui Jiang
- Department of Orthodontics, Peking University School and Hospital of Stomatology, No.22, Zhongguancun Avenue South, Haidian District, Beijing 100081, China.
| | - Yan Qiao
- Beijing National Laboratory for Molecular Sciences (BNLMS), Laboratory of Polymer Physics and Chemistry, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China; University of Chinese Academy of Sciences, Beijing 100049, China.
| | - Yixiang Wang
- Central Laboratory, Peking University School and Hospital of Stomatology, No.22, Zhongguancun Avenue South, Haidian District, Beijing 100081, China.
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Kang B, Mottamal M, Zhong Q, Bratton M, Zhang C, Guo S, Hossain A, Ma P, Zhang Q, Wang G, Payton-Stewart F. Design, Synthesis, and Evaluation of Niclosamide Analogs as Therapeutic Agents for Enzalutamide-Resistant Prostate Cancer. Pharmaceuticals (Basel) 2023; 16:735. [PMID: 37242518 PMCID: PMC10222209 DOI: 10.3390/ph16050735] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Revised: 05/03/2023] [Accepted: 05/09/2023] [Indexed: 05/28/2023] Open
Abstract
Niclosamide effectively downregulates androgen receptor variants (AR-Vs) for treating enzalutamide and abiraterone-resistant prostate cancer. However, the poor pharmaceutical properties of niclosamide due to its solubility and metabolic instability have limited its clinical utility as a systemic treatment for cancer. A novel series of niclosamide analogs was prepared to systematically explore the structure-activity relationship and identify active AR-Vs inhibitors with improved pharmaceutical properties based on the backbone chemical structure of niclosamide. Compounds were characterized using 1H NMR, 13C NMR, MS, and elemental analysis. The synthesized compounds were evaluated for antiproliferative activity and downregulation of AR and AR-V7 in two enzalutamide-resistant cell lines, LNCaP95 and 22RV1. Several of the niclosamide analogs exhibited equivalent or improved anti-proliferation effects in LNCaP95 and 22RV1 cell lines (B9, IC50 LNCaP95 and 22RV1 = 0.130 and 0.0997 μM, respectively), potent AR-V7 down-regulating activity, and improved metabolic stability. In addition, both a traditional structure-activity relationship (SAR) and 3D-QSAR analysis were performed to guide further structural optimization. The presence of two -CF3 groups of the most active B9 in the sterically favorable field and the presence of the -CN group of the least active B7 in the sterically unfavorable field seem to make B9 more potent than B7 in the antiproliferative activity.
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Affiliation(s)
- Borui Kang
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA; (B.K.); (M.M.); (Q.Z.); (C.Z.); (S.G.); (Q.Z.)
- RCMI Cancer Research Center, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA; (M.B.); (A.H.); (P.M.)
| | - Madhusoodanan Mottamal
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA; (B.K.); (M.M.); (Q.Z.); (C.Z.); (S.G.); (Q.Z.)
- RCMI Cancer Research Center, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA; (M.B.); (A.H.); (P.M.)
| | - Qiu Zhong
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA; (B.K.); (M.M.); (Q.Z.); (C.Z.); (S.G.); (Q.Z.)
- RCMI Cancer Research Center, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA; (M.B.); (A.H.); (P.M.)
| | - Melyssa Bratton
- RCMI Cancer Research Center, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA; (M.B.); (A.H.); (P.M.)
| | - Changde Zhang
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA; (B.K.); (M.M.); (Q.Z.); (C.Z.); (S.G.); (Q.Z.)
- RCMI Cancer Research Center, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA; (M.B.); (A.H.); (P.M.)
| | - Shanchun Guo
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA; (B.K.); (M.M.); (Q.Z.); (C.Z.); (S.G.); (Q.Z.)
- RCMI Cancer Research Center, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA; (M.B.); (A.H.); (P.M.)
| | - Ahamed Hossain
- RCMI Cancer Research Center, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA; (M.B.); (A.H.); (P.M.)
| | - Peng Ma
- RCMI Cancer Research Center, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA; (M.B.); (A.H.); (P.M.)
| | - Qiang Zhang
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA; (B.K.); (M.M.); (Q.Z.); (C.Z.); (S.G.); (Q.Z.)
- RCMI Cancer Research Center, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA; (M.B.); (A.H.); (P.M.)
| | - Guangdi Wang
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA; (B.K.); (M.M.); (Q.Z.); (C.Z.); (S.G.); (Q.Z.)
