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Sailo BL, Garhwal A, Mishra A, Hegde M, Vishwa R, Girisa S, Abbas M, Alqahtani MS, Abdulhammed A, Sethi G, Kempson I, Kunnumakkara AB. Potential of capsaicin as a combinatorial agent to overcome chemoresistance and to improve outcomes of cancer therapy. Biochem Pharmacol 2025; 236:116828. [PMID: 40023449 DOI: 10.1016/j.bcp.2025.116828] [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: 11/22/2024] [Revised: 02/10/2025] [Accepted: 02/24/2025] [Indexed: 03/04/2025]
Abstract
Capsaicin (CAPS), a bioactive alkaloid derived from chili peppers, has garnered significant interest for its potential role as a combinatorial and chemosensitizing agent in cancer therapy. Numerous preclinical studies have demonstrated that CAPS enhanced the efficacy of various anticancer agents by promoting apoptosis, modulating autophagy and inhibiting angiogenesis, tumor growth, and metastasis. Additionally, CAPS modulated critical regulators of chemoresistance, such as P-glycoprotein (P-gp), extracellular signal-regulated kinase (ERK), nuclear factor-kappa B (NF-κB) pathway, and signal transducer and activator of transcription 3 (STAT3) pathway, thereby contributing to the reversal of multidrug resistance (MDR). Moreover, when administered in combination with chemotherapeutic agents, CAPS has been shown to improve treatment efficacy at lower drug concentrations. Given its multitargeted mechanism of action, CAPS represents a promising adjunct to conventional cancer therapies. However, due to its lipophilic nature, the development of optimized formulation strategies is essential to enhance its bioavailability and ensure consistent therapeutic outcomes. In conclusion, CAPS holds significant potential as a combinatorial and chemosensitizing agent, helping to overcome chemoresistance and enhance treatment outcomes across various malignancies. These promising findings warrant further preclinical and clinical investigations.
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Affiliation(s)
- Bethsebie Lalduhsaki Sailo
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam 781039, India
| | - Anushka Garhwal
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam 781039, India
| | - Anamika Mishra
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam 781039, India
| | - Mangala Hegde
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam 781039, India
| | - Ravichandran Vishwa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam 781039, India
| | - Sosmitha Girisa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam 781039, India
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, 61421 Abha, Saudi Arabia
| | - Mohammed S Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, 61421 Abha, Saudi Arabia; BioImaging Unit, Space Research Centre, Michael Atiyah Building, University of Leicester, Leicester LE1 7RH, UK
| | - Ayman Abdulhammed
- Department of Biochemistry and Hormone, King Fahad Central Hospital, Gizan 82666, Saudi Arabia
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117600, Singapore; NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117699, Singapore.
| | - Ivan Kempson
- Future Industries Institute, University of South Australia, Mawson Lakes, South Australia 5095, Australia.
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam 781039, India.
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Sailo BL, Chauhan S, Hegde M, Girisa S, Alqahtani MS, Abbas M, Goel A, Sethi G, Kunnumakkara AB. Therapeutic potential of tocotrienols as chemosensitizers in cancer therapy. Phytother Res 2025; 39:1694-1720. [PMID: 38353331 DOI: 10.1002/ptr.8131] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 12/29/2023] [Accepted: 01/15/2024] [Indexed: 04/23/2025]
Abstract
Chemoresistance is the adaptation of cancer cells against therapeutic agents. When exhibited by cancer cells, chemoresistance helps them to avoid apoptosis, cause relapse, and metastasize, making it challenging for chemotherapeutic agents to treat cancer. Various strategies like dosage modification of drugs, nanoparticle-based delivery of chemotherapeutics, antibody-drug conjugates, and so on are being used to target and reverse chemoresistance, one among such is combination therapy. It uses the combination of two or more therapeutic agents to reverse multidrug resistance and improve the effects of chemotherapy. Phytochemicals are known to exhibit chemosensitizing properties and are found to be effective against various cancers. Tocotrienols (T3) and tocopherols (T) are natural bioactive analogs of vitamin E, which exhibit important medicinal value and potential curative properties apart from serving as an antioxidant and nutrient supplement. Notably, T3 exhibits a variety of pharmacological activities like anticancer, anti-inflammatory, antiproliferative, and so on. The chemosensitizing property of tocotrienol is exhibited by modulating several signaling pathways and molecular targets involved in cancer cell survival, proliferation, invasion, migration, and metastasis like NF-κB, STATs, Akt/mTOR, Bax/Bcl-2, Wnt/β-catenin, and many more. T3 sensitizes cancer cells to chemotherapeutic drugs including cisplatin, doxorubicin, and paclitaxel increasing drug concentration and cytotoxicity. Discussed herewith are the chemosensitizing properties of tocotrienols on various cancer cell types when combined with various drugs and biological molecules.
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Affiliation(s)
- Bethsebie Lalduhsaki Sailo
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, India
| | - Suravi Chauhan
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, India
| | - Mangala Hegde
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, India
| | - Sosmitha Girisa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, India
| | - Mohammed S Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, Abha, Saudi Arabia
| | - Arul Goel
- University of California Santa Barbara, Santa Barbara, California, USA
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, India
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Ding Y, Bai Y, Chen T, Chen S, Feng W, Ma S, Zhang Q. Disruption of the sorcin‒PAX5 protein‒protein interaction induces ferroptosis by promoting the FBXL12-mediated ubiquitination of ALDH1A1 in pancreatic cancer. J Hematol Oncol 2025; 18:27. [PMID: 40055736 PMCID: PMC11887212 DOI: 10.1186/s13045-025-01680-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 02/24/2025] [Indexed: 05/13/2025] Open
Abstract
BACKGROUND Pancreatic cancer is one of the most malignant cancers, and limited therapeutic options are available. The induction of ferroptosis is considered to be a novel, promising strategy that has potential in cancer treatment, and ferroptosis inducers may be new options for eradicating malignant cancers that are resistant to traditional drugs. The exact mechanism underlying the function of sorcin in the initiation and progression of pancreatic cancer remains unclear. METHODS The expression of sorcin in cancer tissues was assessed by analyzing TCGA, GEO and immunohistochemical staining data, and the function of sorcin in the induction of ferroptosis in pancreatic cancer cells was investigated. The mechanism underlying the function of sorcin was revealed through proteomics, co-IP, Ch-IP, and luciferase assays. Natural product screening was subsequently performed to screen for products that interact with sorcin to identify new ferroptosis inducers. RESULTS We first showed that sorcin expression was positively correlated with the survival and tumor stages of patients with pancreatic cancer, and we revealed that sorcin inhibited ferroptosis through its noncalcium binding function. Furthermore, we discovered that sorcin interacted with PAX5 in the cytoplasm and inhibited PAX5 nuclear translocation, which in turn decreased FBXL12 protein expression and then reduced ALDH1A1 ubiquitination, thus inhibiting ferroptosis. Moreover, an in-house natural product screen revealed that celastrol inhibited the interaction of sorcin and PAX5 by directly binding to the Cys194 residue of the sorcin protein; disruption of the sorcin-PAX5 interaction promoted the nuclear translocation of PAX5, induced the expression of FBXL12, increased the ubiquitylation of ALDH1A1, and eventually induced ferroptosis in pancreatic cancer cells. CONCLUSION In this study, we revealed the mechanism of action of sorcin, which is a druggable target for inducing ferroptosis, we identified celastrol as a novel agent that induces ferroptosis, and we showed that disrupting the sorcin-PAX5 interaction is a promising therapeutic strategy for treating pancreatic cancer.
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Affiliation(s)
- Yahui Ding
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin, 300353, People's Republic of China
- College of Chemistry, Nankai University, 94 Weijin Road, Tianjin, 300071, People's Republic of China
| | - Yongping Bai
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin, 300353, People's Republic of China
| | - Tianyang Chen
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin, 300353, People's Republic of China
| | - Sisi Chen
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin, 300353, People's Republic of China
| | - Wanjing Feng
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin, 300353, People's Republic of China
| | - Shuoqian Ma
- College of Chemistry, Nankai University, 94 Weijin Road, Tianjin, 300071, People's Republic of China
| | - Quan Zhang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin, 300353, People's Republic of China.
- College of Pharmacy, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin, 300353, People's Republic of China.
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Kumar A, Yap KCH, BharathwajChetty B, Lyu J, Hegde M, Abbas M, Alqahtani MS, Khadlikar S, Zarrabi A, Khosravi A, Kumar AP, Kunnumakkara AB. Regulating the regulators: long non-coding RNAs as autophagic controllers in chronic disease management. J Biomed Sci 2024; 31:105. [PMID: 39716252 DOI: 10.1186/s12929-024-01092-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 10/23/2024] [Indexed: 12/25/2024] Open
Abstract
The increasing prevalence of chronic diseases and their associated morbidities demands a deeper understanding of underlying mechanism and causative factors, with the hope of developing novel therapeutic strategies. Autophagy, a conserved biological process, involves the degradation of damaged organelles or protein aggregates to maintain cellular homeostasis. Disruption of this crucial process leads to increased genomic instability, accumulation of reactive oxygen species (ROS), decreased mitochondrial functions, and suppression of ubiquitination, leading to overall decline in quality of intracellular components. Such deregulation has been implicated in a wide range of pathological conditions such as cancer, cardiovascular, inflammatory, and neurological disorders. This review explores the role of long non-coding RNAs (lncRNAs) as modulators of transcriptional and post-transcriptional gene expression, regulating diverse physiological process like proliferation, development, immunity, and metabolism. Moreover, lncRNAs are known to sequester autophagy related microRNAs by functioning as competing endogenous RNAs (ceRNAs), thereby regulating this vital process. In the present review, we delineate the multitiered regulation of lncRNAs in the autophagic dysfunction of various pathological diseases. Moreover, by highlighting recent findings on the modulation of lncRNAs in different stages of autophagy, and the emerging clinical landscape that recognizes lncRNAs in disease diagnosis and therapy, this review highlights the potential of lncRNAs as biomarkers and therapeutic targets in clinical settings of different stages of autophagic process by regulating ATG and its target genes. This focus on lncRNAs could lead to breakthroughs in personalized medicine, offering new avenues for diagnosis and treatment of complex diseases.
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Affiliation(s)
- Aviral Kumar
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam, 781039, India
| | - Kenneth Chun-Hong Yap
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Bandari BharathwajChetty
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam, 781039, India
| | - Juncheng Lyu
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Mangala Hegde
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam, 781039, India
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, 61421, Abha, Saudi Arabia
| | - Mohammed S Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, 61421, Abha, Saudi Arabia
- BioImaging Unit, Space Research Centre, Michael Atiyah Building, University of Leicester, Leicester, LE1 7RH, UK
| | - Soham Khadlikar
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam, 781039, India
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering & Natural Sciences, Istinye University, 34396, Istanbul, Türkiye
- Department of Research Analytics, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, 600 077, India
- Graduate School of Biotechnology and Bioengineering, Yuan Ze University, Taoyuan, 320315, Taiwan
| | - Arezoo Khosravi
- Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, Istanbul Okan University, 34959, Istanbul, Türkiye
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore.
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam, 781039, India.
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Ghosh S, Sharma A, Kumar RS, Nasare V. Sorcin: mechanisms of action in cancer hallmarks, drug resistance and opportunities in therapeutics. Med Oncol 2024; 42:29. [PMID: 39673665 DOI: 10.1007/s12032-024-02580-6] [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: 10/12/2024] [Accepted: 12/03/2024] [Indexed: 12/16/2024]
Abstract
Soluble resistant related calcium binding protein (Sorcin) plays an important role in tumor progression, angiogenesis, metastasis, and multidrug resistance. Differential expression of Sorcin across different cancers significantly correlates with key clinicopathological characteristics and survival outcomes, underscoring its potential as a prognostic marker. Its involvement in drug-resistant cancers further advert Sorcin as a promising therapeutic target. This review summarizes the mechanistic role of Sorcin in cancer, its contribution to drug resistance, clinical relevance, and the current and emerging therapeutic approaches aimed at translating Sorcin-targeted therapies into clinical practice.
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Affiliation(s)
- Sushmita Ghosh
- Department of Pathology and Cancer Screening, Chittaranjan National Cancer Institute, Kolkata, India
- Department of Life Science and Biotechnology, Jadavpur University, Kolkata, India
| | - Arpana Sharma
- Department of Pathology and Cancer Screening, Chittaranjan National Cancer Institute, Kolkata, India
| | - R Suresh Kumar
- Molecular Biology Division, National Institute of Cancer Prevention and Research, ICMR, Noida, Delhi, India
| | - Vilas Nasare
- Department of Pathology and Cancer Screening, Chittaranjan National Cancer Institute, Kolkata, India.
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Bano S, Majumder A, Srivastava A, Nayak KB. Deciphering the Potentials of Cardamom in Cancer Prevention and Therapy: From Kitchen to Clinic. Biomolecules 2024; 14:1166. [PMID: 39334932 PMCID: PMC11430645 DOI: 10.3390/biom14091166] [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: 07/24/2024] [Revised: 08/31/2024] [Accepted: 09/13/2024] [Indexed: 09/30/2024] Open
Abstract
Cardamom (cardamum) is a spice produced from the seeds of several Elettaria and Amomum plants of the Zingiberaceae family. Cardamom has been demonstrated to offer numerous benefits, including its antioxidant, antimicrobial, anti-inflammatory, and other metabolic (anti-diabetic) properties, and its potential to reduce cancer risk. Recently, researchers have extracted and tested multiple phytochemicals from cardamom to assess their potential effectiveness against various types of human malignancy. These studies have indicated that cardamom can help overcome drug resistance to standard chemotherapy and protect against chemotherapy-induced toxicity due to its scavenging properties. Furthermore, chemical compounds in cardamom, including limonene, cymene, pinene, linalool, borneol, cardamonin, indole-3-carbinol, and diindolylmethane, primarily target the programmed cell death lignin-1 gene, which is more prevalent in cancer cells than in healthy cells. This review provides the medicinal properties and pharmacological uses of cardamom, its cellular effects, and potential therapeutic uses in cancer prevention and treatment, as well as its use in reducing drug resistance and improving the overall health of cancer patients. Based on previous preclinical studies, cardamom shows significant potential as an anti-cancer agent, but further exploration for clinical use is warranted due to its diverse mechanisms of action.
