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Moghbeli M. MicroRNAs as the critical regulators of bone metastasis during prostate tumor progression. Int J Biol Macromol 2025; 309:142912. [PMID: 40203904 DOI: 10.1016/j.ijbiomac.2025.142912] [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: 03/01/2025] [Revised: 04/02/2025] [Accepted: 04/05/2025] [Indexed: 04/11/2025]
Abstract
Prostate cancer (PCa) is the most prevalent cancer among men globally. Although, there are various therapeutic methods for the localized or advanced cancers, there is still a high rate of mortality among PCa patients that is mainly associated with bone metastasis in advanced tumors. There are few options available for treating bone metastasis in PCa, which only provide symptom relief without curing the disease. Therefore, it is crucial to evaluate the molecular mechanisms associated with bone metastasis of PCa cells to suggest the novel diagnostic and therapeutic approaches that could lower the morbidity and mortality rates in PCa patients. MicroRNAs (miRNAs) are involved in regulation of various pathophysiological processes such as tumor growth and osteoblasts/osteoclasts formation. Since, miRNA deregulation has been also frequently observed in PCa patients with bone metastasis, we discussed the role of miRNAs in bone metastasis during PCa progression. It has been reported that miRNAs mainly reduced the ability of PCa tumor cells for the bone metastasis through the regulation of WNT, NF-kB, PI3K/AKT, and TGF-β signaling pathways. They also affected the EMT process, transcription factors, and structural proteins to regulate the bone metastasis during PCa progression. This review paves the way to suggest the miRNAs as the reliable markers not only for the non-invasive early diagnosis, but also for the targeted therapy of PCa tumors with bone metastasis.
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Affiliation(s)
- Meysam Moghbeli
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Abolfazli S, Karav S, Johnston TP, Sahebkar A. Regulatory effects of resveratrol on nitric oxide signaling in cardiovascular diseases. Pharmacol Rep 2025; 77:355-374. [PMID: 39832074 DOI: 10.1007/s43440-025-00694-w] [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: 10/22/2024] [Revised: 01/04/2025] [Accepted: 01/06/2025] [Indexed: 01/22/2025]
Abstract
Cardiovascular illnesses are multifactorial disorders and represent the primary reasons for death worldwide, according to the World Health Organization. As a signaling molecule, nitric oxide (NO) is extremely permeable across cellular membranes owing to its unique molecular features, like its small molecular size, lipophilicity, and free radical properties. Some of the biological effects of NO are vasodilation, inhibition in the growth of vascular smooth muscle cells, and functional regulation of cardiac cells. Several therapeutic approaches have been tested to increase the production of NO or some downstream NO signaling pathways. The health benefits of red wine are typically attributed to the polyphenolic phytoalexin, resveratrol (3,5,4'-trihydroxy-trans-stilbene), which is found in several plant species. Resveratrol has beneficial cardiovascular properties, some of which are mediated through endothelial nitric oxide synthase production (eNOS). Resveratrol promotes NO generation from eNOS through various methods, including upregulation of eNOS expression, activation in the enzymatic activity of eNOS, and reversal of eNOS uncoupling. Additionally, by reducing of oxidative stress, resveratrol inhibits the formation of superoxide and inactivation NO, increasing NO bioavailability. This review discusses the scientific literature on resveratrol's beneficial impact on NO signaling and how this effect improves the function of vascular endothelium.
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Affiliation(s)
- Sajad Abolfazli
- Student Research Committee, School of Pharmacy, Mazandaran University of Medical Science, Sari, Iran
| | - Sercan Karav
- Department of Molecular Biology and Genetics, Canakkale Onsekiz Mart University, Canakkale, 17100, Turkey
| | - Thomas P Johnston
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India.
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Villadangos L, Serrador JM. Subcellular Localization Guides eNOS Function. Int J Mol Sci 2024; 25:13402. [PMID: 39769167 PMCID: PMC11678294 DOI: 10.3390/ijms252413402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 12/03/2024] [Accepted: 12/06/2024] [Indexed: 01/11/2025] Open
Abstract
Nitric oxide synthases (NOS) are enzymes responsible for the cellular production of nitric oxide (NO), a highly reactive signaling molecule involved in important physiological and pathological processes. Given its remarkable capacity to diffuse across membranes, NO cannot be stored inside cells and thus requires multiple controlling mechanisms to regulate its biological functions. In particular, the regulation of endothelial nitric oxide synthase (eNOS) activity has been shown to be crucial in vascular homeostasis, primarily affecting cardiovascular disease and other pathophysiological processes of importance for human health. Among other factors, the subcellular localization of eNOS plays an important role in regulating its enzymatic activity and the bioavailability of NO. The aim of this review is to summarize pioneering studies and more recent publications, unveiling some of the factors that influence the subcellular compartmentalization of eNOS and discussing their functional implications in health and disease.
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Affiliation(s)
| | - Juan M. Serrador
- Interactions with the Environment Program, Immune System Development and Function Unit, Centro de Biología Molecular Severo Ochoa (CBM), Consejo Superior de Investigaciones Científicas (CSIC)—Universidad Autónoma de Madrid, 28049 Madrid, Spain;
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Alkanli N, Ay A, Cevik G. Investigation of the relationships between eNOS T786C, G894T, intron 4 VNTR (4a/b) gene variations and prostate cancer development and progression. Nitric Oxide 2024; 152:69-77. [PMID: 39322022 DOI: 10.1016/j.niox.2024.09.008] [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: 04/07/2024] [Revised: 08/09/2024] [Accepted: 09/20/2024] [Indexed: 09/27/2024]
Abstract
BACKGROUND This study aimed to investigate the relationships between eNOS T786C, G894T, intron 4 VNTR (4a/b) gene variations and prostate cancer development and progression. MATERIALS AND METHODS This study included 88 patients diagnosed with prostate cancer and 91 healthy controls. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods were used to determine the genotype distributions of eNOS T786C, G894T, intron 4 VNTR (4a/b) gene variations. RESULTS In our study, the CC homozygous genotype of eNOS T786C gene variation was determined to be significantly higher in the prostate cancer patient group compared to the healthy control group (OR: 2.343, 95%Cl: 0.990-5.544, p = 0.026), while the CT heterozygous genotype was found to be significantly higher in the healthy control group compared to the prostate cancer patient group was found to be significantly higher (OR: 0.589, 95%Cl: 0.325-1.068, p = 0.041). In addition, while the TT homozygous genotype of the eNOS G894T gene variation was found to be significantly higher in the prostate cancer patient group compared to the healthy control group (OR: 9.068, 95%Cl: 4.396-18.777, p < 0.001), the GT heterozygous genotype was found to be significantly higher in the healthy control group compared to the prostate cancer patient group was determined significantly higher (OR: 0.227, 95%Cl: 0.121-0.427, p < 0.001). For eNOS (4VNTR (4a/b) - G894T) gene variations, aa-TT (p = 0.042) and bb-TT (p < 0.001) haplotype frequencies were significantly higher in the prostate cancer patient group, while aa-GT (p = 0.017), bb-GG (p = 0.049) and bb-GT (p < 0.001) haplotype frequencies were found to be significantly higher in the healthy control group. For eNOS (4VNTR (4a/b) - T786C) gene variations, the bb-CC haplotype frequency was determined to be significantly higher in the patient group (p = 0.049), while the bb-CT haplotype frequency was determined to be significantly higher in the control group (p = 0.008). For eNOS (T786C -G894T) gene variations, TT-TT (p < 0.001) and CC-TT (p = 0.025) haplotype frequencies were found to be significantly higher in the patient group. On the other hand, TT-GT (p = 0.002) and CT-GT (p < 0.001) haplotype frequencies were determined to be significantly higher in the control group. The aa genotype of the intron 4 VNTR (4a/b) gene variation was determined to be significantly higher at Gleason score ≥7 compared to Gleason score <7 (OR: 0.184, 95%Cl: 0.050-0.677, p = 0.005). PSA levels were determined significantly higher in patients with Gleason score 7 and above (p = 0.008). The risk of developing prostate cancer was found to be significantly higher in patients carrying the CC homozygous mutant genotype of the eNOS T786C gene variation (p = 0.024) and in patients carrying the TT homozygous genotype of the G894T gene variation (p = 0.021). CONCLUSIONS In our study, the CC homozygous genotype of the eNOS T786C gene variation was determined as a genetic risk factor for the development of prostate cancer, while the CT heterozygous genotype was determined as a protective factor against prostate cancer. For the eNOS G894T gene variation, the TT homozygous genotype was determined as a genetic risk factor for the development of prostate cancer, while the GT heterozygous genotype was determined as a protective factor against prostate cancer. Additionally, for eNOS (4VNTR (4a/b) - G894T) gene variations, aa-TT and bb-TT haplotypes have been identified as genetic risk factors for the development of prostate cancer, while aa-GT, bb-GG and bb-GT haplotypes have been identified as protective factors against the disease has been determined. For eNOS (4VNTR (4a/b) - T786C) gene variations, the bb-CC haplotype was determined as a genetic risk factor in the development of prostate cancer, while the bb-CT haplotype was determined as a protective factor against the disease. TT-TT and CC-TT haplotypes for eNOS (T786C -G894T) gene variations have been identified as genetic risk factors for the development of prostate cancer. In contrast, TT-GT and CT-GT haplotypes were found to be protective factors against the disease. The aa genotype of the intron 4 VNTR (4a/b) gene variation has also been identified as an important genetic risk factor in prostate cancer progression. Significantly increased PSA levels in patients with Gleason score 7 and above, and significantly increased PSA levels in patients carrying the CC and TT homozygous mutant genotype for T786C and G894T gene variations were determined as important risk factors. It is thought that the genetic biomarkers in our study may play a role as personalized therapeutic agents in slowing down the development of prostate cancer, increasing the effectiveness of treatment in prostate cancer, affecting the responses to drugs that regulate NO signaling, predetermining genetic predisposition to prostate cancer, and risk assessment in patients with prostate cancer.
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Affiliation(s)
- Nevra Alkanli
- Department of Biophysics, Faculty of Medicine, Haliç University, Istanbul, Turkey, 34060.
| | - Arzu Ay
- Department of Biophysics, Faculty of Medicine, Trakya University, Edirne, Turkey, 22030.
| | - Gokhan Cevik
- Department of Urology, Faculty of Medicine, Trakya University, Edirne, Turkey, 22030.
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Kokilakanit P, Koontongkaew S, Utispan K. Nitric oxide has diverse effects on head and neck cancer cell proliferation and glycolysis. Biomed Rep 2024; 21:106. [PMID: 38868526 PMCID: PMC11168032 DOI: 10.3892/br.2024.1794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 05/13/2024] [Indexed: 06/14/2024] Open
Abstract
Glycolysis is a key energy-providing process and one of the hallmarks of cancer. Nitric oxide (NO), a free radical molecule, regulates glycolysis in various cancers. NO can alter the cell cycle and apoptosis in head and neck squamous cell carcinoma (HNSCC) cells. However, the effect of NO on glycolysis in HNSCC cells remains unresolved. The present study investigated the effects of NO on cell proliferation, glucose transporter (GLUT) gene expression and glycolytic indicators in HNSCC cell lines. Two pairs of isogenic HNSCC cell lines, HN18/HN17 and HN30/HN31, were treated with a NO donor, diethylamine NONOate (DEA-NONOate), for 24, 48 and 72 h. Cell proliferation was assessed using MTT assay and NO concentration was measured using the Griess Reagent System. GLUT1, GLUT2, GLUT3, and GLUT4 gene expression was analyzed using reverse transcription-quantitative PCR. Furthermore, hexokinase (HK) activity and lactate production were measured in NO-treated cells using colorimetric assay. NO exhibited concentration-dependent pro- and anti-proliferative effects on the HNSCC cell lines. Lower NO concentrations (5-200 µM) had pro-proliferative effects, whereas NO >200 µM had an anti-proliferative effect on HNSCC cells. NO (5 µM) promoted proliferation and glycolysis in HN18 cells by upregulating GLUT1 and GLUT2 gene expression and increasing HK activity and lactate levels. At 5-20 µM, NO-induced HN17 and HN30 cells demonstrated enhanced proliferation and GLUT2, GLUT3 and GLUT4 gene expression, whereas the glycolytic pathway was not affected. In conclusion, the present study demonstrated distinct proliferative effects of NO on HNSCC cells. NO may promote cell proliferation by stimulating glucose consumption and the glycolytic rate in HN18 cells. The effects of NO in other cell lines may be mediated by a non-glycolysis mechanism and require further investigation.
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Affiliation(s)
- Paopanga Kokilakanit
- Oral Biology Research Unit, Faculty of Dentistry, Thammasat University (Rangsit Campus), Khlong Luang, Pathum Thani 12120, Thailand
| | - Sittichai Koontongkaew
- Department of Oral Health Science, International College of Dentistry, Walailak University, Dusit, Bangkok 10300, Thailand
| | - Kusumawadee Utispan
- Oral Biology Research Unit, Faculty of Dentistry, Thammasat University (Rangsit Campus), Khlong Luang, Pathum Thani 12120, Thailand
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Qiu W, Zhao L, Liu H, Xu P, Qian C. Hypoxia-induced NOS1 as a therapeutic target in hypercholesterolemia-related colorectal cancer. Cancer Metab 2024; 12:14. [PMID: 38755702 PMCID: PMC11100240 DOI: 10.1186/s40170-024-00338-2] [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: 11/20/2023] [Accepted: 03/15/2024] [Indexed: 05/18/2024] Open
Abstract
BACKGROUND It is well established that hypercholesterolemia increases the risk of atherosclerosis, especially because it reduces the availability of nitric oxide (NO). However, the relationship between hypercholesterolemia and NO in regulating colorectal cancer development and progression remains unknown. METHODS We conducted bioinformatics analysis, qRT-PCR, ChIP-qPCR assays, luciferase report assays, clonogenic survival assays, and multiple mouse models to investigate the function and mechanism of hypercholesterolemia in regulating NO signaling. Additionally, NOS inhibitors were used to evaluate the potential of therapeutic strategy in anti-tumor response. RESULTS Here, we show that oxidized low-density lipoprotein (oxLDL) cholesterol and its receptor LOX-1 are essential for hypercholesterolemia-induced colorectal tumorigenesis. Mechanically, the oxLDL promotes the oxidant stress-dependent induction of hypoxia signaling to transcriptionally up-regulate NO synthase (NOS) especially NOS1 expression in colorectal cancer (CRC) cells. More importantly, our results suggested that selective inhibition of NOS1 with its specific inhibitor Nω-Propyl-L-arginine is a suitable therapeutic strategy for hypercholesterolemia-related CRC with both efficacy and toxicity reduction. CONCLUSIONS Our findings established that hypercholesterolemia induces the oxidant stress-dependent induction of hypoxia signaling to transcriptionally up-regulate NOS1 expression in CRC cells, and the clinically applicable NOS1 inhibitor Nω-Propyl-L-arginine represents an effective therapeutic strategy for hypercholesterolemia-related CRC.