- RCMI Cancer Research Center, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA; (M.B.); (A.H.); (P.M.)
| | - Florastina Payton-Stewart
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA; (B.K.); (M.M.); (Q.Z.); (C.Z.); (S.G.); (Q.Z.)
- RCMI Cancer Research Center, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA; (M.B.); (A.H.); (P.M.)
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In silico study of novel niclosamide derivatives, SARS-CoV-2 nonstructural proteins catalytic residue-targeting small molecules drug candidates. ARAB J CHEM 2023; 16:104654. [PMID: 36777994 PMCID: PMC9904858 DOI: 10.1016/j.arabjc.2023.104654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 01/31/2023] [Accepted: 02/02/2023] [Indexed: 02/10/2023] Open
Abstract
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-mediated coronavirus disease 2019 (COVID-19) infection remains a global pandemic and health emergency with overwhelming social and economic impacts throughout the world. Therapeutics for COVID-19 are limited to only remdesivir; therefore, there is a need for combined, multidisciplinary efforts to develop new therapeutic molecules and explore the effectiveness of existing drugs against SARS-CoV-2. In the present study, we reported eight (SCOV-L-02, SCOV-L-09, SCOV-L-10, SCOV-L-11, SCOV-L-15, SCOV-L-18, SCOV-L-22, and SCOV-L-23) novel structurally related small-molecule derivatives of niclosamide (SCOV-L series) for their targeting potential against angiotensin-converting enzyme-2 (ACE2), type II transmembrane serine protease (TMPRSS2), and SARS-COV-2 nonstructural proteins (NSPs) including NSP5 (3CLpro), NSP3 (PLpro), and RdRp. Our correlation analysis suggested that ACE2 and TMPRSS2 modulate host immune response via regulation of immune-infiltrating cells at the site of tissue/organs entries. In addition, we identified some TMPRSS2 and ACE2 microRNAs target regulatory networks in SARS-CoV-2 infection and thus open up a new window for microRNAs-based therapy for the treatment of SARS-CoV-2 infection. Our in vitro study revealed that with the exception of SCOV-L-11 and SCOV-L-23 which were non-active, the SCOV-L series exhibited strict antiproliferative activities and non-cytotoxic effects against ACE2- and TMPRSS2-expressing cells. Our molecular docking for the analysis of receptor-ligand interactions revealed that SCOV-L series demonstrated high ligand binding efficacies (at higher levels than clinical drugs) against the ACE2, TMPRSS2, and SARS-COV-2 NSPs. SCOV-L-18, SCOV-L-15, and SCOV-L-09 were particularly found to exhibit strong binding affinities with three key SARS-CoV-2's proteins: 3CLpro, PLpro, and RdRp. These compounds bind to the several catalytic residues of the proteins, and satisfied the criteria of drug-like candidates, having good adsorption, distribution, metabolism, excretion, and toxicity (ADMET) pharmacokinetic profile. Altogether, the present study suggests the therapeutic potential of SCOV-L series for preventing and managing SARs-COV-2 infection and are currently under detailed investigation in our lab.
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Fabelle NR, Oktavia FARH, Cha GS, Nguyen NA, Choi SK, Yun CH. Production of a major metabolite of niclosamide using bacterial cytochrome P450 enzymes. Enzyme Microb Technol 2023; 165:110210. [PMID: 36764029 DOI: 10.1016/j.enzmictec.2023.110210] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/19/2023] [Accepted: 02/06/2023] [Indexed: 02/11/2023]
Abstract
Niclosamide has been proposed as a possible candidate for a Covid-19 drug. However, the metabolites of niclosamide are difficult to investigate because they are usually not available commercially or they are quite expensive in the commercial market. In this study, the major metabolite of niclosamide in human liver microsomes (HLMs) was confirmed to be 3-OH niclosamide. Because the production of 3-OH niclosamide using HLMs has a slow turnover rate, a new method of producing niclosamide metabolite with an easier and highly cost-efficient method was thus conducted. Bacterial CYP102A1 (BM3) is one of the bacterial cytochrome P450s (CYPs) from Bacillus megaterium that structurally show similar activities to human CYPs. Here, the BM3 mutants were used to produce niclosamide metabolites and the metabolites were analyzed using high-performance liquid chromatography and LC-mass spectrometry. Among a set of mutants tested here, BM3 M14 mutant was the most active in producing 3-OH niclosamide, the major metabolite of niclosamide. Comparing BM3 M14 and HLMs, BM3 M14 production of 3-OH niclosamide was 34-fold higher than that of HLMs. Hence, the engineering of BM3 can be a cost-efficient method to produce 3-OH niclosamide.