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Affiliation(s)
- Shabana Bano
- Department of Medicine, University of California, San Francisco, CA 94158, USA
| | - Avisek Majumder
- Department of Medicine, University of California, San Francisco, CA 94158, USA
| | - Ayush Srivastava
- Department of Neurological Surgery, University of California, San Francisco, CA 94158, USA
| | - Kasturi Bala Nayak
- Quantitative Biosciences Institute, Department of Medicine, University of California, San Francisco, CA 94158, USA
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Sajeev A, Sailo B, Unnikrishnan J, Talukdar A, Alqahtani MS, Abbas M, Alqahtani A, Sethi G, Kunnumakkara AB. Unlocking the potential of Berberine: Advancing cancer therapy through chemosensitization and combination treatments. Cancer Lett 2024; 597:217019. [PMID: 38849013 DOI: 10.1016/j.canlet.2024.217019] [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: 03/21/2024] [Revised: 05/07/2024] [Accepted: 06/02/2024] [Indexed: 06/09/2024]
Abstract
Despite considerable progress in cancer treatment options, resistance to chemotherapeutic drugs remains a significant challenge. This review focuses on Berberine (BBR), an isoquinoline alkaloid found in various medicinal plants, which has garnered attention in the field of oncology for its anticancer potential either alone or in combination with other compounds and its ability to modulate chemoresistance, acting as a natural chemosensitizer. BBR's ability to modulate chemoresistance is attributed to its diverse mechanisms of action, including inducing DNA breaks, inhibition of drug efflux pumps, modulation of apoptosis and necroptosis, downregulating multidrug resistance genes, enhancing immune response, suppressing angiogenesis and targeting multiple pathways within cancer cells, including protein kinase B/mammalian target of rapamycin (Akt/mTOR), epidermal growth factor receptor (EGFR), mitogen-activated protein kinase (MAPK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), poly(ADP-ribose) polymerase (PARP1), janus kinase/signal transducers and activators of transcription (JAK-STAT), Wnt/β-catenin etc. Moreover, BBR, in combination with other compounds, also offers a promising approach to cancer therapy, enforcing its broad-spectrum anticancer effects. Therefore, this review aims to elucidate the intricate mechanism of action of BBR in combinatorial therapy as a potential chemosensitizer to increase the efficiency of several drugs, including cisplatin, doxorubicin, lapatinib, tamoxifen, irinotecan, niraparib, etc. in various cancers. Additionally, this review briefly covers the origin and biological activities of BBR, exploring the specific actions underlying its anticancer effects. Further, pharmacokinetic properties of BBR are also discussed, providing insight into its therapeutic potential and optimization of its use in cancer treatment.
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Affiliation(s)
- Anjana Sajeev
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam, 781039, India
| | - Bethsebie Sailo
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam, 781039, India
| | - Jyothsna Unnikrishnan
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam, 781039, India
| | - Ayesha Talukdar
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam, 781039, India
| | - Mohammed S Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha, 61421, Saudi Arabia; BioImaging Unit, Space Research Centre, Michael Atiyah Building, University of Leicester, Leicester, LE1 7RH, United Kingdom
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, Abha, 61421, Saudi Arabia
| | - Athba Alqahtani
- Research Centre, King Fahad Medical City. P.O. Box: 59046, Riyadh, 11525, Saudi Arabia
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, 117600, Singapore; NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, 117599, Singapore.
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam, 781039, India.
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8
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Li Y, Tian M, Pires Sanches JG, Zhang Q, Hou L, Zhang J. Sorcin Inhibits Mitochondrial Apoptosis by Interacting with STAT3 via NF-κB Pathway. Int J Mol Sci 2024; 25:7206. [PMID: 39000312 PMCID: PMC11241191 DOI: 10.3390/ijms25137206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 06/13/2024] [Accepted: 06/23/2024] [Indexed: 07/16/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a common tumor. Our group has previously reported that sorcin (SRI) plays an important role in the progression and prognosis of HCC. This study aims to explore the mechanism of SRI inhibiting the mitochondrial apoptosis. Bioinformatics analysis, co-IP and immunofluorescence were used to analyze the relationship between SRI and STAT3. MMP and Hoechst staining were performed to detect the effect of SRI on cell apoptosis. The expression of apoptosis-related proteins and NF-κB signaling pathway were examined by Western blot and immunohistochemistry when SRI overexpression or underexpression in vivo and in vitro were found. Moreover, inhibitors were used to further explore the molecular mechanism. Overexpression of SRI inhibited cell apoptosis, which was attenuated by SRI knockdown in vitro and in vivo. Moreover, we identified that STAT3 is an SRI-interacting protein. Mechanistically, SRI interacts with STAT3 and then activates the NF-κB signaling pathway in vitro and in vivo. SRI interacting with STAT3 inhibits apoptosis by the NF-κB pathway and further contributes to the proliferation in HCC, which offers a novel clue and a new potential therapeutic target for HCC.
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Affiliation(s)
- Yizi Li
- Department of Pathology and Forensic Medicine, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Manlin Tian
- Department of Pathology and Forensic Medicine, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Jaceline Gislaine Pires Sanches
- Department of Pathology and Forensic Medicine, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Qingqing Zhang
- Department of Pathology and Forensic Medicine, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Li Hou
- Department of Pathology and Forensic Medicine, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Jun Zhang
- Department of Pathology and Forensic Medicine, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China
- State Key Laboratory of Oncology in South China, Sun Yat-sen University, Guangzhou 510275, China
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Kumar A, Sarangi Y, Gupta A, Sharma A. Gallbladder cancer: Progress in the Indian subcontinent. World J Clin Oncol 2024; 15:695-716. [PMID: 38946839 PMCID: PMC11212610 DOI: 10.5306/wjco.v15.i6.695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 04/25/2024] [Accepted: 05/15/2024] [Indexed: 06/24/2024] Open
Abstract
Gallbladder cancer (GBC) is one of the commonest biliary malignancies seen in India, Argentina, and Japan. The disease has dismal outcome as it is detected quite late due to nonspecific symptoms and signs. Early detection is the only way to improve the outcome. There have been several advances in basic as well as clinical research in the hepatobiliary and pancreatic diseases in the West and other developed countries but not enough has been done in GBC. Therefore, it is important and the responsibility of the countries with high burden of GBC to find solutions to the many unanswered questions like etiopathogenesis, early diagnosis, treatment, and prognostication. As India being one of the largest hubs for GBC in the world, it is important to know how the country has progressed on GBC. In this review, we will discuss the outcome of the publications from India highlighting the work and the developments taken place in past several decades both in basic and clinical research.
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Affiliation(s)
- Ashok Kumar
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Yajnadatta Sarangi
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Annapurna Gupta
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Aarti Sharma
- Division of Haematology, Mayo Clinic Arizona, Phoenix, AZ 85054, United States
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Kumar A, BharathwajChetty B, Manickasamy MK, Unnikrishnan J, Alqahtani MS, Abbas M, Almubarak HA, Sethi G, Kunnumakkara AB. Natural compounds targeting YAP/TAZ axis in cancer: Current state of art and challenges. Pharmacol Res 2024; 203:107167. [PMID: 38599470 DOI: 10.1016/j.phrs.2024.107167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 04/01/2024] [Accepted: 04/02/2024] [Indexed: 04/12/2024]
Abstract
Cancer has become a burgeoning global healthcare concern marked by its exponential growth and significant economic ramifications. Though advancements in the treatment modalities have increased the overall survival and quality of life, there are no definite treatments for the advanced stages of this malady. Hence, understanding the diseases etiologies and the underlying molecular complexities, will usher in the development of innovative therapeutics. Recently, YAP/TAZ transcriptional regulation has been of immense interest due to their role in development, tissue homeostasis and oncogenic transformations. YAP/TAZ axis functions as coactivators within the Hippo signaling cascade, exerting pivotal influence on processes such as proliferation, regeneration, development, and tissue renewal. In cancer, YAP is overexpressed in multiple tumor types and is associated with cancer stem cell attributes, chemoresistance, and metastasis. Activation of YAP/TAZ mirrors the cellular "social" behavior, encompassing factors such as cell adhesion and the mechanical signals transmitted to the cell from tissue structure and the surrounding extracellular matrix. Therefore, it presents a significant vulnerability in the clogs of tumors that could provide a wide window of therapeutic effectiveness. Natural compounds have been utilized extensively as successful interventions in the management of diverse chronic illnesses, including cancer. Owing to their capacity to influence multiple genes and pathways, natural compounds exhibit significant potential either as adjuvant therapy or in combination with conventional treatment options. In this review, we delineate the signaling nexus of YAP/TAZ axis, and present natural compounds as an alternate strategy to target cancer.
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Affiliation(s)
- Aviral Kumar
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam 781039, India
| | - Bandari BharathwajChetty
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam 781039, India
| | - Mukesh Kumar Manickasamy
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam 781039, India
| | - Jyothsna Unnikrishnan
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam 781039, India
| | - Mohammed S Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha 61421, Saudi Arabia; BioImaging Unit, Space Research Centre, Michael Atiyah Building, University of Leicester, Leicester LE1 7RH, United Kingdom
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, Abha 61421, Saudi Arabia
| | - Hassan Ali Almubarak
- Division of Radiology, Department of Medicine, College of Medicine and Surgery, King Khalid University, Abha 61421, Saudi Arabia
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117600, Singapore; NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, 117699, Singapore.
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam 781039, India.
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11
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Pasternack H, Polzer M, Gemoll T, Kümpers C, Sauer T, Lazar-Karsten P, Hinrichs S, Bohnet S, Perner S, Dressler FF, Kirfel J. Proteomic analyses identify HK1 and ATP5A to be overexpressed in distant metastases of lung adenocarcinomas compared to matched primary tumors. Sci Rep 2023; 13:20948. [PMID: 38016997 PMCID: PMC10684588 DOI: 10.1038/s41598-023-47767-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 11/17/2023] [Indexed: 11/30/2023] Open
Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide with lung adenocarcinoma (LUAD) being the most common type. Genomic studies of LUAD have advanced our understanding of its tumor biology and accelerated targeted therapy. However, the proteomic characteristics of LUAD are still insufficiently explored. The prognosis for lung cancer patients is still mostly determined by the stage of disease at the time of diagnosis. Focusing on late-stage metastatic LUAD with poor prognosis, we compared the proteomic profiles of primary tumors and matched distant metastases to identify relevant and potentially druggable differences. We performed high-performance liquid chromatography (HPLC) and electrospray ionization tandem mass spectrometry (ESI-MS/MS) on a total of 38 FFPE (formalin-fixed and paraffin-embedded) samples. Using differential expression analysis and unsupervised clustering we identified several proteins that were differentially regulated in metastases compared to matched primary tumors. Selected proteins (HK1, ATP5A, SRI and ARHGDIB) were subjected to validation by immunoblotting. Thereby, significant differential expression could be confirmed for HK1 and ATP5A, both upregulated in metastases compared to matched primary tumors. Our findings give a better understanding of tumor progression and metastatic spreads in LUAD but also demonstrate considerable inter-individual heterogeneity on the proteomic level.
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Affiliation(s)
- Helen Pasternack
- Institute of Pathology, University Hospital Schleswig-Holstein, Campus Luebeck, Luebeck, Germany
| | - Mirjam Polzer
- Institute of Pathology, University Hospital Schleswig-Holstein, Campus Luebeck, Luebeck, Germany
- Institute of Legal Medicine, University Hospital Münster, Münster, Germany
| | - Timo Gemoll
- Section for Translational Surgical Oncology and Biobanking, Department of Surgery, University Hospital Schleswig-Holstein, Campus Luebeck, Luebeck, Germany
| | - Christiane Kümpers
- Institute of Pathology, University Hospital Schleswig-Holstein, Campus Luebeck, Luebeck, Germany
| | - Thorben Sauer
- Section for Translational Surgical Oncology and Biobanking, Department of Surgery, University Hospital Schleswig-Holstein, Campus Luebeck, Luebeck, Germany
| | - Pamela Lazar-Karsten
- Institute of Pathology, University Hospital Schleswig-Holstein, Campus Luebeck, Luebeck, Germany
| | - Sofie Hinrichs
- Institute of Pathology, University Hospital Schleswig-Holstein, Campus Luebeck, Luebeck, Germany
| | - Sabine Bohnet
- Department of Pulmonology, University Hospital Schleswig-Holstein, Campus Luebeck, Luebeck, Germany
| | - Sven Perner
- Institute of Pathology, University Hospital Schleswig-Holstein, Campus Luebeck, Luebeck, Germany
- Pathology, Research Center Borstel, Leibniz Lung Center, Borstel, Germany
- Institute of Pathology and Hematopathology, Hamburg, Germany
| | - Franz Friedrich Dressler
- Institute of Pathology, University Hospital Schleswig-Holstein, Campus Luebeck, Luebeck, Germany
- Institute of Pathology, Charité -Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Jutta Kirfel
- Institute of Pathology, University Hospital Schleswig-Holstein, Campus Luebeck, Luebeck, Germany.