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Affiliation(s)
- Weiqing Qiu
- Department of General Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 2000 Jiangyue Road, Shanghai, 200012, China
| | - Li Zhao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, 200012, China
| | - Hua Liu
- Department of General Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 2000 Jiangyue Road, Shanghai, 200012, China
| | - Ping Xu
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, 200012, China.
| | - Changlin Qian
- Department of General Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 2000 Jiangyue Road, Shanghai, 200012, China.
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Wang D, Chu Y, Liu S, Tan L. Chitosan-based hybrid nanospheres for vessel normalization towards enhancing tumor chemotherapy. Int J Biol Macromol 2024; 267:131409. [PMID: 38582478 DOI: 10.1016/j.ijbiomac.2024.131409] [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: 11/09/2023] [Revised: 03/04/2024] [Accepted: 04/03/2024] [Indexed: 04/08/2024]
Abstract
Vessel normalization has proved imperative in tumor growth inhibition. In this work, biopolymer-based hybrid nanospheres capable of normalizing blood vessels were designed to improve the therapeutic effect of chemotherapeutic drugs. Zn0.4Fe2.6O4 nanoparticles (ZFO NPs) were synthesized, and were encapsulated in cross-inked chitosan (CS) along with a nitric oxide (NO) precursor, DETA NONOate, forming hybrid ZFO/NO@CS nanospheres highly stable in physiological environment. The structure, morphology and size of the nanospheres were characterized. The ZFO/NO@CS nanospheres could release NO under acidic conditions typical of intratumoral and intracellular environment. The results of related factors expression, wound healing and tube formation assays demonstrated that both the encapsulated ZFO NPs and the released NO were able to inhibit angiogenesis in tumors. The ZFO/NO@CS nanospheres enhanced the antitumor efficacy of the chemotherapeutic drug DOX by normalizing tumor vessels, as evidenced by in vivo experiments for CT26 tumor-bearing mice. By analyzing the contents of Fe in the tumor and different organs, the nanospheres were found to accumulate primarily at the tumor site. The blood analysis showed little side effect of the nanospheres. The ZFO/NO@CS nanospheres have great potential in improving tumor therapeutic effect when used in combination with chemotherapeutic drugs.
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Affiliation(s)
- Ding Wang
- School of Materials Science and Engineering, Shanghai Institute of Technology, Shanghai 201418, China
| | - Yaoqing Chu
- School of Materials Science and Engineering, Shanghai Institute of Technology, Shanghai 201418, China
| | - Shuiping Liu
- College of Textile and Clothing, Yancheng Institute of Technology, Yancheng 224051, China
| | - Lianjiang Tan
- School of Materials Science and Engineering, Shanghai Institute of Technology, Shanghai 201418, China.
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Ay A, Alkanli N, Cevik G. Determination of the Roles of Endothelial Nitric Oxide Synthase 4VNTR (4a/b), G894T, T786C Gene Variations in the Bladder Cancer Development. Indian J Clin Biochem 2024; 39:92-100. [PMID: 38223012 PMCID: PMC10784242 DOI: 10.1007/s12291-022-01090-4] [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: 06/23/2022] [Accepted: 09/13/2022] [Indexed: 10/10/2022]
Abstract
The aim of this study is to determine the roles of eNOS gene variations in BCA development. Our study included 91 patients diagnosed with BCA and 91 healthy controls. eNOS 4VNTR (4a/b), T786C and G894T gene variations genotype distributions were determined by PCR and RFLP methods. The significant difference was determined between these groups in terms of eNOS T786C and eNOS G894T gene variations genotype distributions (p < 0.05). TT genotype for G894T gene variation and CC genotype for T786C gene variation were detected higher in patients. The CC genotype of T786C gene variation was detected significantly higher in male patients than in male controls (p < 0.05). In addition, aa-TT, ab-TT, bb-TT haplotypes of 4VNTR (4a/b)-G894T gene variations, aa-CC, ab-CC, bb-CC haplotypes of 4VNTR (4a/b)-T786C gene variations and TT-TT, TT-CC, TT-CT, GG-CC, GT-CC haplotypes of G894T-T786C gene variations were observed in patient group more than control group. The significant difference was detected between these groups in terms of eNOS (G894T-T786C) haplotypes (p < 0.05). In our study, eNOS T786C and eNOS G894T gene variations were determined important genetic risk factor in the Thrace population of Turkey.
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Affiliation(s)
- Arzu Ay
- Department of Biophysics, Faculty of Medicine, Trakya University, 22030 Edirne, Turkey
| | - Nevra Alkanli
- Department of Biophysics, Faculty of Medicine, Haliç University, 34060 Istanbul, Turkey
| | - Gokhan Cevik
- Department of Urology, Faculty of Medicine, Trakya University, 22030 Edirne, Turkey
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Panneerselvan P, Vasanthakumar K, Muthuswamy K, Krishnan V, Subramaniam S. Insights on the functional dualism of nitric oxide in the hallmarks of cancer. Biochim Biophys Acta Rev Cancer 2023; 1878:189001. [PMID: 37858621 DOI: 10.1016/j.bbcan.2023.189001] [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: 01/29/2023] [Revised: 10/09/2023] [Accepted: 10/09/2023] [Indexed: 10/21/2023]
Abstract
Nitric oxide (NO), a gaseous radical, governs a variety of physiological and pathological processes, including cancer, pro-inflammatory signalling, and vasodilation. The family of nitric oxide synthases (NOS), which comprises the constitutive forms, nNOS and eNOS, and the inducible form, iNOS, produces NO enzymatically. Additionally, NO can be generated non-enzymatically from the nitrate-nitrite-NO pathway. The anti- and pro-oxidant properties of NO and its functional dualism in cancer is due to its highly reactive nature. Numerous malignancies have NOS expression, which interferes with the tumour microenvironment to modulate the tumour's growth in both favourable and unfavourable ways. NO regulates a number of mechanisms in the tumour microenvironment, including metabolism, cell cycle, DNA repair, angiogenesis, and apoptosis/necrosis, depending on its concentration and spatiotemporal profile. This review focuses on the bi-modal impact of nitric oxide on the alteration of a few cancer hallmarks.
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Affiliation(s)
- Prabha Panneerselvan
- Molecular Physiology Laboratory, Department of Biochemistry, Bharathiar University, Coimbatore, Tamil Nadu 641046, India
| | - Keerthana Vasanthakumar
- Molecular Physiology Laboratory, Department of Biochemistry, Bharathiar University, Coimbatore, Tamil Nadu 641046, India
| | - Karthi Muthuswamy
- Molecular Physiology Laboratory, Department of Biochemistry, Bharathiar University, Coimbatore, Tamil Nadu 641046, India
| | - Vasanth Krishnan
- Molecular Biology Laboratory, Department of Botany, Bharathiar University, Coimbatore, Tamil Nadu 641046, India
| | - Selvakumar Subramaniam
- Molecular Physiology Laboratory, Department of Biochemistry, Bharathiar University, Coimbatore, Tamil Nadu 641046, India.
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Andrabi SM, Sharma NS, Karan A, Shahriar SMS, Cordon B, Ma B, Xie J. Nitric Oxide: Physiological Functions, Delivery, and Biomedical Applications. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2303259. [PMID: 37632708 PMCID: PMC10602574 DOI: 10.1002/advs.202303259] [Citation(s) in RCA: 163] [Impact Index Per Article: 81.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Indexed: 08/28/2023]
Abstract
Nitric oxide (NO) is a gaseous molecule that has a central role in signaling pathways involved in numerous physiological processes (e.g., vasodilation, neurotransmission, inflammation, apoptosis, and tumor growth). Due to its gaseous form, NO has a short half-life, and its physiology role is concentration dependent, often restricting its function to a target site. Providing NO from an external source is beneficial in promoting cellular functions and treatment of different pathological conditions. Hence, the multifaceted role of NO in physiology and pathology has garnered massive interest in developing strategies to deliver exogenous NO for the treatment of various regenerative and biomedical complexities. NO-releasing platforms or donors capable of delivering NO in a controlled and sustained manner to target tissues or organs have advanced in the past few decades. This review article discusses in detail the generation of NO via the enzymatic functions of NO synthase as well as from NO donors and the multiple biological and pathological processes that NO modulates. The methods for incorporating of NO donors into diverse biomaterials including physical, chemical, or supramolecular techniques are summarized. Then, these NO-releasing platforms are highlighted in terms of advancing treatment strategies for various medical problems.
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Affiliation(s)
- Syed Muntazir Andrabi
- Department of Surgery‐Transplant and Mary & Dick Holland Regenerative Medicine ProgramCollege of MedicineUniversity of Nebraska Medical CenterOmahaNE68198USA
| | - Navatha Shree Sharma
- Department of Surgery‐Transplant and Mary & Dick Holland Regenerative Medicine ProgramCollege of MedicineUniversity of Nebraska Medical CenterOmahaNE68198USA
| | - Anik Karan
- Department of Surgery‐Transplant and Mary & Dick Holland Regenerative Medicine ProgramCollege of MedicineUniversity of Nebraska Medical CenterOmahaNE68198USA
| | - S. M. Shatil Shahriar
- Department of Surgery‐Transplant and Mary & Dick Holland Regenerative Medicine ProgramCollege of MedicineUniversity of Nebraska Medical CenterOmahaNE68198USA
| | - Brent Cordon
- Department of Surgery‐Transplant and Mary & Dick Holland Regenerative Medicine ProgramCollege of MedicineUniversity of Nebraska Medical CenterOmahaNE68198USA
| | - Bing Ma
- Cell Therapy Manufacturing FacilityMedStar Georgetown University HospitalWashington, DC2007USA
| | - Jingwei Xie
- Department of Surgery‐Transplant and Mary & Dick Holland Regenerative Medicine ProgramCollege of MedicineUniversity of Nebraska Medical CenterOmahaNE68198USA
- Department of Mechanical and Materials EngineeringCollege of EngineeringUniversity of Nebraska LincolnLincolnNE68588USA
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11
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Van Chien T, Van Loc T, The Anh N, Van Sung T, Phuong Thao TT. Cytotoxic and Anti-Inflammatory Activity of 3,19-Isopropylidene-/Arylidene-Andrographolide Analogs. Chem Biodivers 2023; 20:e202300420. [PMID: 37466261 DOI: 10.1002/cbdv.202300420] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Accepted: 07/03/2023] [Indexed: 07/20/2023]
Abstract
A series of 3,19-isopropylidene-/or arylidene-andrographolide analogs were synthesized and their structures were confirmed by NMR spectroscopic methodology. Twenty-five analogs were evaluated for their in vitro cytotoxic activity against HT-29, HepG2 and LNCaP cancer cell lines based on the sulforhodamine B (SRB) assay. Analog 2 f exhibited the most potent cytotoxic activity, with IC50 values of 11.14 and 9.25 μM on HepG2 and LNCaP cancer cell lines, respectively. Esterification of hydroxy functional group at position C-14 in andrographolide analogs, 2 a and 2 b, showed somewhat higher cytotoxicity than the precursor. In addition, andrographolide analogs (2 a-2 d, 2 f, 3 a, 4 a and 4 h) were evaluated for the NO inhibitory activity in the LPS stimulated RAW264.7 macrophages. The most active analog 2 a significantly reduced nitric oxide (NO) production from LPS stimulated RAW264.7 cells, with IC50 values of 0.34±0.02 μM providing encouraging results for anti-inflammatory compound development.
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Affiliation(s)
- Tran Van Chien
- Institute of Chemistry, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet Road, Cau Giay, Hanoi, 10000, Viet Nam
- Graduate University of Science and Technology, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet Road, Cau Giay, Hanoi, 10000, Viet Nam
| | - Tran Van Loc
- Institute of Chemistry, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet Road, Cau Giay, Hanoi, 10000, Viet Nam
| | - Nguyen The Anh
- Institute of Chemistry, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet Road, Cau Giay, Hanoi, 10000, Viet Nam
| | - Tran Van Sung
- Institute of Chemistry, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet Road, Cau Giay, Hanoi, 10000, Viet Nam
| | - Tran Thi Phuong Thao
- Institute of Chemistry, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet Road, Cau Giay, Hanoi, 10000, Viet Nam
- Graduate University of Science and Technology, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet Road, Cau Giay, Hanoi, 10000, Viet Nam
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Jin J, Chowdhury MHU, Hafizur Rahman M, Choi KY, Adnan M. Bioactive Compounds and Signaling Pathways of Wolfiporia extensa in Suppressing Inflammatory Response by Network Pharmacology. Life (Basel) 2023; 13:life13040893. [PMID: 37109422 PMCID: PMC10142087 DOI: 10.3390/life13040893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 03/18/2023] [Accepted: 03/21/2023] [Indexed: 03/30/2023] Open
Abstract
Wolfiporia extensa (WE) is a medicinal mushroom and an excellent source of naturally occurring anti-inflammatory substances. However, the particular bioactive compound(s) and mechanism(s) of action against inflammation have yet to be determined. Here, we studied anti-inflammatory bioactive compounds and their molecular mechanisms through network pharmacology. Methanol (ME) extract of WE (MEWE) was used for GC-MS analysis to identify the bioactives, which were screened by following Lipinski’s rules. Public databases were used to extract selected bioactives and inflammation-related targets, and Venn diagrams exposed the common targets. Then, STRING and Cytoscape tools were used to construct protein-protein (PPI) network and mushroom-bioactives-target (M-C-T) networks. Gene Ontology and KEGG pathway analysis were performed by accessing the DAVID database and molecular docking was conducted to validate the findings. The chemical reactivity of key compounds and standard drugs was explored by the computational quantum mechanical modelling method (DFT study). Results from GC-MS revealed 27 bioactives, and all obeyed Lipinski’s rules. The public databases uncovered 284 compound-related targets and 7283 inflammation targets. A Venn diagram pointed to 42 common targets which were manifested in the PPI and M-C-T networks. KEGG analysis pointed to the HIF-1 signaling pathway and, hence, the suggested strategy for preventing the onset of inflammatory response was inhibition of downstream NFKB, MAPK, mTOR, and PI3K-Akt signaling cascades. Molecular docking revealed the strongest binding affinity for “N-(3-chlorophenyl) naphthyl carboxamide” on five target proteins associated with the HIF-1 signaling pathway. Compared to the standard drug utilized in the DFT (Density Functional Theory) analysis, the proposed bioactive showed a good electron donor component and a reduced chemical hardness energy. Our research pinpoints the therapeutic efficiency of MEWE and this work suggests a key bioactive compound and its action mechanism against inflammation.