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Affiliation(s)
- Nabilla Rizkia Fabelle
- School of Biological Sciences and Biotechnology, Graduate School, Chonnam National University, 77 Yongbongro, Gwangju 61186, Republic of Korea
| | | | - Gun Su Cha
- Namhae Garlic Research Institute, 2465-8 Namdaero, Gyeongsangnamdo 52430, Republic of Korea
| | - Ngoc Anh Nguyen
- School of Biological Sciences and Technology, Chonnam National University, 77 Yongbongro, Gwangju 61186, Republic of Korea
| | - Soo-Keun Choi
- Korea Research Institute of Bioscience & Biotechnology, 125 Gwahak-Ro, Yuseong, Daejon 34141, Republic of Korea.
| | - Chul-Ho Yun
- School of Biological Sciences and Biotechnology, Graduate School, Chonnam National University, 77 Yongbongro, Gwangju 61186, Republic of Korea; School of Biological Sciences and Technology, Chonnam National University, 77 Yongbongro, Gwangju 61186, Republic of Korea.
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Bazvand F, Riazi-Esfahani H, Salari F. Presumed veterinary niclosamide-induced retinal toxicity in a human: a case report. J Med Case Rep 2023; 17:110. [PMID: 36966318 PMCID: PMC10039813 DOI: 10.1186/s13256-023-03868-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 03/01/2023] [Indexed: 03/27/2023] Open
Abstract
BACKGROUND To report the first case of bull's eye maculopathy associated with veterinary niclosamide. CASE PRESENTATION A 27-year-old Iranian female presented with a history of reduced vision and photopsia since 3 years, after accidental ingestion of four boluses of veterinary niclosamide. Fundus examination showed atrophy in parafoveal retinal pigmentary epithelium, appearing as bilateral bull's-eye maculopathy. Optical coherence tomography revealed disruption of the parafoveal ellipsoid zone and outer retinal thinning, appearing as a flying saucer sign. Electroretinography displayed decreased scotopic and photopic amplitudes with normal waveform in both eyes. The causality score was 4, showing "possible" retinopathy due to niclosamide according to Naranjo's causality assessment algorithm. Based on clinical and ancillary findings, a diagnosis of niclosamide-induced maculopathy was made. CONCLUSION Veterinary niclosamide is an anthelmintic drug that in higher doses could be detrimental to the human retina. Awareness about its side effects and appropriate drug labeling could prevent accidental toxicity.
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Affiliation(s)
- Fatemeh Bazvand
- Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, 1336616351, Iran
- Retina & Vitreous Service, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamid Riazi-Esfahani
- Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, 1336616351, Iran
- Retina & Vitreous Service, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Farhad Salari
- Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, 1336616351, Iran.
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Thatikonda S, Pooladanda V, Tokala R, Nagula S, Godugu C. Niclosamide inhibits epithelial-mesenchymal transition with apoptosis induction in BRAF/ NRAS mutated metastatic melanoma cells. Toxicol In Vitro 2023; 89:105579. [PMID: 36870549 DOI: 10.1016/j.tiv.2023.105579] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 02/27/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023]
Abstract
Malignant melanoma is considered a deadly aggressive form of skin cancer that frequently metastasizes to various distal organs, which harbors mutations of the BRAF or NRAS which occur in 30 to 50% of melanoma patients. The growth factors secreted by melanoma cells contribute to tumor angiogenesis with the acquisition of metastatic potential by epithelial-mesenchymal transition (EMT) and drive melanoma growth toward a more aggressive form. Niclosamide (NCL) is an FDA-approved anthelmintic drug and is reported to have strong anti-cancer properties against various solid and liquid tumors. Its role in BRAF or NRAS mutated cells is unknown. In this context, we uncovered the role of NCL in impeding malignant metastatic melanoma in vitro in SK-MEL-2 and SK-MEL-28 cell lines. We found that NCL induces significant ROS generation and apoptosis through a series of molecular mechanisms, such as depolarization of mitochondrial membrane potential, arresting the cell cycle at the sub G1 phase with a significant increase in the DNA cleavage via topoisomerase II in both cell lines. We also found that NCL potently inhibited metastasis, which was examined by scratch wound assay, Additionally, we found that NCL inhibits the most important markers involved in the EMT signaling cascade that are stimulated by TGF-β such as N-cadherin, Snail, Slug, Vimentin, α-SMA and p-Smad 2/3. This work provides useful insights into the mechanism of NCL in BRAF/NRAF mutant melanoma cells via inhibition of molecular signaling events involved in EMT signaling, and apoptosis induction.