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12
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Sajeev A, BharathwajChetty B, Vishwa R, Alqahtani MS, Abbas M, Sethi G, Kunnumakkara AB. Crosstalk between Non-Coding RNAs and Wnt/β-Catenin Signaling in Head and Neck Cancer: Identification of Novel Biomarkers and Therapeutic Agents. Noncoding RNA 2023; 9:63. [PMID: 37888209 PMCID: PMC10610319 DOI: 10.3390/ncrna9050063] [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: 08/21/2023] [Revised: 09/25/2023] [Accepted: 10/08/2023] [Indexed: 10/28/2023] Open
Abstract
Head and neck cancers (HNC) encompass a broad spectrum of neoplastic disorders characterized by significant morbidity and mortality. While contemporary therapeutic interventions offer promise, challenges persist due to tumor recurrence and metastasis. Central to HNC pathogenesis is the aberration in numerous signaling cascades. Prominently, the Wnt signaling pathway has been critically implicated in the etiology of HNC, as supported by a plethora of research. Equally important, variations in the expression of non-coding RNAs (ncRNAs) have been identified to modulate key cancer phenotypes such as cellular proliferation, epithelial-mesenchymal transition, metastatic potential, recurrence, and treatment resistance. This review aims to provide an exhaustive insight into the multifaceted influence of ncRNAs on HNC, with specific emphasis on their interactions with the Wnt/β-catenin (WBC) signaling axis. We further delineate the effect of ncRNAs in either exacerbating or attenuating HNC progression via interference with WBC signaling. An overview of the mechanisms underlying the interplay between ncRNAs and WBC signaling is also presented. In addition, we described the potential of various ncRNAs in enhancing the efficacy of chemotherapeutic and radiotherapeutic modalities. In summary, this assessment posits the potential of ncRNAs as therapeutic agents targeting the WBC signaling pathway in HNC management.
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Affiliation(s)
- Anjana Sajeev
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati 781039, Assam, India; (A.S.); (B.B.); (R.V.)
| | - Bandari BharathwajChetty
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati 781039, Assam, India; (A.S.); (B.B.); (R.V.)
| | - Ravichandran Vishwa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati 781039, Assam, India; (A.S.); (B.B.); (R.V.)
| | - Mohammed S. Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha 61421, Saudi Arabia;
- BioImaging Unit, Space Research Centre, Michael Atiyah Building, University of Leicester, Leicester LE1 7RH, UK
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, Abha 61421, Saudi Arabia;
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
| | - Ajaikumar B. Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati 781039, Assam, India; (A.S.); (B.B.); (R.V.)
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13
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Li Z, Yang Z, Zhu Y, Fu C, Li N, Peng F. Sorcin regulate pyroptosis by interacting with NLRP3 inflammasomes to facilitate the progression of hepatocellular carcinoma. Cell Death Dis 2023; 14:678. [PMID: 37833249 PMCID: PMC10575890 DOI: 10.1038/s41419-023-06096-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 08/09/2023] [Accepted: 08/21/2023] [Indexed: 10/15/2023]
Abstract
A high recurrence rate and easy metastasis are two prominent clinical features of hepatocellular carcinoma (HCC), which is also the most common cause of cancer-related death. However, the molecular pathogenesis of HCC remains unclear. Soluble resistance-related calcium-binding protein (Sorcin) is highly expressed in a variety of tumor cell lines and multidrug-resistant cell lines and participates in the malignant progression of tumors by regulating apoptosis. Pyroptosis is also a form of programmed cell death that plays a crucial role in exerting tumor suppression function and evoking anti-tumor immune responses. However, there is no consensus that Sorcin promotes HCC progression by regulating pyroptosis. Our study manifested that Sorcin was considerably upregulated, whereas pyroptosis-associated proteins were significantly decreased in HCC tissues and cells. Sorcin silencing attenuated the proliferation, migration, and invasion of HCC cells. Knockdown of Sorcin activates pyroptosis, and overexpression of Sorcin inhibits pyroptosis, yet has no significant effect on apoptosis, ferroptosis, and autophagy in HCC cells. Furthermore, coimmunoprecipitation and immunofluorescence assays revealed that Sorcin interacted with NLRP3 inflammasome to regulate pyroptosis in HCC cells. Then, the NLRP3 inhibitor MCC950 inhibited the activation of Sorcin knockdown-induced pyroptosis and reversed the effect of Sorcin silencing-induced weakening of malignant biological behavior in HCC. Similarly, suppression of Caspase-1 reversed the inhibitory effect of Sorcin knockdown on the malignant progression of HCC via knockdown of Caspase-1 or the inhibitor VX765. Consistent with the in vitro results, the nude mouse experiment showed that Sorcin knockdown inhibited the growth of HCC by activating pyroptosis, while Caspase-1 knockdown partially restored the growth inhibition caused by Sorcin knockdown. Collectively, high Sorcin expression in HCC negatively regulates pyroptosis by interacting with the NLRP3 inflammasome to promote HCC proliferation, migration, and invasion. The results of this study provide a scientific basis for Sorcin as a new biomarker and potential therapeutic target for HCC.
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Affiliation(s)
- Zhenfen Li
- Department of Blood Transfusion, Clinical Transfusion Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Health Commission (NHC) Key Laboratory of Cancer Proteomics, Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Ziyue Yang
- Department of Blood Transfusion, Clinical Transfusion Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Health Commission (NHC) Key Laboratory of Cancer Proteomics, Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Yuanyuan Zhu
- Department of Blood Transfusion, Clinical Transfusion Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Health Commission (NHC) Key Laboratory of Cancer Proteomics, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Chunmeng Fu
- Department of Blood Transfusion, Clinical Transfusion Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Health Commission (NHC) Key Laboratory of Cancer Proteomics, Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Ning Li
- Department of Blood Transfusion, Clinical Transfusion Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Fang Peng
- Department of Blood Transfusion, Clinical Transfusion Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China.
- National Health Commission (NHC) Key Laboratory of Cancer Proteomics, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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14
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Tanwar S, Qais FA, Naaz F, Rashid N, Ahmad F, Ur Rehman S. Identification of a novel Sorcin isoform with a different C-terminal but intact dimerization property. Sci Rep 2023; 13:15262. [PMID: 37709787 PMCID: PMC10502117 DOI: 10.1038/s41598-023-40913-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 08/18/2023] [Indexed: 09/16/2023] Open
Abstract
Sorcin (Sri), a member of penta EF-hand protein family plays a diverse role in maintaining calcium homeostasis, cell cycle and vesicular trafficking. Sri is highly conserved amongst mammals and consists of N-terminal glycine rich domain and C-terminal calcium binding domain that mediates its dimerization and interacts with different compounds. In the present study, with the help of combination of computational and molecular biology techniques, we have identified a novel isoform (Sri-N) in mouse which differs only in the C-terminal domain with that of Sri reported earlier. The novel isoform contains a new last exon that is different from the one present in the reported transcript (Sri). The presence of the novel isoform was further validated in different tissues by RT-PCR and DNA sequencing. The transcript was conceptually translated and subjected to in-silico analysis using different bioinformatics tools. The novel transcript variant encodes for a longer protein isoform without any change in the sub-cellular localization as predicted by PSORT-II online tool. Molecular modelling was performed to compare the structural changes in Sri-N and Sri isoforms. The structural characterization of the novel isoform using MD simulation depicted its overall stability under the physiological conditions. The molecular docking of proteins with various chemotherapeutic drugs revealed that their binding affinity is more for Sri-N as compared to that for the previously reported transcript Sri.
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Affiliation(s)
- Supriya Tanwar
- Department of Biochemistry, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Faizan Abul Qais
- Department of Agricultural Microbiology, Faculty of Agricultural Sciences, Aligarh Muslim University, Aligarh, UP, 202002, India
| | - Farheen Naaz
- Department of Biochemistry, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Naira Rashid
- Department of Biochemistry, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Faizan Ahmad
- Department of Biochemistry, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Sayeed Ur Rehman
- Department of Biochemistry, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India.
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15
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Jain V, Akhtar J, Priya R, Sakhuja P, Goyal S, Agarwal AK, Ghose V, Polisetty RV, Sirdeshmukh R, Siraj F, Gautam P. Tissue proteome analysis for profiling proteins associated with lymph node metastasis in gallbladder cancer. BMC Cancer 2023; 23:402. [PMID: 37142981 PMCID: PMC10161508 DOI: 10.1186/s12885-023-10840-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 04/12/2023] [Indexed: 05/06/2023] Open
Abstract
Lymph node (LN) metastasis is the earliest sign of metastatic spread and an established predictor of poor outcome in gallbladder cancer (GBC). Patients with LN positive GBC have a significantly worse survival (median survival- 7 months) than patients with LN negative disease (median survival- ~ 23 months) in spite of standard treatment which includes extended surgery followed by chemotherapy, radiotherapy and targeted therapy. This study aims at understanding the underlying molecular processes associated with LN metastasis in GBC. Here, we used iTRAQ-based quantitative proteomic analysis using tissue cohort comprising of primary tumor of LN negative GBC (n = 3), LN positive GBC (n = 4) and non-tumor controls (Gallstone disease, n = 4), to identify proteins associated with LN metastasis. A total of 58 differentially expressed proteins (DEPs) were found to be specifically associated with LN positive GBC based on the criteria of p value ≤ 0.05, fold change ≥ 2 and unique peptides ≥ 2. These include the cytoskeleton and associated proteins such as keratin, type II cytoskeletal 7 (KRT7), keratin type I cytoskeletal 19 (KRT19), vimentin (VIM), sorcin (SRI) and nuclear proteins such as nucleophosmin Isoform 1 (NPM1), heterogeneous nuclear ribonucleoproteins A2/B1 isoform X1 (HNRNPA2B1). Some of them are reported to be involved in promoting cell invasion and metastasis. Bioinformatic analysis of the deregulated proteins in LN positive GBC using STRING database identified 'neutrophil degranulation' and 'HIF1 activation' to be among the top deregulated pathways. Western blot and IHC analysis showed a significant overexpression of KRT7 and SRI in LN positive GBC in comparison to LN negative GBC. KRT7, SRI and other proteins may be further explored for their diagnostics and therapeutic applications in LN positive GBC.
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Affiliation(s)
- Vaishali Jain
- ICMR-National Institute of Pathology, Safdarjung Hospital Campus, New Delhi, 110029, India
- Manipal Academy of Higher Education (MAHE), Manipal, 576104, India
| | - Javed Akhtar
- ICMR-National Institute of Pathology, Safdarjung Hospital Campus, New Delhi, 110029, India
- Jamia Hamdard-Institute of Molecular Medicine, Jamia Hamdard, New Delhi, 110062, India
| | - Ratna Priya
- ICMR-National Institute of Pathology, Safdarjung Hospital Campus, New Delhi, 110029, India
- Jamia Hamdard-Institute of Molecular Medicine, Jamia Hamdard, New Delhi, 110062, India
| | - Puja Sakhuja
- Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, 110002, India.
| | - Surbhi Goyal
- Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, 110002, India
| | - Anil Kumar Agarwal
- Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, 110002, India
| | - Vivek Ghose
- Manipal Academy of Higher Education (MAHE), Manipal, 576104, India
- Institute of Bioinformatics, International Tech Park, Bangalore, 560066, India
| | - Ravindra Varma Polisetty
- Department of Biochemistry, Sri Venkateswara College, University of Delhi, New Delhi, 110021, India
| | - Ravi Sirdeshmukh
- Manipal Academy of Higher Education (MAHE), Manipal, 576104, India
- Institute of Bioinformatics, International Tech Park, Bangalore, 560066, India
| | - Fouzia Siraj
- ICMR-National Institute of Pathology, Safdarjung Hospital Campus, New Delhi, 110029, India
| | - Poonam Gautam
- ICMR-National Institute of Pathology, Safdarjung Hospital Campus, New Delhi, 110029, India.
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16
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Kunnumakkara AB, Hegde M, Parama D, Girisa S, Kumar A, Daimary UD, Garodia P, Yenisetti SC, Oommen OV, Aggarwal BB. Role of Turmeric and Curcumin in Prevention and Treatment of Chronic Diseases: Lessons Learned from Clinical Trials. ACS Pharmacol Transl Sci 2023; 6:447-518. [PMID: 37082752 PMCID: PMC10111629 DOI: 10.1021/acsptsci.2c00012] [Citation(s) in RCA: 54] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Indexed: 03/08/2023]
Abstract
Turmeric (Curcuma longa) has been used for thousands of years for the prevention and treatment of various chronic diseases. Curcumin is just one of >200 ingredients in turmeric. Almost 7000 scientific papers on turmeric and almost 20,000 on curcumin have been published in PubMed. Scientific reports based on cell culture or animal studies are often not reproducible in humans. Therefore, human clinical trials are the best indicators for the prevention and treatment of a disease using a given agent/drug. Herein, we conducted an extensive literature survey on PubMed and Scopus following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The keywords "turmeric and clinical trials" and "curcumin and clinical trials" were considered for data mining. A total of 148 references were found to be relevant for the key term "turmeric and clinical trials", of which 70 were common in both PubMed and Scopus, 44 were unique to PubMed, and 34 were unique to Scopus. Similarly, for the search term "curcumin and clinical trials", 440 references were found to be relevant, of which 70 were unique to PubMed, 110 were unique to Scopus, and 260 were common to both databases. These studies show that the golden spice has enormous health and medicinal benefits for humans. This Review will extract and summarize the lessons learned about turmeric and curcumin in the prevention and treatment of chronic diseases based on clinical trials.