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Anti-Inflammatory Activity of 3, 5-Diprenyl-4-hydroxyacetophenone Isolated from Ageratina pazcuarensis. Int J Mol Sci 2022; 23:ijms232315012. [PMID: 36499338 PMCID: PMC9741312 DOI: 10.3390/ijms232315012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 11/22/2022] [Accepted: 11/25/2022] [Indexed: 12/05/2022] Open
Abstract
Inflammation is implicated in a wide variety of physiological and pathological processes. Plants are an important source of active anti-inflammatory compounds. The compound 3, 5-diprenyl-4-hydroxyacetophenone (DHAP) was isolated from the dichloromethane extract of the aerial parts of Ageratina pazcuarensis by chromatography and identified by spectroscopic (IR, NMR) and spectrometric (GC-MS) methods. Anti-inflammatory activity was evaluated on ear edema mouse induced with 12-O-tetradecanoylphorbol 13-acetate (TPA) at 2 mg/ear. The antioxidant activity of DHAP was determined using DPPH assay. Cell viability was tested in J774A.1 macrophages, the levels of NO, TNF-α, IL-1β, IL-6, and IL-10 production in macrophages stimulated with lipopolysaccharide (LPS), and membrane lysis induced by hypotonic solution in erythrocytes were evaluated. DHAP diminished the ear edema mouse in 70.10%, and it had scavenger effect against the radical with IC50 of 26.00 ± 0.37 µg/mL. Likewise, 91.78 µM of this compound inhibited the production of NO (38.96%), IL-1β (55.56%), IL-6 (51.62%), and TNF-α (59.14%) in macrophages and increased the levels of IL-10 (61.20%). Finally, 25 and 50 µg/mL DHAP provided the greatest protection against erythrocyte membrane lysis. These results demonstrate that DHAP has anti-inflammatory activity.
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She Z, Chen J, Sun L, Zeng F, Wu S. An NO-responsive probe for detecting acute inflammation using NIR-II fluorescence/optoacoustic imaging. Chem Commun (Camb) 2022; 58:13123-13126. [PMID: 36346386 DOI: 10.1039/d2cc05386a] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2025]
Abstract
An NO-responsive probe for imaging acute inflammation was developed. The probe responds to in situ NO in acute inflammation sites such as LPS-induced acute dermatitis and MIA-induced acute joint inflammation with turn-on NIR-II fluorescence and optoacoustic signals.
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Affiliation(s)
- Zunpan She
- State Key Laboratory of Luminescent Materials and Devices, Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates, College of Materials Science and Engineering, South China University of Technology, Guangzhou 510640, China.
| | - Junjie Chen
- State Key Laboratory of Luminescent Materials and Devices, Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates, College of Materials Science and Engineering, South China University of Technology, Guangzhou 510640, China.
| | - Lihe Sun
- State Key Laboratory of Luminescent Materials and Devices, Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates, College of Materials Science and Engineering, South China University of Technology, Guangzhou 510640, China.
| | - Fang Zeng
- State Key Laboratory of Luminescent Materials and Devices, Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates, College of Materials Science and Engineering, South China University of Technology, Guangzhou 510640, China.
| | - Shuizhu Wu
- State Key Laboratory of Luminescent Materials and Devices, Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates, College of Materials Science and Engineering, South China University of Technology, Guangzhou 510640, China.
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Chen X, Xia Q, Sun N, Zhou H, Xu Z, Yang X, Yan R, Li P, Li T, Qin X, Yang H, Wu C, You F, Liao X, Li S, Liu Y. Shear stress enhances anoikis resistance of cancer cells through ROS and NO suppressed degeneration of Caveolin-1. Free Radic Biol Med 2022; 193:95-107. [PMID: 36243211 DOI: 10.1016/j.freeradbiomed.2022.10.271] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 10/08/2022] [Accepted: 10/08/2022] [Indexed: 12/13/2022]
Abstract
Circulating tumor cells (CTCs) acquire enhanced anti-anoikis abilities after experiencing flow shear stress in the circulatory system. Our previous study demonstrated that low shear stress (LSS) promotes anoikis resistance of human breast carcinoma cells via caveolin-1 (Cav-1)-dependent extrinsic and intrinsic apoptotic pathways. However, the underlying mechanism how LSS enhanced Cav-1 expression in suspended cancer cells remains unclear. Herein, we found that LSS induced redox signaling was involved in the regulation of Cav-1 level and anoikis resistance in suspension cultured cancer cells. Exposure of human breast carcinoma MDA-MB-231 cells to LSS (2 dyn/cm2) markedly induced ROS and •NO generation, which promoted the cell viability and reduced the cancer cell apoptosis. Furthermore, ROS and •NO scavenging inhibited the upregulation of Cav-1 by interfering ubiquitination, and suppressed the anoikis resistance of suspended tumor cells. These findings provide new insight into the mechanism by which LSS-stimulated ROS and •NO generation increases Cav-1 stabilization in suspended cancer cells through inhibition of ubiquitination and proteasomal degradation, which could be a potential target for therapy of metastatic tumors.
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Affiliation(s)
- Xiangyan Chen
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, and School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan, PR China
| | - Qiong Xia
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, and School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan, PR China
| | - Ningwei Sun
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, and School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan, PR China
| | - Hailei Zhou
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, and School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan, PR China
| | - Zhihao Xu
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, and School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan, PR China
| | - Xi Yang
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, and School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan, PR China
| | - Ran Yan
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, and School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan, PR China; TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu, 610072, Sichuan, PR China
| | - Ping Li
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, and School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan, PR China
| | - Tingting Li
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, and School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan, PR China
| | - Xiang Qin
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, and School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan, PR China
| | - Hong Yang
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, and School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan, PR China
| | - Chunhui Wu
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, and School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan, PR China
| | - Fengming You
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu, 610072, Sichuan, PR China
| | - Xiaoling Liao
- Chongqing Engineering Laboratory of Nano/Micro Biomedical Detection Technology, Chongqing University of Science and Technology, Chongqing, 401331, PR China
| | - Shun Li
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, and School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan, PR China.
| | - Yiyao Liu
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, and School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan, PR China; TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu, 610072, Sichuan, PR China.
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16
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Ramírez-Patiño R, Avalos-Navarro G, Figuera LE, Varela-Hernández JJ, Bautista-Herrera LA, Muñoz-Valle JF, Gallegos-Arreola MP. Influence of nitric oxide signaling mechanisms in cancer. Int J Immunopathol Pharmacol 2022; 36:3946320221135454. [PMID: 36260949 PMCID: PMC9585559 DOI: 10.1177/03946320221135454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Nitric oxide (NO) is a molecule with multiple biological functions that is involved in various pathophysiological processes such as neurotransmission and blood vessel relaxation as well as the endocrine system, immune system, growth factors, and cancer. However, in the carcinogenesis process, it has a dual behavior; at low doses, NO regulates homeostatic functions, while at high concentrations, it promotes tissue damage or acts as an agent for immune defense against microorganisms. Thus, its participation in the carcinogenic process is controversial. Cancer is a multifactorial disease that presents complex behavior. A better understanding of the molecular mechanisms associated with the initiation, promotion, and progression of neoplastic processes is required. Some hypotheses have been proposed regarding the influence of NO in activating oncogenic pathways that trigger carcinogenic processes, because NO might regulate some signaling pathways thought to promote cancer development and more aggressive tumor growth. Additionally, NO inhibits apoptosis of tumor cells, together with the deregulation of proteins that are involved in tissue homeostasis, promoting spreading to other organs and initiating metastatic processes. This paper describes the signaling pathways that are associated with cancer, and how the concentration of NO can serve a beneficial or pathological function in the initiation and promotion of neoplastic events.
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Affiliation(s)
- R Ramírez-Patiño
- Departamento de Ciencias Médicas y de la Vida, Centro Universitario de la Ciénega (CUCIÉNEGA), Universidad de Guadalajara, Ocotlán Jalisco, México
| | - G Avalos-Navarro
- Departamento de Ciencias Médicas y de la Vida, Centro Universitario de la Ciénega (CUCIÉNEGA), Universidad de Guadalajara, Ocotlán Jalisco, México
| | - LE Figuera
- División de Génetica, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara Jalisco, México,Doctorado en Genética Humana, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara Jalisco, México
| | - JJ Varela-Hernández
- Departamento de Ciencias Médicas y de la Vida, Centro Universitario de la Ciénega (CUCIÉNEGA), Universidad de Guadalajara, Ocotlán Jalisco, México
| | - LA Bautista-Herrera
- Departamento de Farmacobiología, Centro Universitario de Ciencias Exactas e Ingeniería (CUCEI), Universidad de Guadalajara, Guadalajara Jalisco, México
| | - JF Muñoz-Valle
- Instituto de Investigación en Ciencias Biomédicas (IICB), Centro Universitario de Ciencias de la Salud (CUCS) Universidad de Guadalajara, Guadalajara Jalisco, México
| | - MP Gallegos-Arreola
- División de Génetica, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara Jalisco, México,Martha Patricia Gallegos-Arreola, División de Genética CIBO, IMSS, Sierra Mojada 800, Col, Independencia, Guadalajara, Jalisco 44340, México.
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17
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The Antioxidant and Antitumor Efficiency of Litophyton sp. Extract in DMH-Induced Colon Cancer in Male Rats. Life (Basel) 2022; 12:life12101470. [PMID: 36294905 PMCID: PMC9605502 DOI: 10.3390/life12101470] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 08/26/2022] [Accepted: 09/05/2022] [Indexed: 12/04/2022] Open
Abstract
One of the most common tumors to cause death worldwide is colon cancer. This study aims to investigate the antitumor potency of Litophyton sp. methanolic extract (LME) against DMH-induced colon cancer in adult male rats. Group (1) normal rats served as the control, group (2) normal rats were ip-injected with LME at a dose of 100 μg/kg/day, group (3) DMH-induced colon cancer animals, and group (4) colon cancer-modeled animals were treated with LME (100 μg/kg/day) for six weeks. The results revealed that injection of LME markedly regenerated the colon cancer pathophysiological disorders; this was monitored from the significant reduction in the values of serum biomarkers (CEA, CA19.9, AFP), cytokines (TNF-α and IL1β), and biochemical measurements (ALAT, ASAT, urea, creatinine, cholesterol, and triglycerides) matched significant increase of apoptotic biomarkers (CD4+); similarly, colon DNA fragmentation, MDA, and NO levels were down-regulated. In contrast, a remarkable upregulation in colon SOD, GPx, GSH, and CAT levels was noted. Moreover, the colon histopathological architecture showed obvious regenerations. Chromatography of LME resulted in the purification of two polyhydroxylated steroids (1 and 2) with potential cytotoxic activities. LME performed therapeutic potential colon tumorigenesis; therefore, LME may have a promising chemo-preventive feature against colon cancer, probably via enhancement of the apoptosis pathway, improvement of the immune response, reduction of inflammation, or/and restoration of the impaired oxidative stress.
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18
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Burke AJ, McAuliffe JD, Natoni A, Ridge S, Sullivan FJ, Glynn SA. Chronic nitric oxide exposure induces prostate cell carcinogenesis, involving genetic instability and a pro-tumorigenic secretory phenotype. Nitric Oxide 2022; 127:44-53. [PMID: 35872082 DOI: 10.1016/j.niox.2022.07.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 07/12/2022] [Accepted: 07/15/2022] [Indexed: 11/26/2022]
Abstract
Prostate cancer is a leading cause of cancer death in men. Inflammation and overexpression of inducible nitric oxide synthase (NOS2) have been implicated in prostate carcinogenesis. We aimed to explore the hypothesis that nitric oxide NO exerts pro-tumorigenic effects on prostate cells at physiologically relevant levels contributing to carcinogenesis. We investigated the impact of acute exposure of normal immortalised prostate cells (RWPE-1) to NO on cell proliferation and activation of DNA damage repair pathways. Furthermore we investigated the long term effects of chronic NO exposure on RWPE-1 cell migration and invasion potential and hallmarks of transformation. Our results demonstrate that NO induces DNA damage as indicated by γH2AX foci and p53 activation resulting in a G1/S phase block and activation of 53BP1 DNA damage repair protein. Long term adaption to NO results in increased migration and invasion potential, acquisition of anchorage independent growth and increased resistance to chemotherapy. This was recapitulated in PC3 and DU145 prostate cancer cells which upon chronic exposure to NO displayed increased cell migration, colony formation and increased resistance to chemotherapeutics. These findings indicate that NO may play a key role in the development of prostate cancer and the acquisition of an aggressive metastatic phenotype.
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Affiliation(s)
- Amy J Burke
- Prostate Cancer Institute, School of Medicine, National University of Ireland Galway, Galway, H91 TK33, Ireland
| | - Jake D McAuliffe
- Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway, Galway, H91 TK33, Ireland
| | - Alessandro Natoni
- Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
| | - Sarah Ridge
- Prostate Cancer Institute, School of Medicine, National University of Ireland Galway, Galway, H91 TK33, Ireland
| | - Francis J Sullivan
- Prostate Cancer Institute, School of Medicine, National University of Ireland Galway, Galway, H91 TK33, Ireland
| | - Sharon A Glynn
- Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway, Galway, H91 TK33, Ireland.
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19
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Joshi S, Sharabi A. Targeting myeloid-derived suppressor cells to enhance natural killer cell-based immunotherapy. Pharmacol Ther 2022; 235:108114. [DOI: 10.1016/j.pharmthera.2022.108114] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 01/06/2022] [Accepted: 01/11/2022] [Indexed: 12/09/2022]
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20
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Salihi A, Al-Naqshabandi MA, Khudhur ZO, Housein Z, Hama HA, Abdullah RM, Hussen BM, Alkasalias T. Gasotransmitters in the tumor microenvironment: Impacts on cancer chemotherapy (Review). Mol Med Rep 2022; 26:233. [PMID: 35616143 PMCID: PMC9178674 DOI: 10.3892/mmr.2022.12749] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 04/07/2022] [Indexed: 11/23/2022] Open
Abstract
Nitric oxide, carbon monoxide and hydrogen sulfide are three endogenous gasotransmitters that serve a role in regulating normal and pathological cellular activities. They can stimulate or inhibit cancer cell proliferation and invasion, as well as interfere with cancer cell responses to drug treatments. Understanding the molecular pathways governing the interactions between these gases and the tumor microenvironment can be utilized for the identification of a novel technique to disrupt cancer cell interactions and may contribute to the conception of effective and safe cancer therapy strategies. The present review discusses the effects of these gases in modulating the action of chemotherapies, as well as prospective pharmacological and therapeutic interfering approaches. A deeper knowledge of the mechanisms that underpin the cellular and pharmacological effects, as well as interactions, of each of the three gases could pave the way for therapeutic treatments and translational research.