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Affiliation(s)
- Sowjanya Thatikonda
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana 500037, India; Department of Head and Neck-Endocrine Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Venkatesh Pooladanda
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana 500037, India; Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA 02114, USA; Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, MA 02115, USA
| | - Ramya Tokala
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India
| | - Shankaraiah Nagula
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India
| | - Chandraiah Godugu
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana 500037, India.
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50
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Su W, Qiu W, Li SJ, Wang S, Xie J, Yang QC, Xu J, Zhang J, Xu Z, Sun ZJ. A Dual-Responsive STAT3 Inhibitor Nanoprodrug Combined with Oncolytic Virus Elicits Synergistic Antitumor Immune Responses by Igniting Pyroptosis. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2023; 35:e2209379. [PMID: 36545949 DOI: 10.1002/adma.202209379] [Citation(s) in RCA: 59] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 12/14/2022] [Indexed: 06/17/2023]
Abstract
Immune checkpoint blockade (ICB) therapy shows excellent efficacy against malignancies; however, insufficient tumor immunogenicity and the immunosuppressive tumor microenvironment (TME) are considered as the two major stumbling blocks to a broad ICB response. Here, a combinational therapeutic strategy is reported, wherein TME-reactive oxygen species/pH dual-responsive signal transducers and activators of transcription 3 inhibitor nanoprodrugs MPNPs are combined with oncolytic herpes simplex virus 1 virotherapy to synergistically ignite pyroptosis for enhancing immunotherapy. MPNPs exhibit a certain level of tumor accumulation, reduce tumor cell stemness, and enhance antitumor immune responses. Furthermore, the simultaneous application of oncolytic viruses (OVs) confers MPNPs with higher tumor penetration capacity and remarkable gasdermin-E-mediated pyroptosis, thereby reshaping the TME and transforming "cold" tumors into "hot" ones. This "fire of immunity" strategy successfully activates robust T-cell-dependent antitumor responses, potentiating ICB effects against local recurrence and pulmonary metastasis in preclinical "cold" murine triple-negative breast cancer and syngeneic oral cancer models. Collectively, this work may pave a new way and offer an unprecedented opportunity for the combination of OVs with nanomedicine for cancer immunotherapy.
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Affiliation(s)
- Wen Su
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, P. R. China
| | - Wei Qiu
- Key Laboratory of Luminescence Analysis and Molecular Sensing, Ministry of Education, School of Materials and Energy & Chongqing Engineering Research Center for Micro-Nano Biomedical Materials and Devices, Southwest University, Chongqing, 400715, P. R. China
| | - Shu-Jin Li
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, P. R. China
| | - Shuo Wang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, P. R. China
| | - Jun Xie
- State Key Laboratory of Virology, Medical Research Institute, School of Medicine, Wuhan University, Wuhan, 430079, P. R. China
- Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, 430079, P. R. China
| | - Qi-Chao Yang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, P. R. China
| | - Jiming Xu
- Key Laboratory of Luminescence Analysis and Molecular Sensing, Ministry of Education, School of Materials and Energy & Chongqing Engineering Research Center for Micro-Nano Biomedical Materials and Devices, Southwest University, Chongqing, 400715, P. R. China
| | - Junjie Zhang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, P. R. China
- State Key Laboratory of Virology, Medical Research Institute, School of Medicine, Wuhan University, Wuhan, 430079, P. R. China
- Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, 430079, P. R. China
| | - Zhigang Xu
- Key Laboratory of Luminescence Analysis and Molecular Sensing, Ministry of Education, School of Materials and Energy & Chongqing Engineering Research Center for Micro-Nano Biomedical Materials and Devices, Southwest University, Chongqing, 400715, P. R. China
| | - Zhi-Jun Sun
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, P. R. China
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