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Affiliation(s)
- Ajaikumar B. Kunnumakkara
- Department
of Biosciences and Bioengineering, Indian
Institute of Technology Guwahati, Assam-781039, India
| | - Mangala Hegde
- Department
of Biosciences and Bioengineering, Indian
Institute of Technology Guwahati, Assam-781039, India
| | - Dey Parama
- Department
of Biosciences and Bioengineering, Indian
Institute of Technology Guwahati, Assam-781039, India
| | - Sosmitha Girisa
- Department
of Biosciences and Bioengineering, Indian
Institute of Technology Guwahati, Assam-781039, India
| | - Aviral Kumar
- Department
of Biosciences and Bioengineering, Indian
Institute of Technology Guwahati, Assam-781039, India
| | - Uzini Devi Daimary
- Department
of Biosciences and Bioengineering, Indian
Institute of Technology Guwahati, Assam-781039, India
| | - Prachi Garodia
- Integrative
Research Center, Miami, Florida 33125, United States
| | - Sarat Chandra Yenisetti
- Department
of Zoology, Drosophila Neurobiology Laboratory, Nagaland University (Central), Lumami, Nagaland-798627, India
| | - Oommen V. Oommen
- Department
of Computational Biology and Bioinformatics, University of Kerala, Kariavattom, Thiruvananthapuram, Kerala-695581, India
| | - Bharat B. Aggarwal
- Inflammation
Research Center, San Diego, California 92109, United States
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17
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Venkat R, Verma E, Daimary UD, Kumar A, Girisa S, Dutta U, Ahn KS, Kunnumakkara AB. The Journey of Resveratrol from Vineyards to Clinics. Cancer Invest 2023; 41:183-220. [PMID: 35993769 DOI: 10.1080/07357907.2022.2115057] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
With rising technological advancements, several factors influence the lifestyle of people and stimulate chronic inflammation that severely affects the human body. Chronic inflammation leads to a broad range of physical and pathophysiological distress. For many years, non-steroidal drugs and corticosteroids were most frequently used in treating inflammation and related ailments. However, long-term usage of these drugs aggravates the conditions of chronic diseases and is presented with morbid side effects, especially in old age. Hence, the quest for safe and less toxic anti-inflammatory compounds of high therapeutic potential with least adverse side effects has shifted researchers' attention to ancient medicinal system. Resveratrol (RSV) - 3,4,5' trihydroxystilbene is one such naturally available polyphenolic stilbene derivative obtained from various plant sources. For over 2000 years, these plants have been used in Asian medicinal system for curing inflammation-associated disorders. There is a wealth of in vitro, in vivo and clinical evidence that shows RSV could induce anti-aging health benefits including, anti-cancer, anti-inflammatory, anti-oxidant, phytoesterogenic, and cardio protective properties. However, the issue of rapid elimination of RSV through the metabolic system and its low bio-availability is of paramount importance which is being studied extensively. Therefore, in this article, we scientifically reviewed the molecular targets, biological activities, beneficial and contradicting effects of RSV as evinced by clinical studies for the prevention and treatment of inflammation-mediated chronic disorders.
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Affiliation(s)
- Ramya Venkat
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory, Indian Institute of Technology (IIT) Guwahati, Guwahati, India
| | - Elika Verma
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory, Indian Institute of Technology (IIT) Guwahati, Guwahati, India
| | - Uzini Devi Daimary
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory, Indian Institute of Technology (IIT) Guwahati, Guwahati, India
| | - Aviral Kumar
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory, Indian Institute of Technology (IIT) Guwahati, Guwahati, India
| | - Sosmitha Girisa
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory, Indian Institute of Technology (IIT) Guwahati, Guwahati, India
| | - Uma Dutta
- Department of Zoology, Cell and Molecular Biology Laboratory, Cotton University, Guwahati, India
| | - Kwang Seok Ahn
- Department of Science in Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Ajaikumar B Kunnumakkara
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory, Indian Institute of Technology (IIT) Guwahati, Guwahati, India
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18
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LIU H, LIU X, XIE J, CHEN S. Structure, function and mechanism of edible fungus polysaccharides in human beings chronic diseases. FOOD SCIENCE AND TECHNOLOGY 2023. [DOI: 10.1590/fst.111022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Affiliation(s)
- Huijuan LIU
- Guizhou Medical University, China; Guizhou Medical University, China
| | | | - Jiao XIE
- Guizhou Medical University, China; Guizhou Medical University, China
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19
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Perike N, Edigi PK, Nirmala G, Thumma V, Bujji S, Naikal PS. Synthesis, Anticancer Activity and Molecular Docking Studies of Hybrid Molecules Containing Indole‐Thiazolidinedione‐Triazole Moieties. ChemistrySelect 2022. [DOI: 10.1002/slct.202203778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- Nagaraju Perike
- Department of Chemistry University College of Science Osmania University Hyderabad Telangana 500007 India
| | - Praveen Kumar Edigi
- Department of Chemistry University College of Science Osmania University Hyderabad Telangana 500007 India
| | - Gurrapu Nirmala
- Department of Chemistry University College of Science Osmania University Hyderabad Telangana 500007 India
| | - Vishnu Thumma
- Department of Sciences and Humanities Matrusri Engineering College Hyderabad Telangana 500059 India
| | - Sushmitha Bujji
- Department of Pharmacy University College of Technology Osmania University Hyderabad Telangana 500007 India
| | - Prameela Subhashini Naikal
- Department of Chemistry University College of Science Osmania University Hyderabad Telangana 500007 India
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20
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Jayaprakash S, Hegde M, BharathwajChetty B, Girisa S, Alqahtani MS, Abbas M, Sethi G, Kunnumakkara AB. Unraveling the Potential Role of NEDD4-like E3 Ligases in Cancer. Int J Mol Sci 2022; 23:ijms232012380. [PMID: 36293239 PMCID: PMC9604169 DOI: 10.3390/ijms232012380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 09/28/2022] [Accepted: 10/04/2022] [Indexed: 11/06/2022] Open
Abstract
Cancer is a deadly disease worldwide, with an anticipated 19.3 million new cases and 10.0 million deaths occurring in 2020 according to GLOBOCAN 2020. It is well established that carcinogenesis and cancer development are strongly linked to genetic changes and post-translational modifications (PTMs). An important PTM process, ubiquitination, regulates every aspect of cellular activity, and the crucial enzymes in the ubiquitination process are E3 ubiquitin ligases (E3s) that affect substrate specificity and must therefore be carefully regulated. A surfeit of studies suggests that, among the E3 ubiquitin ligases, neuronal precursor cell-expressed developmentally downregulated 4 (NEDD4)/NEDD4-like E3 ligases show key functions in cellular processes by controlling subsequent protein degradation and substrate ubiquitination. In addition, it was demonstrated that NEDD4 mainly acts as an oncogene in various cancers, but also plays a tumor-suppressive role in some cancers. In this review, to comprehend the proper function of NEDD4 in cancer development, we summarize its function, both its tumor-suppressive and oncogenic role, in multiple types of malignancies. Moreover, we briefly explain the role of NEDD4 in carcinogenesis and progression, including cell survival, cell proliferation, autophagy, cell migration, invasion, metastasis, epithelial-mesenchymal transition (EMT), chemoresistance, and multiple signaling pathways. In addition, we briefly explain the significance of NEDD4 as a possible target for cancer treatment. Therefore, we conclude that targeting NEDD4 as a therapeutic method for treating human tumors could be a practical possibility.
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Affiliation(s)
- Sujitha Jayaprakash
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati 781039, Assam, India
| | - Mangala Hegde
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati 781039, Assam, India
| | - Bandari BharathwajChetty
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati 781039, Assam, India
| | - Sosmitha Girisa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati 781039, Assam, India
| | - Mohammed S. Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha 61421, Saudi Arabia
- BioImaging Unit, Space Research Centre, Michael Atiyah Building, University of Leicester, Leicester LE1 7RH, UK
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, Abha 61421, Saudi Arabia
- Electronics and Communications Department, College of Engineering, Delta University for Science and Technology, Gamasa 35712, Egypt
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
- Correspondence: (G.S.); (A.B.K.)
| | - Ajaikumar B. Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati 781039, Assam, India
- Correspondence: (G.S.); (A.B.K.)
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21
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Aswathy M, Vijayan A, Daimary UD, Girisa S, Radhakrishnan KV, Kunnumakkara AB. Betulinic acid: A natural promising anticancer drug, current situation, and future perspectives. J Biochem Mol Toxicol 2022; 36:e23206. [PMID: 36124371 DOI: 10.1002/jbt.23206] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 07/16/2022] [Accepted: 08/19/2022] [Indexed: 11/07/2022]
Abstract
Natural products serve as the single most productive source for the discovery of drugs and pharmaceutical leads. Among the various chemicals derived from microbes, plants, and animals, phytochemicals have emerged as potential candidates for the development of anticancer drugs due to their structural diversities, complexities, and pleiotropic effects. Herein, we discuss betulinic acid (BA), a ubiquitously distributed lupane structured pentacyclic triterpenoid, scrutinized as a promising natural agent for the prevention, suppression, and management of various human malignancies. Ease of availability, common occurrences, cell-specific cytotoxicity, and astonishing selectivity are the important factors that contribute to the development of BA as an anticancer agent. The current review delineates the mechanistic framework of BA-mediated cancer suppression through the modulation of multiple signaling pathways and also summarizes the key outcomes of BA in preclinical investigations.
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Affiliation(s)
- Maniyamma Aswathy
- Chemical Sciences and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology (CSIR-NIIST), Thiruvananthapuram, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Ajesh Vijayan
- Department of Chemistry, CHRIST (Deemed to be University), Bangalore, India
| | - Uzini D Daimary
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology, Guwahati, Assam, India
| | - Sosmitha Girisa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology, Guwahati, Assam, India
| | - Kokkuvayil V Radhakrishnan
- Chemical Sciences and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology (CSIR-NIIST), Thiruvananthapuram, India
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology, Guwahati, Assam, India
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22
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Sajeev A, Hegde M, Girisa S, Devanarayanan TN, Alqahtani MS, Abbas M, Sil SK, Sethi G, Chen JT, Kunnumakkara AB. Oroxylin A: A Promising Flavonoid for Prevention and Treatment of Chronic Diseases. Biomolecules 2022; 12:1185. [PMID: 36139025 PMCID: PMC9496116 DOI: 10.3390/biom12091185] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/10/2022] [Accepted: 08/16/2022] [Indexed: 11/16/2022] Open
Abstract
There have been magnificent advancements in the understanding of molecular mechanisms of chronic diseases over the past several years, but these diseases continue to be a considerable cause of death worldwide. Most of the approved medications available for the prevention and treatment of these diseases target only a single gene/protein/pathway and are known to cause severe side effects and are less effective than they are anticipated. Consequently, the development of finer therapeutics that outshine the existing ones is far-reaching. Natural compounds have enormous applications in curbing several disastrous and fatal diseases. Oroxylin A (OA) is a flavonoid obtained from the plants Oroxylum indicum, Scutellaria baicalensis, and S. lateriflora, which have distinctive pharmacological properties. OA modulates the important signaling pathways, including NF-κB, MAPK, ERK1/2, Wnt/β-catenin, PTEN/PI3K/Akt, and signaling molecules, such as TNF-α, TGF-β, MMPs, VEGF, interleukins, Bcl-2, caspases, HIF-1α, EMT proteins, Nrf-2, etc., which play a pivotal role in the molecular mechanism of chronic diseases. Overwhelming pieces of evidence expound on the anti-inflammatory, anti-bacterial, anti-viral, and anti-cancer potentials of this flavonoid, which makes it an engrossing compound for research. Numerous preclinical and clinical studies also displayed the promising potential of OA against cancer, cardiovascular diseases, inflammation, neurological disorders, rheumatoid arthritis, osteoarthritis, etc. Therefore, the current review focuses on delineating the role of OA in combating different chronic diseases and highlighting the intrinsic molecular mechanisms of its action.
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Affiliation(s)
- Anjana Sajeev
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Mangala Hegde
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Sosmitha Girisa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Thulasidharan Nair Devanarayanan
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Mohammed S. Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha 61421, Saudi Arabia
- BioImaging Unit, Space Research Center, Michael Atiyah Building, University of Leicester, Leicester LE1 7RH, UK
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, Abha 61421, Saudi Arabia
- Electronics and Communications Department, College of Engineering, Delta University for Science and Technology, Gamasa 35712, Egypt
| | - Samir Kumar Sil
- Cell Physiology and Cancer Biology Laboratory, Department of Human Physiology, Tripura University, Suryamaninagar 799022, India
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
| | - Jen-Tsung Chen
- Department of Life Sciences, National University of Kaohsiung, Kaohsiung 811, Taiwan
| | - Ajaikumar B. Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
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23
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Wang C, Xu X, Zhang P, Xiong S, Yuan J, Gao X, Guan W, Wang F, Li X, Dou H, Xu G. Lipid-coated albumin-paclitaxel nanoparticles loaded with sorcin-siRNA reverse cancer chemoresistance via restoring intracellular calcium ion homeostasis. J Nanobiotechnology 2022; 20:319. [PMID: 35799174 PMCID: PMC9264675 DOI: 10.1186/s12951-022-01487-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 05/31/2022] [Indexed: 12/17/2022] Open
Abstract
Chemoresistance is often a cause of the failure of chemotherapy in cancer treatment. Sorcin (SRI) is a soluble resistance-related calcium-binding protein involved in chemoresistant processes and is overexpressed in many chemoresistant cancer cells, including paclitaxel (PTX)-resistant ovarian cancer. Increased SRI can reduce the concentration of calcium ions in the cytosol and mitochondria and the decrease of calcium ion concentration prevents the occurrence of apoptosis. Here we examined the SRI expression in multiple cancers using a human TissueArray and found that SRI expression was significantly higher in malignant tumor tissues. Furthermore, SRI was overexpressed, while intracellular calcium concentration was decreased, in chemoresistant cancer cells. To restore intracellular calcium homeostasis and overcome chemoresistance, we developed lipid-coated albumin-PTX nanoparticles loaded with SRI-siRNA (LANP-PTX-siSRI) for PTX and SRI-siRNA co-delivery. LANP-PTX-siSRI had dual-target roles in the regulation of SRI and the delivery of PTX into chemoresistant cells. The LANP-PTX-siSRI inhibited the expression of SRI and enhanced intracellular calcium, leading to the induction of apoptosis and the inhibition of the growth of PTX-resistant cancer cells in vitro and in vivo. In addition, the mechanism study revealed that the overexpression of SRI was associated with an impaired TGF-β signaling pathway. The administration of TGF-β1 inhibited two calcium-binding proteins SRI and S100A14. In conclusion, our data unveil that restoring intracellular calcium ion homeostasis via reducing SRI expression can reverse chemoresistance. Thus, the fabricated LANP-PTX-siSRI has a potentially therapeutical application.