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Affiliation(s)
- Abbas Salihi
- Department of Biology, College of Science, Salahaddin University-Erbil, Erbil, Kurdistan Region 44001, Iraq
- Center of Research and Strategic Studies, Lebanese French University, Erbil, Kurdistan Region 44002, Iraq
- Department of Microbiology, Tumor and Cell Biology (MTC), Biomedicum, Karolinska Institutet, SE-17165 Stockholm, Sweden
| | - Mohammed A. Al-Naqshabandi
- Department of Clinical Biochemistry, College of Health Sciences, Hawler Medical University, Erbil, Kurdistan Region 44001, Iraq
| | - Zhikal Omar Khudhur
- Department of Medical Analysis, Faculty of Applied Science, Tishk International University, Erbil, Kurdistan Region 44001, Iraq
| | - Zjwan Housein
- Department of Medical Laboratory Technology, Technical Health and Medical College, Erbil Polytechnique University, Erbil, Kurdistan Region 44002, Iraq
| | - Harmand A. Hama
- Department of Biology, Faculty of Education, Tishk International University, Erbil, Kurdistan Region 44002, Iraq
| | - Ramyar M. Abdullah
- College of Medicine, Hawler Medical University, Erbil, Kurdistan Region 44002, Iraq
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Kurdistan Region 44002, Iraq
| | - Twana Alkasalias
- General Directorate of Scientific Research Center, Salahaddin University-Erbil, Erbil, Kurdistan Region 44002, Iraq
- Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, SE-17176 Stockholm, Sweden
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21
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Pramanik A, Bhattacharyya S. Myeloid derived suppressor cells and innate immune system interaction in tumor microenvironment. Life Sci 2022; 305:120755. [PMID: 35780842 DOI: 10.1016/j.lfs.2022.120755] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 06/23/2022] [Accepted: 06/27/2022] [Indexed: 12/24/2022]
Abstract
The tumor microenvironment is a complex domain that not only contains tumor cells but also a plethora of other host immune cells. By nature, the tumor microenvironment is a highly immunosuppressive milieu providing growing conditions for tumor cells. A major immune cell population that contributes most in the development of this immunosuppressive microenvironment is the MDSC, a heterogenous population of immature cells. Although found in small numbers only in the bone marrow of healthy individuals, they readily migrate to the lymph nodes and tumor site during cancer pathogenesis. MDSC mediated disruption of antitumor T cell activity is a major cause of the immunosuppression at the tumor site, but recent findings have shown that MDSC mediated dysfunction of other major immune cells might also play an important role. In this article we will review how crosstalk with MDSC alters the activity of both conventional and unconventional immune cells that inhibits the antitumor immunity and promotes cancer progression.
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Affiliation(s)
- Anik Pramanik
- Immunobiology and Translational Medicine Laboratory, Department of Zoology, Sidho Kanho Birsha University, Purulia 723104, West Bengal, India
| | - Sankar Bhattacharyya
- Immunobiology and Translational Medicine Laboratory, Department of Zoology, Sidho Kanho Birsha University, Purulia 723104, West Bengal, India.
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22
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Oxidative Stress Markers Are Associated with a Poor Prognosis in Patients with Pancreatic Cancer. Antioxidants (Basel) 2022; 11:antiox11040759. [PMID: 35453444 PMCID: PMC9029757 DOI: 10.3390/antiox11040759] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 04/04/2022] [Accepted: 04/07/2022] [Indexed: 02/01/2023] Open
Abstract
Pancreatic cancer is a malignancy of rising prevalence, especially in developed countries where dietary patterns and sedentariness favor its onset. This malady ranks seventh in cancer-related deaths in the world, although it is expected to rank second in the coming years, behind lung cancer. The low survival rate is due to the asymptomatic course of the early stages, which in many cases leads to metastases when becoming evident in advanced stages. In this context, molecular pathology is on the way towards finding new approaches with biomarkers that allow a better prognosis and monitoring of patients. So the present study aims to evaluate a series of molecular biomarkers, PARP1, NOX1, NOX2, eNOS and iNOS, as promising candidates for prognosis and survival by using immunohistochemistry. The analysis performed in 41 patients with pancreatic cancer showed a correlation between a high expression of all these components with a low survival rate, with high statistical power for all. In addition, a 60-month longitudinal surveillance program was managed, accompanied by several clinical parameters. The derivative Kaplan–Meier curves indicated a low cumulative survival rate as well. Ultimately, our research emphasized the value of these molecules as survival-associated biomarkers in pancreatic cancer, offering new gates for clinical management.
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23
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Chauhan D, Geetika S, Kumar S, Kumar R. Combined Interaction of Cellular and Extracellular Components Causes Genetic Cascade Activation in Breast Cancer Metastasis. Oncology 2022; 100:354-362. [PMID: 35342152 DOI: 10.1159/000524302] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 03/11/2022] [Indexed: 12/24/2022]
Abstract
Breast cancer (BC) consists of malignant cells as well as surrounding non-malignant cells-Fibroblasts, macrophages, endothelial cells, lymphocytes, neutrophils, mesenchymal stem cells, and extracellular matrix (ECM). This surrounding stroma is referred to as the Breast Tumor Microenvironment (BTME). The components of BTME interact with cancerous breast cells for the promotion of BC. The reciprocal cross-talk between BTME and neoplastic breast cells, through the secretion of chemicals, growth factors and chemokines, may lead to cell proliferation, migration, metastasis as well as immune response suppression. Multiple genetic loci, in association with stromal components, are linked to immunological stimuli to induce BC in ductal cells. These genes participate in tumor activation pathways and promote carcinogenesis via Fibroblast, Leukocyte, and Endothelial Cells-mediated responses. The collaborative effect of the cellular components and BTME-associated genes plays vital role in tumor initiation and metastasis of breast cells. This process involves genes which cause degenerative changes in ECM leading to Epithelial-Mesenchymal Transitions (EMT), which finally causes metastatic BC. This shows that metastatic breast cancer results from combined activation of different cellular and extracellular components and their activity is primarily controlled by activation of genetic cascade. These components work simultaneously to cause metastatic BC.
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Affiliation(s)
- Disha Chauhan
- Department of Animal Sciences, Central University of Himachal Pradesh, Kangra, India
| | - Saini Geetika
- Department of Animal Sciences, Central University of Himachal Pradesh, Kangra, India
| | - Sunil Kumar
- Department of Animal Sciences, Central University of Himachal Pradesh, Kangra, India
| | - Ranjit Kumar
- Department of Animal Sciences, Central University of Himachal Pradesh, Kangra, India
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24
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Huang Y, Suguro R, Hu W, Zheng J, Liu Y, Guan M, Zhou N, Zhang X. Nitric oxide and thyroid carcinoma: A review. Front Endocrinol (Lausanne) 2022; 13:1050656. [PMID: 36699047 PMCID: PMC9870175 DOI: 10.3389/fendo.2022.1050656] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 12/14/2022] [Indexed: 01/11/2023] Open
Abstract
Thyroid carcinoma is the most common endocrine cancer in the world, and its incidence has been steadily increasing in recent years. Despite its relatively good prognosis, therapies have not improved greatly in recent years. Therefore, exploring new therapies for thyroid carcinoma represents an unmet need. Nitric oxide (NO) is a short-term endogenous signaling molecule that plays a vital role in various physiological and pathological processes and is synthesized by nitric oxide synthase (NOS). Many studies have been conducted over the past decades to explain its correlation to cancer. NO exerts a wide range of effects on cancer, involving angiogenesis, apoptosis, cell cycle, invasion, and metastasis. It also serves a dual function by promoting and halting tumor development simultaneously. The relationship between NO and thyroid carcinoma has been intensively studied and discussed. This paper reviews the role and molecular mechanism of NO in thyroid carcinoma and discusses potentials of prevention and treatment of thyroid carcinoma.
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Affiliation(s)
- Yu Huang
- School of Pharmacy, Macau University of Science and Technology, Macau, Macau SAR, China
| | - Rinkiko Suguro
- State Key Laboratory of Quality Research in Chinese Medicine, Macau, Macau SAR, China
| | - Wei Hu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau, Macau SAR, China
| | - Jiayu Zheng
- School of Pharmacy, Macau University of Science and Technology, Macau, Macau SAR, China
| | - Yawen Liu
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, China
| | - Mingxin Guan
- College of Pharmacy, Dalian Medical University, Dalian, China
| | - Na Zhou
- School of Pharmacy, Macau University of Science and Technology, Macau, Macau SAR, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau, Macau SAR, China
- *Correspondence: Na Zhou, ; Xin Zhang,
| | - Xin Zhang
- School of Pharmacy, Macau University of Science and Technology, Macau, Macau SAR, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau, Macau SAR, China
- *Correspondence: Na Zhou, ; Xin Zhang,
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Kuwanon T and Sanggenon a Isolated from Morus alba Exert Anti-Inflammatory Effects by Regulating NF-κB and HO-1/Nrf2 Signaling Pathways in BV2 and RAW264.7 Cells. Molecules 2021; 26:molecules26247642. [PMID: 34946724 PMCID: PMC8708433 DOI: 10.3390/molecules26247642] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 12/14/2021] [Accepted: 12/14/2021] [Indexed: 12/26/2022] Open
Abstract
We previously investigated the methanolic extract of Morus alba bark and characterized 11 compounds from the extract: kuwanon G (1), kuwanon E (2), kuwanon T (3), sanggenon A (4), sanggenon M (5), sanggenol A (6), mulberofuran B (7), mulberofuran G (8), moracin M (9), moracin O (10), and norartocarpanone (11). Herein, we investigated the anti-inflammatory effects of these compounds on microglial cells (BV2) and macrophages (RAW264.7). Among them, 3 and 4 markedly inhibited the lipopolysaccharide (LPS)-induced production of nitric oxide in these cells, suggesting the anti-inflammatory properties of these two compounds. These compounds inhibited the production of prostaglandin E2, interleukin-6, and tumor necrosis factor-α, and the expression of inducible nitric oxide synthase and cyclooxygenase-2 following LPS stimulation. Pretreatment with 3 and 4 inhibited the activation of the nuclear factor kappa B signaling pathway in both cell types. The compounds also induced the expression of heme oxygenase (HO)-1 through the activation of nuclear factor erythroid 2-related factor 2. Suppressing the activity of HO-1 reversed the anti-inflammatory effects caused by pretreatment with 3 and 4, suggesting that the anti-inflammatory effects were regulated by HO-1. Taken together, 3 and 4 are potential candidates for developing therapeutic and preventive agents for inflammatory diseases.
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Bakhshinyan D, Adile AA, Liu J, Gwynne WD, Suk Y, Custers S, Burns I, Singh M, McFarlane N, Subapanditha MK, Qazi MA, Vora P, Kameda-Smith MM, Savage N, Desmond KL, Tatari N, Tran D, Seyfrid M, Hope K, Bock NA, Venugopal C, Bader GD, Singh SK. Temporal profiling of therapy resistance in human medulloblastoma identifies novel targetable drivers of recurrence. SCIENCE ADVANCES 2021; 7:eabi5568. [PMID: 34878832 PMCID: PMC8654291 DOI: 10.1126/sciadv.abi5568] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 10/16/2021] [Indexed: 05/20/2023]
Abstract
Medulloblastoma (MB) remains a leading cause of cancer-related mortality among children. The paucity of MB samples collected at relapse has hindered the functional understanding of molecular mechanisms driving therapy failure. New models capable of accurately recapitulating tumor progression in response to conventional therapeutic interventions are urgently needed. In this study, we developed a therapy-adapted PDX MB model that has a distinct advantage of generating human MB recurrence. The comparative gene expression analysis of MB cells collected throughout therapy led to identification of genes specifically up-regulated after therapy, including one previously undescribed in the setting of brain tumors, bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4). Subsequent functional validation resulted in a markedly diminished in vitro proliferation, self-renewal, and longevity of MB cells, translating into extended survival and reduced tumor burden in vivo. Targeting endothelial nitric oxide synthase, a downstream substrate of BPIFB4, impeded growth of several patient-derived MB lines at low nanomolar concentrations.
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Affiliation(s)
- David Bakhshinyan
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada
| | - Ashley A. Adile
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada
| | - Jeff Liu
- The Donnelly Centre, University of Toronto, Toronto, ON, Canada
| | - William D. Gwynne
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada
| | - Yujin Suk
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada
| | - Stefan Custers
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada
| | - Ian Burns
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada
| | - Mohini Singh
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada
| | - Nicole McFarlane
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada
- Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
| | - Minomi K. Subapanditha
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada
| | - Maleeha A. Qazi
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada
| | - Parvez Vora
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada
- Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
| | - Michelle M. Kameda-Smith
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada
- Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
| | - Neil Savage
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada
| | - Kim L. Desmond
- Department of Psychology, Neuroscience and Behaviour, McMaster University, Hamilton, ON, Canada
| | - Nazanin Tatari
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada
| | - Damian Tran
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada
| | - Mathieu Seyfrid
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada
- Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
| | - Kristin Hope
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada
| | - Nicholas A. Bock
- Department of Psychology, Neuroscience and Behaviour, McMaster University, Hamilton, ON, Canada
| | - Chitra Venugopal
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada
- Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
| | - Gary D. Bader
- The Donnelly Centre, University of Toronto, Toronto, ON, Canada
- Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Toronto, ON, Canada
- Princess Margaret Cancer Centre at University Health Network, Department of Molecular Genetics and Department of Computer Science, Toronto, ON, Canada
| | - Sheila K. Singh
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada
- Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
- Corresponding author.
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Villanueva CM, Espinosa A, Gracia-Lavedan E, Vlaanderen J, Vermeulen R, Molina AJ, Amiano P, Gómez-Acebo I, Castaño-Vinyals G, Vineis P, Kogevinas M. Exposure to widespread drinking water chemicals, blood inflammation markers, and colorectal cancer. ENVIRONMENT INTERNATIONAL 2021; 157:106873. [PMID: 34543938 DOI: 10.1016/j.envint.2021.106873] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 08/12/2021] [Accepted: 09/08/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND Trihalomethanes (THMs) and nitrate are widespread chemicals in drinking water associated with colorectal cancer risk but mechanisms are not well understood. OBJECTIVES We explored the association between exposure to THMs and nitrate in drinking water and inflammation markers, and the link with colorectal cancer risk. METHODS A subset of 198 colorectal cancer cases and 205 controls from the multicase-control study MCC-Spain were included. Average concentration of THMs (chloroform, bromodichloromethane, dibromochloromethane, bromoform) and nitrate in tap water at the residence was estimated from age 18 until 2 years before the interview ("long term") and for a recent period (3 years before diagnosis). Serum levels of EGF, eotaxin, G-CSF, IL-17E, IL-1rA, IL-8, IP-10, MDC, MPO, periostin, VEGF, and C-reactive protein (CRP) were measured. We estimated the linear association between inflammation markers and exposure among controls, and the odds ratio of colorectal cancer associated with THM and nitrate exposure, and inflammation markers. A mediation analysis was conducted to identify inflammation markers in the pathway between THM/nitrate exposure and colorectal cancer. RESULTS Serum concentrations of EGF, IL-8, IL-17E and eotaxin increased with recent residential levels of brominated THMs, chloroforom and/or total THM. No associations were observed for nitrate and for long-term residential THM levels. All residential exposures except chloroform were positively associated with colorectal cancer. Serum concentrations of VEGF and periostin were positively associated with colorectal cancer, while EGF was inversely associated. One protein-exposure combination (periostin-recent ingested brominated THMs) slightly mediated the association with colorectal cancer risk. DISCUSSION Results suggest that estimated THM exposure is involved in inflammation processes. However, the study design was limited to stablish etiologically relevant associations between the protein levels and colorectal cancer risk. The lack of association between nitrate exposure and inflammation markers suggests other biological mechanisms are involved in the link with colorectal cancer.
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Affiliation(s)
- Cristina M Villanueva
- ISGlobal, Barcelona, Spain; CIBER epidemiología y salud pública (CIBERESP), Madrid, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
| | - Ana Espinosa
- ISGlobal, Barcelona, Spain; CIBER epidemiología y salud pública (CIBERESP), Madrid, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | - Esther Gracia-Lavedan
- ISGlobal, Barcelona, Spain; CIBER epidemiología y salud pública (CIBERESP), Madrid, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - Jelle Vlaanderen
- Institute for Risk Assessment Sciences (IRAS), Utrecht University, Utrecht, the Netherlands
| | - Roel Vermeulen
- Institute for Risk Assessment Sciences (IRAS), Utrecht University, Utrecht, the Netherlands
| | - Antonio José Molina
- The Research Group in Gene - Environment and Health Interactions (GIIGAS)/Institute of Biomedicine (IBIOMED), Universidad de León, León, Spain; Faculty of Health Sciences, Department of Biomedical Sciences, Area of Preventive Medicine and Public Health, Universidad de León, Spain
| | - Pilar Amiano
- CIBER epidemiología y salud pública (CIBERESP), Madrid, Spain; Public Health Division of Gipuzkoa, Biodonostia Research Institute, San Sebastian, Spain
| | - Inés Gómez-Acebo
- CIBER epidemiología y salud pública (CIBERESP), Madrid, Spain; Universidad de Cantabria, Santander, Spain
| | - Gemma Castaño-Vinyals
- ISGlobal, Barcelona, Spain; CIBER epidemiología y salud pública (CIBERESP), Madrid, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | - Paolo Vineis
- School of Public Health, Imperial College London, London, UK; Italian Institute of Technology, Genova, Liguria, Italy
| | - Manolis Kogevinas
- ISGlobal, Barcelona, Spain; CIBER epidemiología y salud pública (CIBERESP), Madrid, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
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Self-assembled drug-polymer micelles with NO precursor loaded for synergistic cancer therapy. JOURNAL OF POLYMER RESEARCH 2021. [DOI: 10.1007/s10965-021-02645-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Zou D, Song J, Deng M, Ma Y, Yang C, Liu J, Wang S, Wen Z, Tang Y, Qu X, Zhang Y. Bufalin inhibits peritoneal dissemination of gastric cancer through endothelial nitric oxide synthase-mitogen-activated protein kinases signaling pathway. FASEB J 2021; 35:e21601. [PMID: 33913201 DOI: 10.1096/fj.202002780r] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 02/19/2021] [Accepted: 04/01/2021] [Indexed: 01/11/2023]
Abstract
Peritoneal dissemination threatens the survival of patients with gastric cancer (GC). Bufalin is an extract of traditional Chinese medicine, which has been proved to have anticancer effect. The target of bufalin in suppressing gastric cancer peritoneal dissemination (GCPD) and the underlying mechanism are still unclear. In this research, GC cell line MGC-803 and high-potential peritoneal dissemination cell line MKN-45P were treated with bufalin or L-NAME. Malignant biological behavior and protein level of GC cell lines were detected with MTT, wound healing, transwell, adhesion, and western blotting. Bioinformatics analysis and patient tissues were used to verify the role of endothelial nitric oxide synthase (NOS3) in GC. Mice model was used to assess the effect of bufalin and role of NOS3 in vivo. We found that bufalin inhibited the proliferation, invasion, and migration in GC cell lines. NOS3, which was an independent prognostic factor of GC patients, was predicted to be a potential target of bufalin. Further experiments proved that bufalin reduced the phosphorylation of NOS3, thereby inhibiting the mitogen-activated protein kinase (MAPK) signaling pathway, and ultimately suppressed GCPD by inhibiting EMT process. In conclusion, NOS3 was a potential therapeutic target and prognostic biomarker of GC. Bufalin could suppress GCPD through NOS3-MAPK signaling pathway, which provided more evidence support for intraperitoneal perfusion of bufalin to treat GCPD.
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Affiliation(s)
- Dan Zou
- The First Laboratory of Cancer Institute, the First Hospital of China Medical University, Shenyang, China
| | - Jincheng Song
- The First Laboratory of Cancer Institute, the First Hospital of China Medical University, Shenyang, China.,Department of Oncology, the Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Mingming Deng
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Yanju Ma
- Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, Shenyang, China
| | - Chunjiao Yang
- The First Laboratory of Cancer Institute, the First Hospital of China Medical University, Shenyang, China
| | - Jiaqing Liu
- The First Laboratory of Cancer Institute, the First Hospital of China Medical University, Shenyang, China
| | - Song Wang
- The First Laboratory of Cancer Institute, the First Hospital of China Medical University, Shenyang, China
| | - Zhenpeng Wen
- The First Laboratory of Cancer Institute, the First Hospital of China Medical University, Shenyang, China
| | - Yu Tang
- Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, Shenyang, China
| | - Xiujuan Qu
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, China
| | - Ye Zhang
- The First Laboratory of Cancer Institute, the First Hospital of China Medical University, Shenyang, China
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Barnawi I, Hawsawi Y, Dash P, Oyouni AAA, Mustafa SK, Hussien NA, Al-Amer O, Alomar S, Mansour L. Nitric Oxide Synthase Potentiates the Resistance of Cancer Cell Lines to Anticancer Chemotherapeutics. Anticancer Agents Med Chem 2021; 22:1397-1406. [PMID: 34165414 DOI: 10.2174/1871520621666210623094526] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 04/21/2021] [Accepted: 04/26/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Despite the advancement in the fields of medical science and molecular biology, cancer is still the leading cause of death worldwide. Chemotherapy is a choice for treatment; however, the acquisition of chemo-resistance is a major impediment to cancer management. Many mechanisms have been postulated regarding the acquisition of chemo-resistance in breast cancer the impact on cellular signaling and the induction of apoptosis in tumour cells. The mechanism of the apoptotic mutation of p53 and bcl-2 proteins is commonly associated with increased resistance to apoptosis and, therein, to chemotherapy. OBJECTIVES The current study was aimed to investigate A172 and MDA-MB-231 cancer cells' sensitivity against chemotherapeutic drugs, including cisplatin, doxorubicin, and paclitaxel with different doses. Moreover, it estimates the resistance of cancer cells by evaluating nitric oxide synthase (NOS) expression and evaluate its correlation with the expression profile proteins of the apoptosis regulating Bcl-2 family. METHODS Dose-dependent sensitivity to cisplatin, doxorubicin, or paclitaxel was evaluated on spheroid cultured A172 and MDA-MB-231 cells lines as measured by time-lapse microscopy over a 72h period. Expressions of two nitric oxides (NO) synthases isoforms (iNOS, eNOS), anti-apoptotic (Bcl-2, phospho-Bcl-2, Mcl-1, and Bcl-xL), and pro-apoptotic (BID, Bim, Bok, Bad, Puma, and Bax) were evaluated by Western blot. The effect of NO modulation on anti- and pro-apoptotic molecule expression was also studied using Western blot. RESULT A172 cells show more resistance to chemotherapy drugs than MDA-MB-231 cancer cells. Therefore, they need higher doses for apoptosis. Resistance of gliomas might be returned to the higher significant expression of endothelial eNOS expression. It was clear that there is not a significant effect of NO modulation on the expression of pro-and anti-apoptotic proteins on both cell lines. CONCLUSION The present work provides a putative mechanism for the acquisition of drug resistance in breast cancer and glioma, which might be significant for clinical outcomes.
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Affiliation(s)
- Ibrahim Barnawi
- Department of Biology, Faculty of Sciences, University of Taiba, Madina, Saudi Arabia
| | - Yousef Hawsawi
- Research Center, King Faisal Specialist Hospital and Research Center, Jeddah 21499, P.O. Box 40047, Saudi Arabia
| | - Philip Dash
- University of Reading Faculty of Life Sciences, school of science, Reading, Reading, United Kingdom
| | | | - Syed Khalid Mustafa
- Department of Biology, Faculty of Sciences, University of Tabuk, Tabuk, Saudi Arabia
| | - Nahed A Hussien
- Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt
| | - Osama Al-Amer
- Department of Medical Laboratory Technology, Faculty of Applied Medical Science, University of Tabuk, Tabuk, Saudi Arabia
| | - Suliman Alomar
- Doping Research Chair, Department of Zoology, College of Science, King Saud University PO. Box: 2455, Riyadh, 11451, Saudi Arabia
| | - Lamjed Mansour
- Doping Research Chair, Department of Zoology, College of Science, King Saud University PO. Box: 2455, Riyadh, 11451, Saudi Arabia
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Navarro-Becerra JA, Franco-Urquijo CA, Ríos A, Escalante B. Localized Delivery of Caveolin-1 Peptide Assisted by Ultrasound-Mediated Microbubble Destruction Potentiates the Inhibition of Nitric Oxide-Dependent Vasodilation Response. ULTRASOUND IN MEDICINE & BIOLOGY 2021; 47:1559-1572. [PMID: 33736878 DOI: 10.1016/j.ultrasmedbio.2021.02.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 02/02/2021] [Accepted: 02/04/2021] [Indexed: 06/12/2023]
Abstract
In the endothelium, nitric oxide synthase (eNOS) is the enzyme that generates nitric oxide, a key molecule involved in a variety of biological functions and cancer-related events. Therefore, selective inhibition of eNOS represents an attractive therapeutic approach for NO-related diseases and anticancer therapy. Ultrasound-mediated microbubble destruction (UMMD) conjugated with cell-permeable peptides has been investigated as a drug delivery system for effective delivery of anticancer molecules. We investigated the feasibility of loading antennapedia-caveolin-1 peptide (AP-Cav), a specific eNOS inhibitor, onto microbubbles to be delivered by UMMD in rat aortic endothelium. AP-Cav-loaded microbubbles (AP-Cav-MBs) and US parameters were characterized. Aortas were treated with UMMD for 30 s with 1.3 × 108 MBs/mL AP-Cav (8 μM)-MBs at 100-Hz pulse repetition frequency, 0.5-MPa acoustic pressure, 0.5 mechanical index and 10% duty cycle. NO-dependent vascular responses were assessed using an isolated organ system, 21 h post-treatment. Maximal relaxation response was inhibited 61.8% ± 1.6% in aortas treated with UMMD-AP-Cav-MBs, while in aortas treated with previously disrupted AP-Cav-MBs and then US, the inhibition was 31.6% ± 1.6%. The vascular contractile response was not affected. The impact of UMMD was evaluated in aortas treated with free AP-Cav; 30 μM of free AP-Cav was necessary to reach an inhibition response similar to that obtained with UMMD-AP-Cav-MBs. In conclusion, UMMD enhances the delivery and potentiates the effect of AP-Cav in the endothelial layer of rat aorta segments.
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Affiliation(s)
- J Angel Navarro-Becerra
- Centro de Investigación y de Estudios Avanzados del IPN, Unidad-Monterrey, Apodaca NL, México
| | - Carlos A Franco-Urquijo
- Centro de Investigación y de Estudios Avanzados del IPN, Unidad-Monterrey, Apodaca NL, México
| | - Amelia Ríos
- Centro de Investigación y de Estudios Avanzados del IPN, Unidad-Monterrey, Apodaca NL, México.
| | - Bruno Escalante
- Centro de Investigación y de Estudios Avanzados del IPN, Unidad-Monterrey, Apodaca NL, México; Universidad de Monterrey, San Pedro Garza García, NL, México
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Zalfa C, Paust S. Natural Killer Cell Interactions With Myeloid Derived Suppressor Cells in the Tumor Microenvironment and Implications for Cancer Immunotherapy. Front Immunol 2021; 12:633205. [PMID: 34025641 PMCID: PMC8133367 DOI: 10.3389/fimmu.2021.633205] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 02/12/2021] [Indexed: 12/17/2022] Open
Abstract
The tumor microenvironment (TME) is a complex and heterogeneous environment composed of cancer cells, tumor stroma, a mixture of tissue-resident and infiltrating immune cells, secreted factors, and extracellular matrix proteins. Natural killer (NK) cells play a vital role in fighting tumors, but chronic stimulation and immunosuppression in the TME lead to NK cell exhaustion and limited antitumor functions. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of myeloid cells with potent immunosuppressive activity that gradually accumulate in tumor tissues. MDSCs interact with innate and adaptive immune cells and play a crucial role in negatively regulating the immune response to tumors. This review discusses MDSC-mediated NK cell regulation within the TME, focusing on critical cellular and molecular interactions. We review current strategies that target MDSC-mediated immunosuppression to enhance NK cell cytotoxic antitumor activity. We also speculate on how NK cell-based antitumor immunotherapy could be improved.