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Affiliation(s)
- Chenglong Wang
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai, 201508, People's Republic of China
| | - Xiaolin Xu
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai, 201508, People's Republic of China
| | - Peipei Zhang
- State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai, 200240, People's Republic of China
| | - Shuhan Xiong
- State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai, 200240, People's Republic of China
| | - Jia Yuan
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai, 201508, People's Republic of China
| | - Xuzhu Gao
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai, 201508, People's Republic of China
| | - Wencai Guan
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai, 201508, People's Republic of China
| | - Fanchen Wang
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai, 201508, People's Republic of China
| | - Xin Li
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai, 201508, People's Republic of China
| | - Hongjing Dou
- State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai, 200240, People's Republic of China.
| | - Guoxiong Xu
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai, 201508, People's Republic of China.
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24
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Parama D, Girisa S, Khatoon E, Kumar A, Alqahtani MS, Abbas M, Sethi G, Kunnumakkara AB. An Overview of the Pharmacological Activities of Scopoletin against Different Chronic Diseases. Pharmacol Res 2022; 179:106202. [DOI: 10.1016/j.phrs.2022.106202] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/29/2022] [Accepted: 03/30/2022] [Indexed: 12/24/2022]
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25
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Fu M, Wang B, Yi L, Jin X, Yan Y, Ding CF. Bi-amino acid functionalized biomimetic honeycomb chitosan membrane as a multifunctional hydrophilic probe for specific capture of N-linked glycopeptides in nasopharyngeal carcinoma's disease patient's serum. J Sep Sci 2022; 45:1580-1589. [PMID: 35182004 DOI: 10.1002/jssc.202100993] [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: 12/14/2021] [Revised: 01/16/2022] [Accepted: 01/26/2022] [Indexed: 11/08/2022]
Abstract
In this work, a novel porous bifunctionalized composite material was synthesized via a simple method. Gold nanoparticles are uniformly dispersed on the surface of the biomimetic honeycomb chitosan membrane through the interaction between amino and Au, and then cysteine and glutathione are successfully grafted onto the surface of the Au by the Au-S bond. The ingenious synergistic effect of cysteine and glutathione makes this bifunctionalized composite material have significant advantages of both superhydrophilicity and small steric hindrance. This material manifests excellent property in glycopeptides enrichment, with high selectivity (1:5000), low detection limit (0.1 fmol·μL-1 ), high recovery rate (99.4 ± 0.5%) and good repeatability. In addition, with the help of nano-flow liquid chromatography tandem mass spectrometry, this composite achieved excellent performance in efficiently enriching glycopeptides in the serum of healthy people and nasopharyngeal carcinoma's disease patient. More excitingly, further gene ontology analysis of molecular function and biological process indicated that 41 original glycoproteins of the identified glycopeptides from serum of nasopharyngeal carcinoma's disease patient significantly partake in numerous cancer-associated events, including protease binding, calcium ion binding, enzyme binding, extracellular matrix organization, cellular response to tumor necrosis factor and inflammatory response. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Mengyao Fu
- Key Laboratory of Advanced Mass Spectrometry and Molecular Analysis of Zhejiang Province, School of Materials Science and Chemical Engineering, Institute of Mass Spectrometry, Ningbo University, Ningbo, 315211, P. R. China
| | - Baichun Wang
- Key Laboratory of Advanced Mass Spectrometry and Molecular Analysis of Zhejiang Province, School of Materials Science and Chemical Engineering, Institute of Mass Spectrometry, Ningbo University, Ningbo, 315211, P. R. China
| | - Linhua Yi
- Key Laboratory of Advanced Mass Spectrometry and Molecular Analysis of Zhejiang Province, School of Materials Science and Chemical Engineering, Institute of Mass Spectrometry, Ningbo University, Ningbo, 315211, P. R. China
| | - Xueting Jin
- Key Laboratory of Advanced Mass Spectrometry and Molecular Analysis of Zhejiang Province, School of Materials Science and Chemical Engineering, Institute of Mass Spectrometry, Ningbo University, Ningbo, 315211, P. R. China
| | - Yinghua Yan
- Key Laboratory of Advanced Mass Spectrometry and Molecular Analysis of Zhejiang Province, School of Materials Science and Chemical Engineering, Institute of Mass Spectrometry, Ningbo University, Ningbo, 315211, P. R. China
| | - Chuan-Fan Ding
- Key Laboratory of Advanced Mass Spectrometry and Molecular Analysis of Zhejiang Province, School of Materials Science and Chemical Engineering, Institute of Mass Spectrometry, Ningbo University, Ningbo, 315211, P. R. China
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26
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Banik K, Khatoon E, Harsha C, Rana V, Parama D, Thakur KK, Bishayee A, Kunnumakkara AB. Wogonin and its analogs for the prevention and treatment of cancer: A systematic review. Phytother Res 2022; 36:1854-1883. [DOI: 10.1002/ptr.7386] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 12/18/2021] [Accepted: 01/08/2022] [Indexed: 12/24/2022]
Affiliation(s)
- Kishore Banik
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering Indian Institute of Technology‐Guwahati Guwahati India
- DBT‐AIST International Center for Translational and Environmental Research Indian Institute of Technology‐Guwahati Guwahati India
| | - Elina Khatoon
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering Indian Institute of Technology‐Guwahati Guwahati India
- DBT‐AIST International Center for Translational and Environmental Research Indian Institute of Technology‐Guwahati Guwahati India
| | - Choudhary Harsha
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering Indian Institute of Technology‐Guwahati Guwahati India
- DBT‐AIST International Center for Translational and Environmental Research Indian Institute of Technology‐Guwahati Guwahati India
| | - Varsha Rana
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering Indian Institute of Technology‐Guwahati Guwahati India
- DBT‐AIST International Center for Translational and Environmental Research Indian Institute of Technology‐Guwahati Guwahati India
| | - Dey Parama
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering Indian Institute of Technology‐Guwahati Guwahati India
- DBT‐AIST International Center for Translational and Environmental Research Indian Institute of Technology‐Guwahati Guwahati India
| | - Krishan Kumar Thakur
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering Indian Institute of Technology‐Guwahati Guwahati India
- DBT‐AIST International Center for Translational and Environmental Research Indian Institute of Technology‐Guwahati Guwahati India
| | - Anupam Bishayee
- College of Osteopathic medicine Lake Erie College of Osteopathic Medicine Bradenton Florida USA
| | - Ajaikumar B. Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering Indian Institute of Technology‐Guwahati Guwahati India
- DBT‐AIST International Center for Translational and Environmental Research Indian Institute of Technology‐Guwahati Guwahati India
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27
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Guo SB, Huang WJ, Tian XP. Brusatol modulates diverse cancer hallmarks and signaling pathways as a potential cancer therapeutic. ACTA MATERIA MEDICA 2022; 1. [DOI: 10.15212/amm-2022-0014] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/14/2024]
Abstract
Cancer is a consequence of uncontrolled cell proliferation that is associated with cell-cycle disruption. It is a multifactorial disease that depends on the modulation of numerous oncogenic signaling pathways and targets. Although a battle against cancer has been waged for centuries, this disease remains a major cause of death worldwide. Because of the development of resistance to current anticancer drugs, substantial effort has been focused on discovering more effective agents for tumor therapy. Natural products have powerful prospects as anticancer drugs. Brusatol, a component isolated from the plant Brucea javanica, has been demonstrated to efficiently combat a wide variety of tumors. Extensive studies have indicated that brusatol exhibits anticancer effects by arresting the cell cycle; promoting apoptosis; inducing autophagy; attenuating epithelial-mesenchymal transition; inhibiting migration, invasion and angiogenesis; and increasing chemosensitivity and radiosensitivity. These effects involve various oncogenic signaling pathways, including the MAPK, NF-κB, PI3K/AKT/mTOR, JAK/STAT and Keap1/Nrf2/ARE signaling pathways. This review describes the evidence suggesting that brusatol is a promising drug candidate for cancer therapeutics.
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Affiliation(s)
- Song-Bin Guo
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Wei-Juan Huang
- Department of Pharmacology, College of Pharmacy, Jinan University, Guangzhou, P.R. China
| | - Xiao-Peng Tian
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
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28
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Altharawi A, Ahmad S, Alamri MA, Tahir Ul Qamar M. Structural insight into the binding pattern and interaction mechanism of chemotherapeutic agents with Sorcin by docking and molecular dynamic simulation. Colloids Surf B Biointerfaces 2021; 208:112098. [PMID: 34509085 DOI: 10.1016/j.colsurfb.2021.112098] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 08/14/2021] [Accepted: 09/02/2021] [Indexed: 12/15/2022]
Abstract
Sorcin (SOluble Resistance-related Calcium bInding proteiN) is a calcium binding protein that plays a key role in multidrug resistance (MDR) in human cancers. This study aimed at understanding the binding mechanism and structural basis for the interaction of structurally and functionally unrelated chemotherapeutic agent, namely doxorubicin, etoposide, omacetaxine mepesuccinate and paclitaxel with Sorcin by utilizing docking and molecular dynamic simulation approaches. The docking evaluation of etoposide, omacetaxine mepesuccinate and paclitaxel have shown a high affinity binding with Sorcin at the Ca2+-binding C-terminal domain (SCBD) in a comparable mode and affinity of binding to doxorubicin. Moreover, all of the docked compounds were shown to interact both hydrophilically and hydrophobically with the same residues within the active pocket which is located at interface of the Sorcin and collectively formed by EF5 loop, G helix and EF4 loop. However, the MD simulations revealed that the dynamics of Sorcin structure is different in the presence of the compounds when compared and contrasted to the Apo Sorcin, particularly in the first 25 ns, after which each system gained considerable structure stability. The difference in dynamics might be the outcome of high N and C-terminal flexibility that seem not to disturb compounds binding conformation but more likely is affecting chemical interaction network by breaking and establishing old and new hydrogen bonds, respectively. This detailed mechanistic understanding of different chemotherapeutic agents binding to Sorcin might be useful to open windows for designing and developing new inhibitors that are potentially capable of reversing the MDR in human cancers.
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Affiliation(s)
- Ali Altharawi
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Sajjad Ahmad
- Department of Health and Biological Sciences, Abasyn University, Peshawar, Pakistan
| | - Mubarak A Alamri
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia.
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29
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Devi Daimary U, Girisa S, Parama D, Verma E, Kumar A, Kunnumakkara AB. Embelin: A novel XIAP inhibitor for the prevention and treatment of chronic diseases. J Biochem Mol Toxicol 2021; 36:e22950. [PMID: 34842329 DOI: 10.1002/jbt.22950] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 09/28/2021] [Accepted: 11/01/2021] [Indexed: 12/19/2022]
Abstract
Chronic diseases are a serious health concern worldwide, especially in the elderly population. Most chronic diseases like cancer, cardiovascular ailments, neurodegenerative disorders, and autoimmune diseases are caused due to the abnormal functioning of multiple signaling pathways that give rise to critical anomalies in the body. Although a lot of advanced therapies are available, these have failed to entirely cure the disease due to their less efficacy. Apart from this, they have been shown to manifest disturbing side effects which hamper the patient's quality of life to the extreme. Since the last few decades, extensive studies have been done on natural herbs due to their excellent medicinal benefits. Components present in natural herbs target multiple signaling pathways involved in diseases and therefore hold high potential in the prevention and treatment of various chronic diseases. Embelin, a benzoquinone, is one such agent isolated from Embelia ribes, which has shown excellent biological activities toward several chronic ailments by upregulating a number of antioxidant enzymes (e.g., SOD, CAT, GSH, etc.), inhibiting anti-apoptotic genes (e.g., TRAIL, XIAP, survivin, etc.), modulating transcription factors (e.g., NF-κB, STAT3, etc.) blocking inflammatory biomarkers (e.g., NO, IL-1β, IL-6, TNF-α, etc.), monitoring cell cycle synchronizing genes (e.g., p53, cyclins, CDKs, etc.), and so forth. Several preclinical studies have confirmed its excellent therapeutic activities against malicious diseases like cancer, obesity, heart diseases, Alzheimer's, and so forth. This review presents an overview of embelin, its therapeutic prospective, and the molecular targets in different chronic diseases.
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Affiliation(s)
- Uzini Devi Daimary
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, India
| | - Sosmitha Girisa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, India
| | - Dey Parama
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, India
| | - Elika Verma
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, India
| | - Aviral Kumar
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, India
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, India
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30
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Ling F, Zhang H, Sun Y, Meng J, Sanches JGP, Huang H, Zhang Q, Yu X, Wang B, Hou L, Zhang J. AnnexinA7 promotes epithelial-mesenchymal transition by interacting with Sorcin and contributes to aggressiveness in hepatocellular carcinoma. Cell Death Dis 2021; 12:1018. [PMID: 34716295 PMCID: PMC8556303 DOI: 10.1038/s41419-021-04287-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 08/29/2021] [Accepted: 10/07/2021] [Indexed: 11/23/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and metastasis is the major cause of the high mortality of HCC. In this study, we identified that AnnexinA7 (ANXA7) and Sorcin (SRI) are overexpressed and interacting proteins in HCC tissues and cells. In vitro functional investigations revealed that the interaction between ANXA7 and SRI regulated epithelial-mesenchymal transition (EMT), and then affected migration, invasion, and proliferation in HCC cells. Furthermore overexpression/knockdown of ANXA7 was remarkably effective in promoting/inhibiting tumorigenicity and EMT in vivo. Altogether, our study unveiled a mechanism that ANXA7 promotes EMT by interacting with SRI and further contributes to the aggressiveness in HCC, which provides a novel potential therapeutic target for preventing recurrence and metastasis in HCC.
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Affiliation(s)
- Fei Ling
- Department of Pathology and Forensics, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Huan Zhang
- Department of Pathology and Forensics, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Yunliang Sun
- Department of Pathology, Dalian Municipal Central Hospital affiliated with Dalian Medical University, Dalian, 116033, China
| | - Jinyi Meng
- Department of Pathology, Dalian Municipal Central Hospital affiliated with Dalian Medical University, Dalian, 116033, China
| | | | - He Huang
- Department of Pathology and Forensics, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Qingqing Zhang
- Department of Pathology and Forensics, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Xiao Yu
- Department of Pathology and Forensics, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Bo Wang
- Department of Pathology and Forensics, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Li Hou
- Department of Pathology and Forensics, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China.
| | - Jun Zhang
- Department of Pathology and Forensics, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China.