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Affiliation(s)
| | - Silke Paust
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, United States
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Salari N, Bokaee S, Farshchian N, Mohammadi M, Kazeminia M. The role of polymorphisms rs2070744 and rs1799983 eNOS gene in patients with POAG: a systematic review and meta-analysis. Int Ophthalmol 2021; 41:2747-2763. [PMID: 33837898 DOI: 10.1007/s10792-021-01832-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 03/29/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND Glaucoma is a progressive disease of the optic nerve that has several underlying causes, but in most cases, the cause is unknown. Given the importance of the role of nitric oxide in the occurrence of ocular nerve damage and the effect of eNOS gene polymorphic sites on protein function, to better understand the mechanism of formation of POAG, the relationship between polymorphisms rs2070744 and rs1799983 eNOS gene with POAG risk was investigated in this study using meta-analysis. METHODS In this study, systematic review and meta-analysis of study data related to the study of polymorphisms rs2070744 and rs1799983 eNOS gene in patients with POAG using the keywords eNOS, NOS3, Gluuc8898, POAG, primary open-angle glaucoma. It was extracted from SID, MagIran, IranMedex, IranDoc, ScienceDirect, Embase, Scopus, PubMed, Web of Science, and Google Scholar search engines without a time limit until May 2020. To perform the analysis of qualified studies, the model of random effects was used and the inconsistency of studies with the I2 index was investigated. Data analysis was performed with Comprehensive Meta-Analysis (Version 2). RESULTS In a review of 16 studies (9 studies on polymorphism rs2070744 and seven studies on polymorphism rs1799983) with a sample size of 1631 subjects and a control group of 2405 subjects related to polymorphism rs2070744 and a group of 1456 subjects and a control group of 2240 subjects related to polymorphism 9997 rs1, the odds ratio of TT, CT, and CC genotypes was reported to be 0.95, 1.01, and 1.14, respectively, and the odds ratio of GG, GT and TT genotypes to be 0.88, 0.97, and 1.31, respectively, was reported in patients with POAG. CONCLUSION The results of our systematic review and meta-analysis study show that the eNOS gene polymorphisms rs2070744 and rs1799983 may increase the risk of POAG among individuals. However, further studies are needed to confirm these findings.
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Affiliation(s)
- Nader Salari
- Department of Biostatistics, School of Health, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Shadi Bokaee
- Faculty of Health and Life Sciences, School of Life Sciences, Coventry University, Coventry, UK
| | - Nushin Farshchian
- Department of Ophthalmology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoud Mohammadi
- Department of Nursing, School of Nursing and Midwifery, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| | - Mohsen Kazeminia
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
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Ibrahim RS, El-Banna AA. Network pharmacology-based analysis for unraveling potential cancer-related molecular targets of Egyptian propolis phytoconstituents accompanied with molecular docking and in vitro studies. RSC Adv 2021; 11:11610-11626. [PMID: 35423607 PMCID: PMC8695995 DOI: 10.1039/d1ra01390d] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 03/13/2021] [Indexed: 12/13/2022] Open
Abstract
Cancer is one of the predominant causes of death worldwide. The new trend nowadays is to exploit natural products with the hope of developing new anticancer agents with fewer side effects. Propolis is one of these natural products which showed effectiveness in cancer treatment. The aim of this study is to understand the multi-level mechanism of action of propolis constituents in cancer treatment using an integrated approach of network pharmacology-based analysis, molecular docking and in vitro cytotoxicity testing. An inhouse database of chemical constituents from Egyptian propolis was compiled and assessed for its ADME properties using the QikProp module in the Schrodinger software. STITCH, UniProt, STRING, KEGG and DAVID databases were used for construction of constituent-target gene, gene-pathway, and constituent-target gene-pathway networks with the aid of Cytoscape 3.8.2. The network pharmacology-based analysis showed that the hit propolis constituents related to cancer targets were genistein, luteolin, benzoic acid, quercetin and vanillic acid, whereas the main cancer-associated targets were CYP1A1, CYP19A1, ESR1, NOS3, CASP3 and AKT1. Twenty-four cancer-related pathways were recognized where the most enriched ones were pathways in cancer and estrogen signaling pathway. The most enriched biological processes involved in the mechanism of action of propolis constituents in cancer treatment were negative regulation of the apoptotic process and the metabolic process and negative regulation of cellular glucuronidation. Molecular docking analysis of the top hit compounds against the most enriched target proteins in the constructed networks was carried out using the Maestro interface of the Schrodinger software. Among hit compounds, quercetin and genistein exhibited the most stabilized interaction. Finally, confirmation of the potential anticancer activity of propolis was assured by in vitro cytotoxicity testing of propolis extract on human prostate cancer (DU-145), breast adenocarcinoma (MCF-7) and colorectal adenocarcinoma (Caco-2) cell lines. This study presents deeper insights about propolis molecular mechanisms of action in cancer for the first time using an integrated approach of network pharmacology, molecular docking and in vitro testing.
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Affiliation(s)
- Reham S Ibrahim
- Department of Pharmacognosy, Faculty of Pharmacy, Alexandria University Alexandria 21521 Egypt +201223821098
| | - Alaa A El-Banna
- Department of Pharmacognosy, Faculty of Pharmacy, Alexandria University Alexandria 21521 Egypt +201223821098
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35
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Zou D, Li Z, Lv F, Yang Y, Yang C, Song J, Chen Y, Jin Z, Zhou J, Jiang Y, Ma Y, Jing Z, Tang Y, Zhang Y. Pan-Cancer Analysis of NOS3 Identifies Its Expression and Clinical Relevance in Gastric Cancer. Front Oncol 2021; 11:592761. [PMID: 33747912 PMCID: PMC7969995 DOI: 10.3389/fonc.2021.592761] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 02/08/2021] [Indexed: 12/12/2022] Open
Abstract
Background:NOS3 (endothelial NOS, eNOS) is a member of the nitric oxide synthase (NOS) enzyme family, mainly participating in nitric oxide (NO) generation. NOS3 has been reported to inhibit apoptosis and promote angiogenesis, proliferation, and invasiveness. However, the expression pattern of NOS3 and its diagnostic and prognostic potential has not been investigated in a pan-cancer perspective. Methods: Data from the Genotype-Tissue Expression (GTEx), the Cancer Genome Atlas (TCGA), the Cancer Cell Line Encyclopedia (CCLE), and the Cancer Therapeutics Response Portal (CTRP) were employed and NOS3 expression was comprehensively analyzed in normal tissues, cancer tissues, and cell lines. Immunohistochemical staining of tissue sections were used to validate the prognostic role of NOS3 in gastric cancer patients. GSVA and GSEA analyses were performed to investigate signaling pathways related to NOS3 expression. Results: In normal tissues, NOS3 was expressed highest in the spleen and lowest in the blood. NOS3 expression was increased in stomach adenocarcinoma (STAD) and significantly associated with poor prognosis of patients. Immunohistochemical staining validated that NOS3 was an independent prognostic factor of gastric cancer. Several canonical cancer-related pathways were found to be correlated with NOS3 expression in STAD. The expression of NOS3 was related to the response to QS-11 and brivinib in STAD. Conclusions:NOS3 was an independent prognostic factor for patients with STAD. Increased expression of NOS3 influenced occurrence and development of STAD through several canonical cancer-related pathways. Drug response analysis reported drugs to suppress NOS3. NOS3 might be a novel target for gastric cancer treatment.
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Affiliation(s)
- Dan Zou
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, China
| | - Zhi Li
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China
| | - Fei Lv
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, China
| | - Yi Yang
- Laboratory Animal Center, China Medical University, Shenyang, China
| | - Chunjiao Yang
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, China
| | - Jincheng Song
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, China.,Lymphoma and Myeloma Diagnosis and Treatment Center, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yang Chen
- Department of Respiratory and Infectious Disease of Geriatrics, The First Hospital of China Medical University, Shenyang, China
| | - Zi Jin
- The First Department of Oncology, Shenyang Fifth People's Hospital, Shenyang, China
| | - Jinpeng Zhou
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, China
| | - Yang Jiang
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, China.,Department of Neurosurgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yanju Ma
- Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, Shenyang, China
| | - Zhitao Jing
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, China
| | - Yu Tang
- Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, Shenyang, China
| | - Ye Zhang
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, China
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Effect of mesenchymal stem cells on cytochrome-c release and inflammation in colon cancer induced by 1,2-dimethylhydrazine in Wistar albino rats. Biosci Rep 2021; 41:227886. [PMID: 33604610 PMCID: PMC7926179 DOI: 10.1042/bsr20204356] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 02/06/2021] [Accepted: 02/17/2021] [Indexed: 02/07/2023] Open
Abstract
Colon cancer is one of the most common causes of deaths by cancer worldwide. Stem cells have immunosuppressive properties that promote tumor targeting and circumvent obstacles currently in gene therapy. Bone marrow stem cells are believed to have anticancer potential. The transplantation of mesenchymal stem cells (MSCs), a type of bone marrow stem cells, has been considered a potential therapy for patients with solid tumors due to their capability to enhance the immune response; MSC transplantation has received renewed interest in recent years. The present study aimed to evaluate the antiapoptotic effects of the MSCs on 1,2-dimethylhydrazine (DMH)-induced inflammation in the rat model of colorectal cancer. The rats were randomly allocated into four groups: control, treated with MSCs, induced by DMH, and induced by DMH and treated with MSCs. The MSCs were intra-rectally injected, and DMH was subcutaneously injected at 20 mg/kg body weight once a week for 15 weeks. The administration of MSCs into rats starting from day 0 of the DMH injection was found to enhance the histopathological picture. The MSC treatment resulted in fewer inflammatory cells than in the DMH group. Therefore, our findings suggest that BMCs have antitumor effects by modulating the cellular redox status and down-regulating the pro-inflammatory genes. Thus, BMCs may provide therapeutic value for colon cancer treatment.
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Khan FH, Dervan E, Bhattacharyya DD, McAuliffe JD, Miranda KM, Glynn SA. The Role of Nitric Oxide in Cancer: Master Regulator or NOt? Int J Mol Sci 2020; 21:ijms21249393. [PMID: 33321789 PMCID: PMC7763974 DOI: 10.3390/ijms21249393] [Citation(s) in RCA: 93] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/06/2020] [Accepted: 12/07/2020] [Indexed: 02/06/2023] Open
Abstract
Nitric oxide (NO) is a key player in both the development and suppression of tumourigenesis depending on the source and concentration of NO. In this review, we discuss the mechanisms by which NO induces DNA damage, influences the DNA damage repair response, and subsequently modulates cell cycle arrest. In some circumstances, NO induces cell cycle arrest and apoptosis protecting against tumourigenesis. NO in other scenarios can cause a delay in cell cycle progression, allowing for aberrant DNA repair that promotes the accumulation of mutations and tumour heterogeneity. Within the tumour microenvironment, low to moderate levels of NO derived from tumour and endothelial cells can activate angiogenesis and epithelial-to-mesenchymal transition, promoting an aggressive phenotype. In contrast, high levels of NO derived from inducible nitric oxide synthase (iNOS) expressing M1 and Th1 polarised macrophages and lymphocytes may exert an anti-tumour effect protecting against cancer. It is important to note that the existing evidence on immunomodulation is mainly based on murine iNOS studies which produce higher fluxes of NO than human iNOS. Finally, we discuss different strategies to target NO related pathways therapeutically. Collectively, we present a picture of NO as a master regulator of cancer development and progression.
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Affiliation(s)
- Faizan H. Khan
- Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway (NUIG), H91 YR71 Galway, Ireland; (F.H.K.); (E.D.); (D.D.B.); (J.D.M.)
| | - Eoin Dervan
- Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway (NUIG), H91 YR71 Galway, Ireland; (F.H.K.); (E.D.); (D.D.B.); (J.D.M.)
| | - Dibyangana D. Bhattacharyya
- Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway (NUIG), H91 YR71 Galway, Ireland; (F.H.K.); (E.D.); (D.D.B.); (J.D.M.)
| | - Jake D. McAuliffe
- Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway (NUIG), H91 YR71 Galway, Ireland; (F.H.K.); (E.D.); (D.D.B.); (J.D.M.)
| | - Katrina M. Miranda
- Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA;
| | - Sharon A. Glynn
- Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway (NUIG), H91 YR71 Galway, Ireland; (F.H.K.); (E.D.); (D.D.B.); (J.D.M.)
- Correspondence:
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38
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Advances in inorganic-based colloidal nanovehicles functionalized for nitric oxide delivery. Colloids Surf B Biointerfaces 2020; 199:111508. [PMID: 33340932 DOI: 10.1016/j.colsurfb.2020.111508] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 11/12/2020] [Accepted: 11/30/2020] [Indexed: 01/25/2023]
Abstract
Nitric oxide (NO) is an important pharmaceutical agent of considerable therapeutic interest ascribed to its vasodilative, tumoricidal and antibacterial effects. Rapid development of functional nanomaterials has provided opportunities for us to achieve controllable exogenous delivery of NO. In the current review, a variety of functionalized colloidal nanovehicles that have been developed to date for nitric oxide delivery are reported. Specifically, we focus on inorganic nanomaterials such as semiconductor quantum dots, silica nanoparticles, upconversion nanomaterials, carbon/graphene nanodots, gold nanoparticles, iron oxide nanoparticles as the functional or/and supporting materials to carry NO donors. N-diazeniumdiolates, S-nitrosothiols, nitrosyl metal complexes and organic nitrates as main types of NO donors have their own unique properties and molecular structures. Conjugating the NO donors of different forms with appropriate nanomaterials results in NO delivery nanovehicles capable of releasing NO in a dose-controllable or/and on-demand manner. We also consider the therapeutic applications of those NO delivery nanovehicles, especially their applications for cancer therapy. In the end, we discuss possible future directions for developing exogenous NO delivery systems with more desired structure and improved performance. This review aims to offer the readers an overall view of the advances in functionalized colloidal nanovehicles for NO delivery. It will be attractive to scientists and researchers in the areas of material science, nanotechnology, biomedical engineering, chemical biology, etc.