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Kumar A, Harsha C, Parama D, Girisa S, Daimary UD, Mao X, Kunnumakkara AB. Current clinical developments in curcumin-based therapeutics for cancer and chronic diseases. Phytother Res 2021; 35:6768-6801. [PMID: 34498308 DOI: 10.1002/ptr.7264] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 06/16/2021] [Accepted: 08/14/2021] [Indexed: 12/19/2022]
Abstract
The last decade has seen an unprecedented rise in the prevalence of chronic diseases worldwide. Different mono-targeted approaches have been devised to treat these multigenic diseases, still most of them suffer from limited success due to the off-target debilitating side effects and their inability to target multiple pathways. Hence a safe, efficacious, and multi-targeted approach is the need for the hour to circumvent these challenging chronic diseases. Curcumin, a natural compound extracted from the rhizomes of Curcuma longa, has been under intense scrutiny for its wide medicinal and biological properties. Curcumin is known to manifest antibacterial, antiinflammatory, antioxidant, antifungal, antineoplastic, antifungal, and proapoptotic effects. A plethora of literature has already established the immense promise of curcuminoids in the treatment and clinical management of various chronic diseases like cancer, cardiovascular, metabolic, neurological, inflammatory, and infectious diseases. To date, more than 230 clinical trials have opened investigations to understand the pharmacological aspects of curcumin in human systems. Still, further randomized clinical studies in different ethnic populations warrant its transition to a marketed drug. This review summarizes the results from different clinical trials of curcumin-based therapeutics in the prevention and treatment of various chronic diseases.
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Affiliation(s)
- Aviral Kumar
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, India
| | - Choudhary Harsha
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, India
| | - Dey Parama
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, India
| | - Sosmitha Girisa
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, India
| | - Uzini Devi Daimary
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, India
| | - Xinliang Mao
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, India
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Parama D, Rana V, Girisa S, Verma E, Daimary UD, Thakur KK, Kumar A, Kunnumakkara AB. The promising potential of piperlongumine as an emerging therapeutics for cancer. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2021; 2:323-354. [PMID: 36046754 PMCID: PMC9400693 DOI: 10.37349/etat.2021.00049] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 07/04/2021] [Indexed: 12/24/2022] Open
Abstract
In spite of the immense advancement in the diagnostic and treatment modalities, cancer continues to be one of the leading causes of mortality across the globe, responsible for the death of around 10 million patients every year. The foremost challenges faced in the treatment of this disease are chemoresistance, adverse effects of the drugs, and the high cost of treatment. Though scientific studies over the past few decades have foreseen and are focusing on the cancer-preventive and therapeutic potential of natural products and their underlying mechanism of action, many more of these agents are not still explored. Piperlongumine (PL), or piplartine, is one such alkaloid isolated from Piper longum Linn. which is shown to be safe and has significant potential in the prevention and therapy of cancer. Numerous shreds of evidence have established the ability of this alkaloid and its analogs and nanoformulations in modulating various complex molecular pathways such as phosphatidylinositol-3-kinase/protein kinase B /mammalian target of rapamycin, nuclear factor kappa-B, Janus kinases/signal transducer and activator of transcription 3, etc. and inhibit different hallmarks of cancer such as cell survival, proliferation, invasion, angiogenesis, epithelial-mesenchymal-transition, metastases, etc. In addition, PL was also shown to inhibit radioresistance and chemoresistance and sensitize the cancer cells to the standard chemotherapeutic agents. Therefore, this compound has high potential as a drug candidate for the prevention and treatment of different cancers. The current review briefly reiterates the anti-cancer properties of PL against different types of cancer, which permits further investigation by conducting clinical studies.
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Affiliation(s)
- Dey Parama
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Varsha Rana
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Sosmitha Girisa
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Elika Verma
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Uzini Devi Daimary
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Krishan Kumar Thakur
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Aviral Kumar
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Ajaikumar B. Kunnumakkara
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
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Girisa S, Henamayee S, Parama D, Rana V, Dutta U, Kunnumakkara AB. Targeting Farnesoid X receptor (FXR) for developing novel therapeutics against cancer. MOLECULAR BIOMEDICINE 2021; 2:21. [PMID: 35006466 PMCID: PMC8607382 DOI: 10.1186/s43556-021-00035-2] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 03/17/2021] [Indexed: 12/14/2022] Open
Abstract
Cancer is one of the lethal diseases that arise due to the molecular alterations in the cell. One of those alterations associated with cancer corresponds to differential expression of Farnesoid X receptor (FXR), a nuclear receptor regulating bile, cholesterol homeostasis, lipid, and glucose metabolism. FXR is known to regulate several diseases, including cancer and cardiovascular diseases, the two highly reported causes of mortality globally. Recent studies have shown the association of FXR overexpression with cancer development and progression in different types of cancers of breast, lung, pancreas, and oesophagus. It has also been associated with tissue-specific and cell-specific roles in various cancers. It has been shown to modulate several cell-signalling pathways such as EGFR/ERK, NF-κB, p38/MAPK, PI3K/AKT, Wnt/β-catenin, and JAK/STAT along with their targets such as caspases, MMPs, cyclins; tumour suppressor proteins like p53, C/EBPβ, and p-Rb; various cytokines; EMT markers; and many more. Therefore, FXR has high potential as novel biomarkers for the diagnosis, prognosis, and therapy of cancer. Thus, the present review focuses on the diverse role of FXR in different cancers and its agonists and antagonists.
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Affiliation(s)
- Sosmitha Girisa
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India
| | - Sahu Henamayee
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India
| | - Dey Parama
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India
| | - Varsha Rana
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India
| | - Uma Dutta
- Cell and Molecular Biology Lab, Department of Zoology, Cotton University, Guwahati, Assam, 781001, India.
| | - Ajaikumar B Kunnumakkara
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India.
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Girisa S, Saikia Q, Bordoloi D, Banik K, Monisha J, Daimary UD, Verma E, Ahn KS, Kunnumakkara AB. Xanthohumol from Hop: Hope for cancer prevention and treatment. IUBMB Life 2021; 73:1016-1044. [PMID: 34170599 DOI: 10.1002/iub.2522] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 06/17/2021] [Accepted: 06/21/2021] [Indexed: 12/16/2022]
Abstract
Cancer is a major public health concern due to high mortality and poor quality of life of patients. Despite the availability of advanced therapeutic interventions, most treatment modalities are not efficacious, very expensive, and cause several adverse side effects. The factors such as drug resistance, lack of specificity, and low efficacy of the cancer drugs necessitate developing alternative strategies for the prevention and treatment of this disease. Xanthohumol (XN), a prenylated chalcone present in Hop (Humulus lupulus), has been found to possess prominent activities against aging, diabetes, inflammation, microbial infection, and cancer. Thus, this manuscript thoroughly reviews the literature on the anti-cancer properties of XN and its various molecular targets. XN was found to exert its inhibitory effect on the growth and proliferation of cancer cells via modulation of multiple signaling pathways such as Akt, AMPK, ERK, IGFBP2, NF-κB, and STAT3, and also modulates various proteins such as Notch1, caspases, MMPs, Bcl-2, cyclin D1, oxidative stress markers, tumor-suppressor proteins, and miRNAs. Thus, these reports suggest that XN possesses enormous therapeutic potential against various cancers and could be potentially used as a multi-targeted anti-cancer agent with minimal adverse effects.
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Affiliation(s)
- Sosmitha Girisa
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Queen Saikia
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Devivasha Bordoloi
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Kishore Banik
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Javadi Monisha
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Uzini Devi Daimary
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Elika Verma
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Kwang Seok Ahn
- Department of Science in Korean Medicine, College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, South Korea
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
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Wang Y, Zhu Y, Pu Z, Li Z, Deng Y, Li N, Peng F. Soluble resistance-related calcium-binding protein participates in multiple diseases via protein-protein interactions. Biochimie 2021; 189:76-86. [PMID: 34153376 DOI: 10.1016/j.biochi.2021.06.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 05/21/2021] [Accepted: 06/14/2021] [Indexed: 11/17/2022]
Abstract
Soluble resistance-related calcium-binding protein (sorcin), a 22 kDa penta-EF-hand protein, has been intensively studied in cancers and multidrug resistance over a prolonged period. Sorcin is widely distributed in tissues and participates in the regulation of Ca2+ homeostasis and Ca2+-dependent signaling. Protein-protein interactions (PPIs) are essential for regulating protein functions in almost all biological processes. Sorcin interaction partners tend to vary in type, including Ca2+ receptors, Ca2+ transporters, endoplasmic reticulum stress markers, transcriptional regulatory elements, immunomodulation-related factors, and viral proteins. Recent studies have shown that sorcin is involved in a broad range of pathological conditions, such as cardiomyopathy, type 2 diabetes mellitus, neurodegenerative diseases, liver diseases, and viral infections. As a multifunctional cellular protein, in these diseases, sorcin has a role by interacting with or regulating the expression of other proteins, such as sarcoplasmic reticulum/endoplasmic reticulum Ca2+ ATPase, ryanodine receptors, presenilin 2, L-type Ca2+ channels, carbohydrate-responsive element-binding protein, tau, α-synuclein, signal transducer and activator of transcription 3, HCV nonstructural 5A protein, and viral capsid protein 1. This review summarizes the roles that sorcin plays in various diseases, mainly via different PPIs, and focuses principally on non-neoplastic diseases to help acquire a more comprehensive understanding of sorcin's multifunctional characteristics.
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Affiliation(s)
- Yinmiao Wang
- Department of Blood Transfusion, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province 410008, China; NHC Key Laboratory of Cancer Proteomics, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province 410008, China
| | - Yuanyuan Zhu
- Department of Blood Transfusion, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province 410008, China; NHC Key Laboratory of Cancer Proteomics, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province 410008, China
| | - Zhangya Pu
- Department of Infectious Diseases and Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province 410008, China
| | - Zhenfen Li
- Department of Blood Transfusion, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province 410008, China; NHC Key Laboratory of Cancer Proteomics, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province 410008, China
| | - Ying Deng
- People's Hospital of Ningxiang, Changsha, Hunan Province 410600, China
| | - Ning Li
- Department of Blood Transfusion, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province 410008, China
| | - Fang Peng
- Department of Blood Transfusion, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province 410008, China; NHC Key Laboratory of Cancer Proteomics, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province 410008, China.
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Berrocal M, Saez L, Mata AM. Sorcin Activates the Brain PMCA and Blocks the Inhibitory Effects of Molecular Markers of Alzheimer's Disease on the Pump Activity. Int J Mol Sci 2021; 22:ijms22116055. [PMID: 34205207 PMCID: PMC8200006 DOI: 10.3390/ijms22116055] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 05/26/2021] [Accepted: 06/01/2021] [Indexed: 11/16/2022] Open
Abstract
Since dysregulation of intracellular calcium (Ca2+) levels is a common occurrence in neurodegenerative diseases, including Alzheimer’s disease (AD), the study of proteins that can correct neuronal Ca2+ dysregulation is of great interest. In previous work, we have shown that plasma membrane Ca2+-ATPase (PMCA), a high-affinity Ca2+ pump, is functionally impaired in AD and is inhibited by amyloid-β peptide (Aβ) and tau, two key components of pathological AD hallmarks. On the other hand, sorcin is a Ca2+-binding protein highly expressed in the brain, although its mechanism of action is far from being clear. Sorcin has been shown to interact with the intracellular sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), and other modulators of intracellular Ca2+ signaling, such as the ryanodine receptor or presenilin 2, which is closely associated with AD. The present work focuses on sorcin in search of new regulators of PMCA and antagonists of Aβ and tau toxicity. Results show sorcin as an activator of PMCA, which also prevents the inhibitory effects of Aβ and tau on the pump, and counteracts the neurotoxicity of Aβ and tau by interacting with them.
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Girisa S, Rana V, Parama D, Dutta U, Kunnumakkara AB. Differential roles of farnesoid X receptor (FXR) in modulating apoptosis in cancer cells. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2021; 126:63-90. [PMID: 34090620 DOI: 10.1016/bs.apcsb.2021.02.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cancer is one of the leading causes of mortality in the world. The conventional treatment strategies of cancer are surgery, radiation, and chemotherapy. However, in the advanced stage of the disease chemotherapy is the prime treatment and it is effective in only less than 10% of the patients. Therefore, there is an urgent need to find out novel therapeutic targets and delineate the mechanism of action of these targets for better management of this disease. Recent studies have shown that some of the proteins have differential role in different cancers. Therefore, it is pertinent that the targeting of these proteins should be based on the type of cancer. The nuclear receptor, FXR, is one of the vital proteins that regulate cell apoptosis. Besides, it also regulates other processes such as cell proliferation, angiogenesis, invasion, and migration. Studies suggest that the low or high expression of FXR is associated with the progression of carcinogenesis depending on the cancer types. Due to the diverse expression, it functions as both tumor suppressor and promoter. Previous studies suggest the overexpression of FXR in breast, lung, esophageal, and prostate cancer, which is related to poor survival and poor prognosis in patients. Therefore, targeting FXR with agonists and antagonists play different outcome in different cancers. Hence, this review describes the role of FXR in different cancers and the role of its inhibitors and activators for the prevention and treatment of various cancers.
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Affiliation(s)
- Sosmitha Girisa
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Varsha Rana
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Dey Parama
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Uma Dutta
- Cell and Molecular Biology Laboratory, Department of Zoology, Cotton University, Guwahati, Assam, India
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India.
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Aswathy M, Banik K, Parama D, Sasikumar P, Harsha C, Joseph AG, Sherin DR, Thanathu MK, Kunnumakkara AB, Vasu RK. Exploring the Cytotoxic Effects of the Extracts and Bioactive Triterpenoids from Dillenia indica against Oral Squamous Cell Carcinoma: A Scientific Interpretation and Validation of Indigenous Knowledge. ACS Pharmacol Transl Sci 2021; 4:834-847. [PMID: 33860206 DOI: 10.1021/acsptsci.1c00011] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Indexed: 02/08/2023]
Abstract
Triterpenoids are ubiquitously distributed secondary metabolites, primarily scrutinized as a source of medication and preventive measures for various chronic diseases. The ease of isolation and excellent pharmacological properties of triterpenoids are notable reasons behind the exponential rise of extensive research on the bioactive triterpenoids over the past few decades. Herein, we attempted to explore the anticancer potential of the fruit extract of the ethnomedicinal plant Dillenia indica against oral squamous cell carcinoma (OSCC) and have exclusively attributed the efficacy of the extracts to the presence of two triterpenoids, namely, betulinic acid (BA) and koetjapic acid (KA). Preliminary in vitro screening of both BA and KA unveiled that the entities could impart cytotoxicity and induce apoptosis in OSCC cell lines, which were further well-supported by virtual screening based on ligand binding affinity and molecular dynamic simulations. Additionally, the aforementioned metabolites could significantly modulate the critical players such as Akt/mTOR, NF-κB, and JAK/STAT3 signaling pathways involved in the regulation of important hallmarks of cancer like cell survival, proliferation, invasion, angiogenesis, and metastasis. The present findings provide insight and immense scientific support and integrity to a piece of indigenous knowledge. However, in vivo validation is a requisite for moving to clinical trials and developing it as a commercial drug.
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Affiliation(s)
- Maniyamma Aswathy
- Chemical Sciences and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology (CSIR-NIIST), Thiruvananthapuram 695019, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Kishore Banik
- Cancer Biology Laboratory and DBT-AIST International Center for Translational & Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology, Guwahati 781 039, Assam, India
| | - Dey Parama
- Cancer Biology Laboratory and DBT-AIST International Center for Translational & Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology, Guwahati 781 039, Assam, India
| | - Parameswaran Sasikumar
- Chemical Sciences and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology (CSIR-NIIST), Thiruvananthapuram 695019, India
| | - Choudhary Harsha
- Cancer Biology Laboratory and DBT-AIST International Center for Translational & Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology, Guwahati 781 039, Assam, India
| | - Anuja Gracy Joseph
- Chemical Sciences and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology (CSIR-NIIST), Thiruvananthapuram 695019, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Daisy R Sherin
- Centre for Computational Modeling and Data Engineering, Indian Institute of Information Technology and Management-Kerala (IIITM-K), Thiruvananthapuram 695581, India
| | - Manojkumar K Thanathu
- Centre for Computational Modeling and Data Engineering, Indian Institute of Information Technology and Management-Kerala (IIITM-K), Thiruvananthapuram 695581, India
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory and DBT-AIST International Center for Translational & Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology, Guwahati 781 039, Assam, India
| | - Radhakrishnan Kokkuvayil Vasu
- Chemical Sciences and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology (CSIR-NIIST), Thiruvananthapuram 695019, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
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Ahmed SA, Parama D, Daimari E, Girisa S, Banik K, Harsha C, Dutta U, Kunnumakkara AB. Rationalizing the therapeutic potential of apigenin against cancer. Life Sci 2020; 267:118814. [PMID: 33333052 DOI: 10.1016/j.lfs.2020.118814] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 11/14/2020] [Accepted: 11/20/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Despite the remarkable advances made in the diagnosis and treatment of cancer during the past couple of decades, it remains the second largest cause of mortality in the world, killing approximately 9.6 million people annually. The major challenges in the treatment of the advanced stage of this disease are the development of chemoresistance, severe adverse effects of the drugs, and high treatment cost. Therefore, the development of drugs that are safe, efficacious, and cost-effective remains a 'Holy Grail' in cancer research. However, the research over the past four decades shed light on the cancer-preventive and therapeutic potential of natural products and their underlying mechanism of action. Apigenin is one such compound, which is known to be safe and has significant potential in the prevention and therapy of this disease. AIM To assess the literature available on the potential of apigenin and its analogs in modulating the key molecular targets leading to the prevention and treatment of different types of cancer. METHOD A comprehensive literature search has been carried out on PubMed for obtaining information related to the sources and analogs, chemistry and biosynthesis, physicochemical properties, biological activities, bioavailability and toxicity of apigenin. KEY FINDINGS The literature search resulted in many in vitro, in vivo and a few cohort studies that evidenced the effectiveness of apigenin and its analogs in modulating important molecular targets and signaling pathways such as PI3K/AKT/mTOR, JAK/STAT, NF-κB, MAPK/ERK, Wnt/β-catenin, etc., which play a crucial role in the development and progression of cancer. In addition, apigenin was also shown to inhibit chemoresistance and radioresistance and make cancer cells sensitive to these agents. Reports have further revealed the safety of the compound and the adaptation of nanotechnological approaches for improving its bioavailability. SIGNIFICANCE Hence, the present review recapitulates the properties of apigenin and its pharmacological activities against different types of cancer, which warrant further investigation in clinical settings.
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Affiliation(s)
- Semim Akhtar Ahmed
- Cell and Molecular Biology Laboratory, Department of Zoology, Cotton University, Pan Bazar, Guwahati, Assam 781001, India
| | - Dey Parama
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Enush Daimari
- Cell and Molecular Biology Laboratory, Department of Zoology, Cotton University, Pan Bazar, Guwahati, Assam 781001, India
| | - Sosmitha Girisa
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Kishore Banik
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Choudhary Harsha
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Uma Dutta
- Cell and Molecular Biology Laboratory, Department of Zoology, Cotton University, Pan Bazar, Guwahati, Assam 781001, India.
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India.
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Ramchandani S, Naz I, Dhudha N, Garg M. An overview of the potential anticancer properties of cardamonin. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2020; 1:413-426. [PMID: 36046386 PMCID: PMC9400778 DOI: 10.37349/etat.2020.00026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 11/26/2020] [Indexed: 12/24/2022] Open
Abstract
Cancer is one of the leading causes of mortality, contributing to 9.6 million deaths globally in 2018 alone. Although several cancer treatments exist, they are often associated with severe side effects and high toxicities, leaving room for significant advancements to be made in the field. In recent years, several phytochemicals from plants and natural bioresources have been extracted and tested against various human malignancies using both in vitro and in vivo preclinical model systems. Cardamonin, a chalcone extracted from the Alpinia species, is an example of a natural therapeutic agent that has anti-cancer and anti-inflammatory effects against human cancer cell lines, including breast, lung, colon, and gastric, in both in vitro culture systems as well as xenograft mouse models. Earlier, cardamonin was used as a natural medicine against stomach related issues, diarrhea, insulin resistance, nephroprotection against cisplatin treatment, vasorelaxant and antinociceptive. The compound is well-known to inhibit proliferation, migration, invasion, and induce apoptosis, through the involvement of Wnt/β-catenin, NF-κB, and PI3K/Akt pathways. The good biosafety and pharmacokinetic profiling of cardamonin satisfy it as an attractive molecule for the development of an anticancer agent. The present review has summarized the chemo-preventive ability of cardamonin as an anticancer agent against numerous human malignancies.
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Affiliation(s)
- Shanaya Ramchandani
- Department of Pharmacology Biomedicine, the University of Melbourne, Parkville Victoria 3010, Australia
| | - Irum Naz
- Department of Biochemistry, Quaid-i-Azam University, Higher Education Commission of Pakistan, Islamabad 44000, Pakistan
| | - Namrata Dhudha
- Department of Biotechnology and Microbiology, School of Sciences, Noida International University, Noida 201301, India
| | - Manoj Garg
- Amity Institute of Molecular Medicine and Stem cell Research (AIMMSCR), Amity University Uttar Pradesh, Noida 201313, India
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Daimary UD, Parama D, Rana V, Banik K, Kumar A, Harsha C, Kunnumakkara AB. Emerging roles of cardamonin, a multitargeted nutraceutical in the prevention and treatment of chronic diseases. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2020; 2:100008. [PMID: 34909644 PMCID: PMC8663944 DOI: 10.1016/j.crphar.2020.100008] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 11/13/2020] [Accepted: 11/13/2020] [Indexed: 02/08/2023] Open
Abstract
Although chronic diseases are often caused by the perturbations in multiple cellular components involved in different biological processes, most of the approved therapeutics target a single gene/protein/pathway which makes them not as efficient as they are anticipated and are also known to cause severe side effects. Therefore, the pursuit of safe, efficacious, and multitargeted agents is imperative for the prevention and treatment of these diseases. Cardamonin is one such agent that has been known to modulate different signaling molecules such as transcription factors (NF-κB and STAT3), cytokines (TNF-α, IL-1β, and IL-6) enzymes (COX-2, MMP-9 and ALDH1), other proteins and genes (Bcl-2, XIAP and cyclin D1), involved in the development and progression of chronic diseases. Multiple lines of evidence emerging from pre-clinical studies advocate the promising potential of this agent against various pathological conditions like cancer, cardiovascular diseases, diabetes, neurological disorders, inflammation, rheumatoid arthritis, etc., despite its poor bioavailability. Therefore, further studies are paramount in establishing its efficacy in clinical settings. Hence, the current review focuses on highlighting the underlying molecular mechanism of action of cardamonin and delineating its potential in the prevention and treatment of different chronic diseases.
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Affiliation(s)
- Uzini Devi Daimary
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, 781039, India
| | - Dey Parama
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, 781039, India
| | - Varsha Rana
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, 781039, India
| | - Kishore Banik
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, 781039, India
| | - Aviral Kumar
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, 781039, India
| | - Choudhary Harsha
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, 781039, India
| | - Ajaikumar B. Kunnumakkara
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, 781039, India
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Singh AK, Roy NK, Bordoloi D, Padmavathi G, Banik K, Khwairakpam AD, Kunnumakkara AB, Sukumar P. Orai-1 and Orai-2 regulate oral cancer cell migration and colonisation by suppressing Akt/mTOR/NF-κB signalling. Life Sci 2020; 261:118372. [PMID: 32882268 DOI: 10.1016/j.lfs.2020.118372] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 08/17/2020] [Accepted: 08/28/2020] [Indexed: 12/24/2022]
Abstract
Despite remarkable progress in understanding and treating oral cancer (OC), it still remains one of the life-threatening diseases and predominant cancers in the world. Therefore, deciphering the molecular mechanisms of this disease would help us to develop highly efficacious therapies. Multiple lines of evidence suggest that calcium and its dysregulation play significant role in the development of various cancers. As an adaptation of survival mechanism, upon depletion of ER calcium stores, store-operated calcium entry (SOCE) has been induced via SOCE channels (SOCC) in various mammalian cells. SOCC are regulated by Orai-1, Orai-2 and Orai-3 located on plasma membrane and two calcium-sensing ER membrane proteins known as stromal interaction molecules (STIM-1 and STIM-2). Hence, the present study was aimed at analysing the role of Orai-1 and Orai-2 in oral cancer and the underlying mechanism. Our results suggest that both Orai-1 and Orai-2 proteins were overexpressed in oral cancer tissues and cell lines (SAS) compared to normal epithelial tissues and cell lines respectively. In addition, silencing of Orai-1 and Orai-2 via chemical SOCE inhibitors and siRNAs inhibited calcium uptake and suppressed oral cancer cell proliferation, colony formation and migration. Furthermore, silencing of Orai-1 and Orai-2 inhibited Akt/mTOR/NF-κB pathway in oral cancer cells. Interestingly, tobacco carcinogen NNN and synthetic carcinogen 4-NQO, enhanced the expression of Orai-1 and Orai-2 in SAS cells. Therefore, we conclude that Orai-1 and Orai-2 have significant role in oral cancer and can be further explored to develop novel therapies for the treatment of this disease.
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Affiliation(s)
- Anuj Kumar Singh
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Nand Kishor Roy
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Devivasha Bordoloi
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Ganesan Padmavathi
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Kishore Banik
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Amrita Devi Khwairakpam
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India.
| | - Piruthivi Sukumar
- Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds LS2 9JT, UK.
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Girisa S, Parama D, Harsha C, Banik K, Kunnumakkara AB. Potential of guggulsterone, a farnesoid X receptor antagonist, in the prevention and treatment of cancer. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2020; 1:313-342. [PMID: 36046484 PMCID: PMC9400725 DOI: 10.37349/etat.2020.00019] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 09/14/2020] [Indexed: 12/13/2022] Open
Abstract
Cancer is one of the most dreadful diseases in the world with a mortality of 9.6 million annually. Despite the advances in diagnosis and treatment during the last couple of decades, it still remains a serious concern due to the limitations associated with currently available cancer management strategies. Therefore, alternative strategies are highly required to overcome these glitches. The importance of medicinal plants as primary healthcare has been well-known from time immemorial against various human diseases, including cancer. Commiphora wightii that belongs to Burseraceae family is one such plant which has been used to cure various ailments in traditional systems of medicine. This plant has diverse pharmacological properties such as antioxidant, antibacterial, antimutagenic, and antitumor which mostly owes to the presence of its active compound guggulsterone (GS) that exists in the form of Z- and E-isomers. Mounting evidence suggests that this compound has promising anticancer activities and was shown to suppress several cancer signaling pathways such as NF-κB/ERK/MAPK/AKT/STAT and modulate the expression of numerous signaling molecules such as the farnesoid X receptor, cyclin D1, survivin, caspases, HIF-1α, MMP-9, EMT proteins, tumor suppressor proteins, angiogenic proteins, and apoptotic proteins. The current review is an attempt to summarize the biological activities and diverse anticancer activities (both in vitro and in vivo) of the compound GS and its derivatives, along with its associated mechanism against various cancers.