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Gao Y, Zou T, Liang W, Zhang Z, Qie M. Long non-coding RNA HAND2-AS1 delays cervical cancer progression via its regulation on the microRNA-21-5p/TIMP3/VEGFA axis. Cancer Gene Ther 2020; 28:619-633. [PMID: 33139818 DOI: 10.1038/s41417-020-00243-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 09/01/2020] [Accepted: 09/29/2020] [Indexed: 12/19/2022]
Abstract
Cervical cancer is a common cause of cancer-related mortality in women. Mounting evidence suggests that long non-coding RNAs (lncRNAs) function vitally in many cancers. In this study, we discovered that the regulation of the heart and neural crest derivatives expressed 2-antisense RNA 1 (HAND2-AS1) in cervical cancer. RT-qPCR was conducted to detect the expression of HAND2-AS1 and microRNA-21-5p (miR-21-5p). The relationship of HAND2-AS1 and miR-21-5p was identified by dual-luciferase reporter gene assay. The roles of HAND2-AS1, miR-21-5p and tissue inhibitor of metalloproteinases-3 (TIMP3) in cervical cancer were accessed via gain- and loss-of-function approaches. The expression of related proteins in the vascular endothelial growth factor A (VEGFA) signaling pathway was detected through Western blot analysis. Finally, xenografts of cervical cancer in nude mice were established to assess the effect of HAND2-AS1 on tumorigenesis in vivo. HAND2-AS1 and TIMP3 were downregulated in cervical cancer, which were identified to be associated with a poor prognosis of patients with cervical cancer. Moreover, HAND2-AS1 was upregulated the expression of TIMP3 through competitively binding to miR-21-5p. Overexpressed HAND2-AS1 or downregulated miR-21-5p inhibited cell proliferation, migration, and invasion while promoting cell apoptosis, in association with increased expression of proteins in VEGFA signaling pathway. These changes were reversed by silencing of TIMP3. Overexpressed HAND2-AS1 reduced the tumor formation ability in nude mice. In summary, HAND2-AS1 may exert inhibitory effects on cervical cancer cell growth and cervical cancer development through its regulation on the miR-21-5p/TIMP3/VEGFA axis. This highlights that HAND2-AS1 may serve as a potential target for cervical cancer diagnosis and treatment.
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Affiliation(s)
- Yan Gao
- Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, 610041, P.R. China.,Department of Gynecology, Guizhou Provincial People's Hospital, Guiyang, 550002, P.R. China.,Key Laboratory of Obstetrics and Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, 610041, P.R. China
| | - Ting Zou
- Department of Gynecology, Guizhou Provincial People's Hospital, Guiyang, 550002, P.R. China
| | - Wentong Liang
- Department of Gynecology, Guizhou Provincial People's Hospital, Guiyang, 550002, P.R. China
| | - Zhijun Zhang
- Department of Gynecology, Guizhou Provincial People's Hospital, Guiyang, 550002, P.R. China
| | - Mingrong Qie
- Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, 610041, P.R. China. .,Key Laboratory of Obstetrics and Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, 610041, P.R. China.
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Karagiannidis I, de Santana Van Vilet E, Said Abu Egal E, Phinney B, Jacenik D, Prossnitz ER, Beswick EJ. G-CSF and G-CSFR Induce a Pro-Tumorigenic Macrophage Phenotype to Promote Colon and Pancreas Tumor Growth. Cancers (Basel) 2020; 12:cancers12102868. [PMID: 33036138 PMCID: PMC7601499 DOI: 10.3390/cancers12102868] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 10/01/2020] [Accepted: 10/04/2020] [Indexed: 12/13/2022] Open
Abstract
Tumor-associated macrophages (TAMs) in the gastrointestinal tumor microenvironment (TME) are known to polarize into populations exhibiting pro- or anti-tumoral activity in response to stimuli such as growth factors and cytokines. Our previous work has recognized granulocyte colony-stimulating factor (G-CSF) as a cytokine capable of influencing immune cells of the TME exhibiting pro-tumoral activity. Here, we aimed to focus on how G-CSF regulates TAM phenotype and function and the effects on gastrointestinal (GI) tumor progression. Thus, wildtype (WT) and G-CSFR-/- macrophages were examined for cytokine production, gene expression, and transcription factor activity. Adoptive transfer of WT or G-CSFR-/- macrophages into tumor-bearing mice was performed to study their influence in the progression of colon (MC38) and pancreatic (PK5L1940) tumor mouse models. Finally, the difference in cytotoxic potential between WT and G-CSFR-/- macrophages was examined both in vitro and in vivo. Our results indicate that G-CSF promotes increased IL-10 production and decreased IL-12 production, which was reversed in G-CSFR-/- macrophages for a pro-inflammatory phenotype. Furthermore, G-CSFR-/- macrophages were characterized by higher levels of NOS2 expression and NO production, which led to greater tumor related cytotoxicity both in vitro and in vivo. Our results suggest that in the absence of G-CSFR, macrophage-related tumor cytotoxicity was amplified. These findings, along with our previous reports, pinpoint G-CSF /G-CSFR as a prominent target for possible clinical applications that aim to control the TME and the GI tumor progression.
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Affiliation(s)
- Ioannis Karagiannidis
- Division of Gastroenterology, Department of Internal Medicine, University of Utah, Salt Lake City, UT 84132, USA; (I.K.); (E.d.S.V.V.); (E.S.A.E.)
| | - Eliane de Santana Van Vilet
- Division of Gastroenterology, Department of Internal Medicine, University of Utah, Salt Lake City, UT 84132, USA; (I.K.); (E.d.S.V.V.); (E.S.A.E.)
| | - Erika Said Abu Egal
- Division of Gastroenterology, Department of Internal Medicine, University of Utah, Salt Lake City, UT 84132, USA; (I.K.); (E.d.S.V.V.); (E.S.A.E.)
| | - Brandon Phinney
- Division of Molecular Medicine, Department of Internal Medicine; Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Comprehensive Cancer Center; University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; (B.P.); (D.J.); (E.R.P.)
| | - Damian Jacenik
- Division of Molecular Medicine, Department of Internal Medicine; Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Comprehensive Cancer Center; University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; (B.P.); (D.J.); (E.R.P.)
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland
| | - Eric R. Prossnitz
- Division of Molecular Medicine, Department of Internal Medicine; Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Comprehensive Cancer Center; University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; (B.P.); (D.J.); (E.R.P.)
| | - Ellen J. Beswick
- Division of Gastroenterology, Department of Internal Medicine, University of Utah, Salt Lake City, UT 84132, USA; (I.K.); (E.d.S.V.V.); (E.S.A.E.)
- Correspondence:
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Vong LB, Nagasaki Y. Nitric Oxide Nano-Delivery Systems for Cancer Therapeutics: Advances and Challenges. Antioxidants (Basel) 2020; 9:E791. [PMID: 32858970 PMCID: PMC7555477 DOI: 10.3390/antiox9090791] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 08/21/2020] [Accepted: 08/25/2020] [Indexed: 02/07/2023] Open
Abstract
Nitric oxide (NO) plays important roles in various physiological and pathological functions and processes in the human body. Therapeutic application of NO molecules has been investigated in various diseases, including cardiovascular disease, cancer, and infections. However, the extremely short half-life of NO, which limits its clinical use considerably, along with non-specific distribution, has resulted in a low therapeutic index and undesired adverse effects. To overcome the drawbacks of using this gaseous signaling molecule, researchers in the last several decades have focused on innovative medical technologies, specifically nanoparticle-based drug delivery systems (DDSs), because these systems alter the biodistribution of the therapeutic agent through controlled release at the target tissues, resulting in a significant therapeutic drug effect. Thus, the application of nano-systems for NO delivery in the field of biomedicine, particularly in the development of new drugs for cancer treatment, has been increasing worldwide. In this review, we discuss NO delivery nanoparticle systems, with the aim of improving drug delivery development for conventional chemotherapies and controlling multidrug resistance in cancer treatments.
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Affiliation(s)
- Long Binh Vong
- School of Biomedical Engineering, International University, Ho Chi Minh 700000, Vietnam
- Vietnam National University Ho Chi Minh City (VNU-HCM), Ho Chi Minh 700000, Vietnam
| | - Yukio Nagasaki
- Department of Materials Science, Graduate School of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8573, Japan
- Master’s School of Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan
- Center for Research in Isotopes and Environmental Dynamics (CRiED), University of Tsukuba, Tennoudai 1-1-1, Tsukuba, Ibaraki 305-8573, Japan
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Wang H, Wang L, Xie Z, Zhou S, Li Y, Zhou Y, Sun M. Nitric Oxide (NO) and NO Synthases (NOS)-Based Targeted Therapy for Colon Cancer. Cancers (Basel) 2020; 12:E1881. [PMID: 32668616 PMCID: PMC7408898 DOI: 10.3390/cancers12071881] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 07/10/2020] [Accepted: 07/10/2020] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most lethal malignancies worldwide and CRC therapy remains unsatisfactory. In recent decades, nitric oxide (NO)-a free-radical gas-plus its endogenous producer NO synthases (NOS), have attracted considerable attention. NO exerts dual effects (pro- and anti-tumor) in cancers. Endogenous levels of NO promote colon neoplasms, whereas exogenously sustained doses lead to cytotoxic functions. Importantly, NO has been implicated as an essential mediator in many signaling pathways in CRC, such as the Wnt/β-catenin and extracellular-signal-regulated kinase (ERK) pathways, which are closely associated with cancer initiation, metastasis, inflammation, and chemo-/radio-resistance. Therefore, NO/NOS have been proposed as promising targets in the regulation of CRC carcinogenesis. Clinically relevant NO-donating agents have been developed for CRC therapy to deliver a high level of NO to tumor sites. Notably, inducible NOS (iNOS) is ubiquitously over-expressed in inflammatory-associated colon cancer. The development of iNOS inhibitors contributes to targeted therapies for CRC with clinical benefits. In this review, we summarize the multifaceted mechanisms of NO-mediated networks in several hallmarks of CRC. We review the clinical manifestation and limitations of NO donors and NOS inhibitors in clinical trials. We also discuss the possible directions of NO/NOS therapies in the immediate future.
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Affiliation(s)
- Hao Wang
- College of Laboratory Medicine, Jilin Medical University, Jilin 132013, China;
| | - Liye Wang
- Department of Pharmacological and Pharmaceutical Science, College of Pharmacy, University of Houston, Houston, TX, 77204, USA; (L.W.); (Z.X.); (S.Z.); (Y.L.)
| | - Zuoxu Xie
- Department of Pharmacological and Pharmaceutical Science, College of Pharmacy, University of Houston, Houston, TX, 77204, USA; (L.W.); (Z.X.); (S.Z.); (Y.L.)
| | - Shuang Zhou
- Department of Pharmacological and Pharmaceutical Science, College of Pharmacy, University of Houston, Houston, TX, 77204, USA; (L.W.); (Z.X.); (S.Z.); (Y.L.)
| | - Yan Li
- Department of Pharmacological and Pharmaceutical Science, College of Pharmacy, University of Houston, Houston, TX, 77204, USA; (L.W.); (Z.X.); (S.Z.); (Y.L.)
| | - Yue Zhou
- Department of Statistics, North Dakota University, Fargo, ND 58105, USA;
| | - Meiyan Sun
- College of Laboratory Medicine, Jilin Medical University, Jilin 132013, China;
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Identification of GSN and LAMC2 as Key Prognostic Genes of Bladder Cancer by Integrated Bioinformatics Analysis. Cancers (Basel) 2020; 12:cancers12071809. [PMID: 32640634 PMCID: PMC7408759 DOI: 10.3390/cancers12071809] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 06/26/2020] [Accepted: 07/03/2020] [Indexed: 12/14/2022] Open
Abstract
Bladder cancer is a common malignancy with mechanisms of pathogenesis and progression. This study aimed to identify the prognostic hub genes, which are the central modulators to regulate the progression and proliferation in the specific subtype of bladder cancer. The identification of the candidate hub gene was performed by weighted gene co-expression network analysis to construct a free-scale gene co-expression network. The gene expression profile of GSE97768 from the Gene Expression Omnibus database was used. The association between prognosis and hub gene was evaluated by The Cancer Genome Atlas database. Four gene-expression modules were significantly related to bladder cancer disease: the red module (human adenocarcinoma lymph node metastasis), the darkturquioise module (grade 2 carcinoma), the lightgreen module (grade 3 carcinoma), and the royalblue module (transitional cell carcinoma lymphatic metastasis). Based on betweenness centrality and survival analysis, we identified laminin subunit gamma-2 (LAMC2) in the grade 2 carcinoma, gelsolin (GSN) in the grade 3 carcinoma, and homeodomain-interacting protein kinase 2 (HIPK2) in the transitional cell carcinoma lymphatic metastasis. Subsequently, the protein levels of LAMC2 and GSN were respectively down-regulated and up-regulated in tumor tissue with the Human Protein Atlas (HPA) database. Our results suggested that LAMC2 and GSN are the central modulators to transfer information in the specific subtype of the disease.
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Wu H, Wei M, Jiang X, Tan J, Xu W, Fan X, Zhang R, Ding C, Zhao F, Shao X, Zhang Z, Shi R, Zhang W, Wu G. lncRNA PVT1 Promotes Tumorigenesis of Colorectal Cancer by Stabilizing miR-16-5p and Interacting with the VEGFA/VEGFR1/AKT Axis. MOLECULAR THERAPY. NUCLEIC ACIDS 2020; 20:438-450. [PMID: 32276209 PMCID: PMC7139143 DOI: 10.1016/j.omtn.2020.03.006] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 03/12/2020] [Indexed: 01/07/2023]
Abstract
Recently, the long noncoding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) was reported to be involved in the pathogenesis of several cancers, including human colorectal cancer (CRC). However, the molecular basis for cancer initiation, development, and progression remains unclear. In this study, we observe that upregulated PVT1 is associated with poor prognosis and bad clinicopathological features of CRC patients. In vitro means of PVT1 loss in a CRC cell line inhibit cell proliferation, migration, and invasion. Furthermore, dual-luciferase reporter and RNA pull-down assays indicated that PVT1 binds to miR-16-5p, which has been shown to play strong tumor suppressive roles in CRC. Targeted loss of miR-16-5p partially rescues the suppressive effect induced by PVT1 knockdown. Vascular endothelial growth factor A (VEGFA), a direct downstream target of miR-16-5p, was suppressed by PVT1 knockdown in CRC cells. Overexpression of VEGFA is known to modulate the AKT signaling cascade by activating vascular endothelial growth factor receptor 1 (VEGFR1). We, therefore, show that PVT1 loss combined with miR-16-5p overexpression reduces tumor volume maximally when propagated within a mouse xenograft model. We conclude that the PVT1-miR-16-5p/VEGFA/VEGFR1/AKT axis directly coordinates the response in CRC pathogenesis and suggest PVT1 as a novel target for potential CRC therapy.