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Affiliation(s)
- Sosmitha Girisa
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Dey Parama
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Choudhary Harsha
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Kishore Banik
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Ajaikumar B. Kunnumakkara
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
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Klümper T, Bruckmueller H, Diewock T, Kaehler M, Haenisch S, Pott C, Bruhn O, Cascorbi I. Expression differences of miR-142-5p between treatment-naïve chronic myeloid leukemia patients responding and non-responding to imatinib therapy suggest a link to oncogenic ABL2, SRI, cKIT and MCL1 signaling pathways critical for development of therapy resistance. Exp Hematol Oncol 2020; 9:26. [PMID: 32999756 PMCID: PMC7519530 DOI: 10.1186/s40164-020-00183-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 09/21/2020] [Indexed: 12/22/2022] Open
Abstract
Background Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by constitutive activity of the tyrosine kinase BCR-ABL1. Although the introduction of tyrosine kinase inhibitors (TKIs) has substantially improved patients’ prognosis, drug resistance remains one of the major challenges in CML therapy. MicroRNAs (miRNAs), a class of short non-coding RNAs acting as post-transcriptional regulators, are implicated in CML progression and drug resistance. The aim of the present study was to analyze the miRNA expression profiles of 45 treatment-naïve CML patients in chronic phase (28 peripheral blood and 17 bone marrow samples) with respect to future response to imatinib therapy. Methods TaqMan low density arrays were used to analyze the miRNA expression pattern of the patient samples. For selected microRNAs, reporter gene assays were performed to study their ability to regulate CML associated target genes. Results Significant lower expression levels of miR-142-5p were identified in both, peripheral blood and bone marrow samples of future non-responders suggesting a potential tumor suppressor role of this miRNA. This was supported by reporter gene assays that identified the survival, proliferation and invasion promoting CML related genes ABL2, cKIT, MCL1 and SRI as targets of miR-142-5p and miR-365a-3p, the latter identified as potential biomarker in peripheral blood samples. Conclusion MiR-142-5p and to a certain extend also miR-365a-3p were able to discriminate treatment-naïve CML patients not responding to imatinib in the course of their treatment from patients, who responded to therapy. However, further large-scale studies should clarify if the identified miRNAs have the potential as predictive biomarkers for TKI resistance.
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Affiliation(s)
- Theresa Klümper
- Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
| | - Henrike Bruckmueller
- Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
| | - Tobias Diewock
- Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
| | - Meike Kaehler
- Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
| | - Sierk Haenisch
- Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
| | - Christiane Pott
- Department of Medicine II, Haematology and Oncology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
| | - Oliver Bruhn
- Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
| | - Ingolf Cascorbi
- Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
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Parama D, Boruah M, Yachna K, Rana V, Banik K, Harsha C, Thakur KK, Dutta U, Arya A, Mao X, Ahn KS, Kunnumakkara AB. Diosgenin, a steroidal saponin, and its analogs: Effective therapies against different chronic diseases. Life Sci 2020; 260:118182. [PMID: 32781063 DOI: 10.1016/j.lfs.2020.118182] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/24/2020] [Accepted: 07/28/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Chronic diseases are a major cause of mortality worldwide, and despite the recent development in treatment modalities, synthetic drugs have continued to show toxic side effects and development of chemoresistance, thereby limiting their application. The use of phytochemicals has gained attention as they show minimal side effects. Diosgenin is one such phytochemical which has gained importance for its efficacy against the life-threatening diseases, such as cardiovascular diseases, cancer, nervous system disorders, asthma, arthritis, diabetes, and many more. AIM To evaluate the literature available on the potential of diosgenin and its analogs in modulating different molecular targets leading to the prevention and treatment of chronic diseases. METHOD A detailed literature search has been carried out on PubMed for gathering information related to the sources, biosynthesis, physicochemical properties, biological activities, pharmacokinetics, bioavailability and toxicity of diosgenin and its analogs. KEY FINDINGS The literature search resulted in many in vitro, in vivo and clinical trials that reported the efficacy of diosgenin and its analogs in modulating important molecular targets and signaling pathways such as PI3K/AKT/mTOR, JAK/STAT, NF-κB, MAPK, etc., which play a crucial role in the development of most of the diseases. Reports have also revealed the safety of the compound and the adaptation of nanotechnological approaches for enhancing its bioavailability and pharmacokinetic properties. SIGNIFICANCE Thus, the review summarizes the efficacy of diosgenin and its analogs for developing as a potent drug against several chronic diseases.
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Affiliation(s)
- Dey Parama
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Monikongkona Boruah
- Cell and Molecular Biology Lab, Department of Zoology, Cotton University, Guwahati, Assam 781001, India
| | - Kumari Yachna
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Varsha Rana
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Kishore Banik
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Choudhary Harsha
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Krishan Kumar Thakur
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Uma Dutta
- Cell and Molecular Biology Lab, Department of Zoology, Cotton University, Guwahati, Assam 781001, India
| | - Aditya Arya
- Department of Pharmacology and Therapeutics, School of Medicine, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Malaysia
| | - Xinliang Mao
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, 12 Jichang Road, Baiyun District, Guangzhou 510405, China; Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu 215123, China
| | - Kwang Seok Ahn
- Department of Science in Korean Medicine, College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India.
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Khatoon E, Banik K, Harsha C, Sailo BL, Thakur KK, Khwairakpam AD, Vikkurthi R, Devi TB, Gupta SC, Kunnumakkara AB. Phytochemicals in cancer cell chemosensitization: Current knowledge and future perspectives. Semin Cancer Biol 2020; 80:306-339. [DOI: 10.1016/j.semcancer.2020.06.014] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 06/11/2020] [Accepted: 06/12/2020] [Indexed: 02/07/2023]
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Wu Y, Tao L, Liang J, Qiao Y, Liu W, Yu H, Yu X, Liu L. miR-187-3p increases gemcitabine sensitivity in breast cancer cells by targeting FGF9 expression. Exp Ther Med 2020; 20:952-960. [PMID: 32765654 PMCID: PMC7388565 DOI: 10.3892/etm.2020.8770] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2018] [Accepted: 01/10/2020] [Indexed: 02/07/2023] Open
Abstract
Breast cancer is the most common type of malignancy in women, which remains a significant health concern worldwide. Gemcitabine is a frequently applied anticancer pharmacological agent. However, the efficacy of gemcitabine is limited by chemoresistance. In the present study, a combination of reverse transcription quantitative-PCR, cell viability, flow cytometry, luciferase reporter assay and western blot analysis were performed to elucidate the potential effects of miR-187-3p on gemcitabine sensitivity in the breast cancer cell line, MDA-MB-231. The results revealed that miR-187-3p was significantly decreased in the breast cancer tumor tissues. Moreover, the overexpression of miR-187-3p significantly inhibited cell viability and promoted apoptosis in MDA-MB-231 cells. In addition, miR-187-3p overexpression enhanced the anti-proliferative and pro-apoptotic effects of gemcitabine, indicating that miR-187-3p regulated gemcitabine sensitivity in breast cancer cells. Mechanistically, miR-187-3p negatively regulated the expression of fibroblast growth factor 9 (FGF9) by binding to its 3'-untranslated region. Overexpression of FGF9 reversed the aforementioned effects of miR-187-3p overexpression on cell viability and apoptosis in the presence of gemcitabine. In conclusion, the present study indicated that miR-187-3p increased gemcitabine sensitivity in breast cancer cells by targeting FGF9 expression.
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Affiliation(s)
- Yingqi Wu
- Breast Surgery Department, Chifeng Municipal Hospital, Chifeng, Inner Mongolia 024000, P.R. China
| | - Li Tao
- Breast Surgery Department, Chifeng Municipal Hospital, Chifeng, Inner Mongolia 024000, P.R. China
| | - Junwei Liang
- Oncology Department, Affiliated Hospital of Chengde Medical College, Chengde, Hebei 067000, P.R. China
| | - Yashun Qiao
- Breast Surgery Department, Chifeng Municipal Hospital, Chifeng, Inner Mongolia 024000, P.R. China
| | - Weiwei Liu
- Oncology Department, Affiliated Hospital of Chengde Medical College, Chengde, Hebei 067000, P.R. China
| | - Haina Yu
- Breast Surgery Department, Chifeng Municipal Hospital, Chifeng, Inner Mongolia 024000, P.R. China
| | - Xinghui Yu
- Breast Surgery Department, Chifeng Municipal Hospital, Chifeng, Inner Mongolia 024000, P.R. China
| | - Lanfang Liu
- Oncology Department, Affiliated Hospital of Chengde Medical College, Chengde, Hebei 067000, P.R. China
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Harsha C, Banik K, Ang HL, Girisa S, Vikkurthi R, Parama D, Rana V, Shabnam B, Khatoon E, Kumar AP, Kunnumakkara AB. Targeting AKT/mTOR in Oral Cancer: Mechanisms and Advances in Clinical Trials. Int J Mol Sci 2020; 21:ijms21093285. [PMID: 32384682 PMCID: PMC7246494 DOI: 10.3390/ijms21093285] [Citation(s) in RCA: 124] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 05/02/2020] [Accepted: 05/03/2020] [Indexed: 12/18/2022] Open
Abstract
Oral cancer (OC) is a devastating disease that takes the lives of lots of people globally every year. The current spectrum of treatment modalities does not meet the needs of the patients. The disease heterogeneity demands personalized medicine or targeted therapies. Therefore, there is an urgent need to identify potential targets for the treatment of OC. Abundant evidence has suggested that the components of the protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) pathway are intrinsic factors for carcinogenesis. The AKT protein is central to the proliferation and survival of normal and cancer cells, and its downstream protein, mTOR, also plays an indispensable role in the cellular processes. The wide involvement of the AKT/mTOR pathway has been noted in oral squamous cell carcinoma (OSCC). This axis significantly regulates the various hallmarks of cancer, like proliferation, survival, angiogenesis, invasion, metastasis, autophagy, and epithelial-to-mesenchymal transition (EMT). Activated AKT/mTOR signaling is also associated with circadian signaling, chemoresistance and radio-resistance in OC cells. Several miRNAs, circRNAs and lncRNAs also modulate this pathway. The association of this axis with the process of tumorigenesis has culminated in the identification of its specific inhibitors for the prevention and treatment of OC. In this review, we discussed the significance of AKT/mTOR signaling in OC and its potential as a therapeutic target for the management of OC. This article also provided an update on several AKT/mTOR inhibitors that emerged as promising candidates for therapeutic interventions against OC/head and neck cancer (HNC) in clinical studies.
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Affiliation(s)
- Choudhary Harsha
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India; (C.H.); (K.B.); (S.G.); (R.V.); (D.P.); (V.R.); (B.S.); (E.K.)
| | - Kishore Banik
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India; (C.H.); (K.B.); (S.G.); (R.V.); (D.P.); (V.R.); (B.S.); (E.K.)
| | - Hui Li Ang
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore;
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore
| | - Sosmitha Girisa
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India; (C.H.); (K.B.); (S.G.); (R.V.); (D.P.); (V.R.); (B.S.); (E.K.)
| | - Rajesh Vikkurthi
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India; (C.H.); (K.B.); (S.G.); (R.V.); (D.P.); (V.R.); (B.S.); (E.K.)
| | - Dey Parama
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India; (C.H.); (K.B.); (S.G.); (R.V.); (D.P.); (V.R.); (B.S.); (E.K.)
| | - Varsha Rana
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India; (C.H.); (K.B.); (S.G.); (R.V.); (D.P.); (V.R.); (B.S.); (E.K.)
| | - Bano Shabnam
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India; (C.H.); (K.B.); (S.G.); (R.V.); (D.P.); (V.R.); (B.S.); (E.K.)
| | - Elina Khatoon
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India; (C.H.); (K.B.); (S.G.); (R.V.); (D.P.); (V.R.); (B.S.); (E.K.)
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore;
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore
- Correspondence: (A.P.K.); (A.B.K.); Tel.: +65-6516-5456 (A.P.K.); +91-361-258-2231 (A.B.K.); Fax: +65-6873-9664 (A.P.K.); +91-361-258-2249 (A.B.K.)
| | - Ajaikumar B. Kunnumakkara
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India; (C.H.); (K.B.); (S.G.); (R.V.); (D.P.); (V.R.); (B.S.); (E.K.)
- Correspondence: (A.P.K.); (A.B.K.); Tel.: +65-6516-5456 (A.P.K.); +91-361-258-2231 (A.B.K.); Fax: +65-6873-9664 (A.P.K.); +91-361-258-2249 (A.B.K.)
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Banik K, Ranaware AM, Harsha C, Nitesh T, Girisa S, Deshpande V, Fan L, Nalawade SP, Sethi G, Kunnumakkara AB. Piceatannol: A natural stilbene for the prevention and treatment of cancer. Pharmacol Res 2020; 153:104635. [DOI: 10.1016/j.phrs.2020.104635] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 12/19/2019] [Accepted: 01/06/2020] [Indexed: 12/13/2022]
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50
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Abstract
Two decades ago a class of ion channels, hitherto unsuspected, was discovered. In mammals these Transient Receptor Potential channels (TRPs) have not only expanded in number (to 26 functional channels) but also expanded the view of our interface with the physical and chemical environment. Some are heat and cold sensors while others monitor endogenous and/or exogenous chemical signals. Some TRP channels monitor osmotic potential, and others measure cell movement, stretching, and fluid flow. Many TRP channels are major players in nociception and integration of pain signals. One member of the vanilloid sub-family of channels is TRPV6. This channel is highly selective for divalent cations, particularly calcium, and plays a part in general whole-body calcium homeostasis, capturing calcium in the gut from the diet. TRPV6 can be greatly elevated in a number of cancers deriving from epithelia and considerable study has been made of its role in the cancer phenotype where calcium control is dysfunctional. This review compiles and updates recent published work on TRPV6 as a promising drug target in a number of cancers including those afflicting breast, ovarian, prostate and pancreatic tissues.
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Affiliation(s)
- John M. Stewart
- Soricimed Biopharma Inc. 18 Botsford Street, Moncton, NB, Canada, E1C 4W7
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