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Affiliation(s)
- Hailu Wu
- Medical School of Southeast University, Nanjing 210009, People's Republic of China; Department of Gastroenterology, Zhongda Hospital, Southeast University, Nanjing 210009, People's Republic of China
| | - Ming Wei
- Department of Gastroenterology, Zhongda Hospital, Southeast University, Nanjing 210009, People's Republic of China
| | - Xinglu Jiang
- Medical School of Southeast University, Nanjing 210009, People's Republic of China
| | - Jiacheng Tan
- Department of Gastroenterology, Zhongda Hospital, Southeast University, Nanjing 210009, People's Republic of China
| | - Wei Xu
- Medical School of Southeast University, Nanjing 210009, People's Republic of China
| | - Xiaobo Fan
- Medical School of Southeast University, Nanjing 210009, People's Republic of China
| | - Rui Zhang
- Medical School of Southeast University, Nanjing 210009, People's Republic of China
| | - Chenbo Ding
- Medical School of Southeast University, Nanjing 210009, People's Republic of China
| | - Fengfeng Zhao
- Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing 210009, People's Republic of China
| | - Xiangyu Shao
- Department of Gastrointestinal Surgery, Zhongda Hospital, Southeast University, Nanjing 210009, People's Republic of China
| | - Zhigang Zhang
- Medical School of Southeast University, Nanjing 210009, People's Republic of China; Department of Gastrointestinal Surgery, Zhongda Hospital, Southeast University, Nanjing 210009, People's Republic of China
| | - Ruihua Shi
- Department of Gastroenterology, Zhongda Hospital, Southeast University, Nanjing 210009, People's Republic of China
| | - Weijia Zhang
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
| | - Guoqiu Wu
- Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing 210009, People's Republic of China.
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45
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Ding H, Wang L, Zhang L, Zhu B, Hou L, Huang G, Xu Z. RGD-modified ZnO nanoparticles loaded with nitric oxide precursor for targeted cancer therapy. Chem Phys Lett 2020. [DOI: 10.1016/j.cplett.2020.137445] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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46
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Ploetz E, Zimpel A, Cauda V, Bauer D, Lamb DC, Haisch C, Zahler S, Vollmar AM, Wuttke S, Engelke H. Metal-Organic Framework Nanoparticles Induce Pyroptosis in Cells Controlled by the Extracellular pH. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2020; 32:e1907267. [PMID: 32182391 DOI: 10.1002/adfm.201909062] [Citation(s) in RCA: 139] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 03/01/2020] [Accepted: 03/02/2020] [Indexed: 05/23/2023]
Abstract
Ion homeostasis is essential for cellular survival, and elevated concentrations of specific ions are used to start distinct forms of programmed cell death. However, investigating the influence of certain ions on cells in a controlled way has been hampered due to the tight regulation of ion import by cells. Here, it is shown that lipid-coated iron-based metal-organic framework nanoparticles are able to deliver and release high amounts of iron ions into cells. While high concentrations of iron often trigger ferroptosis, here, the released iron induces pyroptosis, a form of cell death involving the immune system. The iron release occurs only in slightly acidic extracellular environments restricting cell death to cells in acidic microenvironments and allowing for external control. The release mechanism is based on endocytosis facilitated by the lipid-coating followed by degradation of the nanoparticle in the lysosome via cysteine-mediated reduction, which is enhanced in slightly acidic extracellular environment. Thus, a new functionality of hybrid nanoparticles is demonstrated, which uses their nanoarchitecture to facilitate controlled ion delivery into cells. Based on the selectivity for acidic microenvironments, the described nanoparticles may also be used for immunotherapy: the nanoparticles may directly affect the primary tumor and the induced pyroptosis activates the immune system.
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Affiliation(s)
- Evelyn Ploetz
- Department of Chemistry and Center for NanoScience (CeNS), LMU Munich, Munich, 81377, Germany
- Nanosystems Initiative Munich (NIM), LMU Munich, Munich, 81377, Germany
- Center for Integrated Protein Science Munich (CiPSM), LMU Munich, Munich, 81377, Germany
| | - Andreas Zimpel
- Department of Chemistry and Center for NanoScience (CeNS), LMU Munich, Munich, 81377, Germany
| | - Valentina Cauda
- Department of Applied Science and Technology, Politecnico di Torino, Torino, 10129, Italy
| | - David Bauer
- Department of Chemistry, TU Munich, Munich, 81377, Germany
| | - Don C Lamb
- Department of Chemistry and Center for NanoScience (CeNS), LMU Munich, Munich, 81377, Germany
- Nanosystems Initiative Munich (NIM), LMU Munich, Munich, 81377, Germany
- Center for Integrated Protein Science Munich (CiPSM), LMU Munich, Munich, 81377, Germany
| | | | - Stefan Zahler
- Department of Pharmacy, LMU Munich, Munich, 81377, Germany
| | | | - Stefan Wuttke
- BCMaterials, Basque Center for Materials, UPV/EHU Science Park, Leioa, 48940, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, 48013, Spain
| | - Hanna Engelke
- Department of Chemistry and Center for NanoScience (CeNS), LMU Munich, Munich, 81377, Germany
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Jani MS, Zou J, Veetil AT, Krishnan Y. A DNA-based fluorescent probe maps NOS3 activity with subcellular spatial resolution. Nat Chem Biol 2020; 16:660-666. [PMID: 32152543 DOI: 10.1038/s41589-020-0491-3] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 12/05/2019] [Accepted: 02/04/2020] [Indexed: 12/15/2022]
Abstract
Nitric oxide synthase 3 (NOS3) produces the gasotransmitter nitric oxide (NO), which drives critical cellular signaling pathways by S-nitrosylating target proteins. Endogenous NOS3 resides at two distinct subcellular locations: the plasma membrane and the trans-Golgi network (TGN). However, NO generation arising from the activities of both these pools of NOS3 and its relative contribution to physiology or disease is not yet resolvable. We describe a fluorescent DNA-based probe technology, NOckout, that can be targeted either to the plasma membrane or the TGN, where it can quantitatively map the activities of endogenous NOS3 at these locations in live cells. We found that, although NOS3 at the Golgi is tenfold less active than at the plasma membrane, its activity is essential for the structural integrity of the Golgi. The newfound ability to spatially map NOS3 activity provides a platform to discover selective regulators of the distinct pools of NOS3.
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Affiliation(s)
- Maulik S Jani
- Department of Chemistry, University of Chicago, Chicago, IL, USA.,Grossman Institute of Neuroscience, Quantitative Biology and Human Behavior, University of Chicago, Chicago, IL, USA
| | - Junyi Zou
- Department of Chemistry, University of Chicago, Chicago, IL, USA.,Grossman Institute of Neuroscience, Quantitative Biology and Human Behavior, University of Chicago, Chicago, IL, USA
| | - Aneesh T Veetil
- Department of Chemistry, University of Chicago, Chicago, IL, USA.,Grossman Institute of Neuroscience, Quantitative Biology and Human Behavior, University of Chicago, Chicago, IL, USA
| | - Yamuna Krishnan
- Department of Chemistry, University of Chicago, Chicago, IL, USA. .,Grossman Institute of Neuroscience, Quantitative Biology and Human Behavior, University of Chicago, Chicago, IL, USA.
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Steins A, Klaassen R, Jacobs I, Schabel MC, van Lier MGJTB, Ebbing EA, Hectors SJ, Tas SW, Maracle CX, Punt CJA, Siebes M, Bergman JJGHM, Medema JP, Wilmink JW, Mathot RAA, Strijkers GJ, Bijlsma MF, van Laarhoven HWM. Rapid stromal remodeling by short-term VEGFR2 inhibition increases chemotherapy delivery in esophagogastric adenocarcinoma. Mol Oncol 2020; 14:704-720. [PMID: 31733011 PMCID: PMC7138404 DOI: 10.1002/1878-0261.12599] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 10/30/2019] [Accepted: 11/13/2019] [Indexed: 12/11/2022] Open
Abstract
Anti-angiogenic agents combined with chemotherapy is an important strategy for the treatment of solid tumors. However, survival benefit is limited, urging the improvement of combination therapies. We aimed to clarify the effects of vascular endothelial growth factor receptor 2 (VEGFR2) targeting on hemodynamic function and penetration of drugs in esophagogastric adenocarcinoma (EAC). Patient-derived xenograft (PDX) models of EAC were subjected to long-term and short-term treatment with anti-VEGFR2 therapy followed by chemotherapy injection or multi-agent dynamic contrast-enhanced (DCE-) MRI and vascular casting. Long-term anti-VEGFR2-treated tumors showed a relatively lower flow and vessel density resulting in reduced chemotherapy uptake. On the contrary, short-term VEGFR2 targeting resulted in relatively higher flow, rapid vasodilation, and improved chemotherapy delivery. Assessment of the extracellular matrix (ECM) revealed that short-term anti-angiogenic treatment drastically remodels the tumor stroma by inducing nitric oxide synthesis and hyaluronan degradation, thereby dilating the vasculature and improving intratumoral chemotherapy delivery. These previously unrecognized beneficial effects could not be maintained by long-term VEGFR2 inhibition. As the identified mechanisms are targetable, they offer direct options to enhance the treatment efficacy of anti-angiogenic therapy combined with chemotherapy in EAC patients.
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Affiliation(s)
- Anne Steins
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, The Netherlands.,Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, The Netherlands.,Oncode Institute, Amsterdam UMC, University of Amsterdam, The Netherlands
| | - Remy Klaassen
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, The Netherlands.,Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, The Netherlands
| | - Igor Jacobs
- Department of Biomedical Engineering, Biomedical NMR, Eindhoven, The Netherlands.,Oncology Solutions, Philips Research, Eindhoven, The Netherlands
| | - Matthias C Schabel
- Advanced Imaging Research Center, Oregon Health and Science University, Portland, OR, USA
| | - Monique G J T B van Lier
- Department of Biomedical Engineering and Physics, Amsterdam UMC, University of Amsterdam, The Netherlands
| | - Eva A Ebbing
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, The Netherlands
| | - Stefanie J Hectors
- Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Sander W Tas
- Department of Rheumatology and Immunology, Amsterdam UMC, University of Amsterdam, The Netherlands.,Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam, The Netherlands
| | - Chrissta X Maracle
- Department of Rheumatology and Immunology, Amsterdam UMC, University of Amsterdam, The Netherlands.,Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam, The Netherlands
| | - Cornelis J A Punt
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, The Netherlands
| | - Maria Siebes
- Department of Biomedical Engineering and Physics, Amsterdam UMC, University of Amsterdam, The Netherlands
| | - Jacques J G H M Bergman
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, The Netherlands
| | - Jan Paul Medema
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, The Netherlands.,Oncode Institute, Amsterdam UMC, University of Amsterdam, The Netherlands
| | - Johanna W Wilmink
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, The Netherlands
| | - Ron A A Mathot
- Department of Hospital Pharmacy, Amsterdam UMC, University of Amsterdam, The Netherlands
| | - Gustav J Strijkers
- Department of Biomedical Engineering and Physics, Amsterdam UMC, University of Amsterdam, The Netherlands
| | - Maarten F Bijlsma
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, The Netherlands.,Oncode Institute, Amsterdam UMC, University of Amsterdam, The Netherlands
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49
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SETD3 acts as a prognostic marker in breast cancer patients and modulates the viability and invasion of breast cancer cells. Sci Rep 2020; 10:2262. [PMID: 32042016 PMCID: PMC7010743 DOI: 10.1038/s41598-020-59057-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Accepted: 01/21/2020] [Indexed: 12/14/2022] Open
Abstract
In several carcinomas, the SET Domain Containing 3, Actin Histidine Methyltransferase (SETD3) is associated with oncogenesis. However, there is little knowledge about the role of SETD3 in the progression and prognosis of breast cancer. In this study, we first analyzed the prognostic value of SETD3 in breast cancer patients using the database of the public Kaplan-Meier plotter. Moreover, in vitro assays were performed to assess the role of SETD3 in the viability and capacity of invasion of human breast cancer cell lines. We observed that the high expression of SETD3 was associated with better relapse-free survival (RFS) of the whole collective of 3,951 patients, of Estrogen Receptor-positive, and of Luminal A-type breast cancer patients. However, in patients lacking expression of estrogen-, progesterone- and HER2-receptor, and those affected by a p53-mutation, SETD3 was associated with poor RFS. In vitro analysis showed that SETD3 siRNA depletion affects the viability of triple-negative cells as well as the cytoskeletal function and capacity of invasion of highly invasive MDA-MB-231 cells. Interestingly, SETD3 regulates the expression of other genes associated with cancer such as β-actin, FOXM1, FBXW7, Fascin, eNOS, and MMP-2. Our study suggests that SETD3 expression can act as a subtype-specific biomarker for breast cancer progression and prognosis.
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50
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Kamm A, Przychodzen P, Kuban-Jankowska A, Jacewicz D, Dabrowska AM, Nussberger S, Wozniak M, Gorska-Ponikowska M. Nitric oxide and its derivatives in the cancer battlefield. Nitric Oxide 2019; 93:102-114. [PMID: 31541733 DOI: 10.1016/j.niox.2019.09.005] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 08/06/2019] [Accepted: 09/16/2019] [Indexed: 12/14/2022]
Abstract
Elevated levels of reactive nitrogen species, alteration in redox balance and deregulated redox signaling are common hallmarks of cancer progression and chemoresistance. However, depending on the cellular context, distinct reactive nitrogen species are also hypothesized to mediate cytotoxic activity and are thus used in anticancer therapies. We present here the dual face of nitric oxide and its derivatives in cancer biology. Main derivatives of nitric oxide, such as nitrogen dioxide and peroxynitrite cause cell death by inducing protein and lipid peroxidation and/or DNA damage. Moreover, they control the activity of important protein players within the pro- and anti-apoptotic signaling pathways. Thus, the control of intracellular reactive nitrogen species may become a sophisticated tool in anticancer strategies.
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Affiliation(s)
- Anna Kamm
- Department of Medical Chemistry, Faculty of Medicine, Medical University of Gdansk, Gdansk, Poland
| | - Paulina Przychodzen
- Department of Medical Chemistry, Faculty of Medicine, Medical University of Gdansk, Gdansk, Poland
| | - Alicja Kuban-Jankowska
- Department of Medical Chemistry, Faculty of Medicine, Medical University of Gdansk, Gdansk, Poland
| | | | | | - Stephan Nussberger
- Department of Biophysics, Institute of Biomaterials and Biomolecular Systems, University of Stuttgart, Stuttgart, Germany
| | - Michal Wozniak
- Department of Medical Chemistry, Faculty of Medicine, Medical University of Gdansk, Gdansk, Poland
| | - Magdalena Gorska-Ponikowska
- Department of Medical Chemistry, Faculty of Medicine, Medical University of Gdansk, Gdansk, Poland; Department of Biophysics, Institute of Biomaterials and Biomolecular Systems, University of Stuttgart, Stuttgart, Germany; Euro-Mediterranean Institute of Science and Technology, Palermo, Italy.
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