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1
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Liang X, Chen R, Wang C, Wang Y, Zhang J. Targeting HSP90 for Cancer Therapy: Current Progress and Emerging Prospects. J Med Chem 2024; 67:15968-15995. [PMID: 39256986 DOI: 10.1021/acs.jmedchem.4c00966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/12/2024]
Abstract
Heat shock protein 90 (HSP90), a highly conserved member of the heat shock protein family, regulates various proteins and signaling pathways involved in cancer, making it a promising target for cancer therapy. Traditional HSP90 inhibitors have demonstrated significant antitumor potential in preclinical trials, with over 20 compounds advancing to clinical trials and showing promising results. However, the limited clinical efficacy and shared toxicity of these inhibitors restrict their further clinical use. Encouragingly, developing novel inhibitors using conventional medicinal chemistry approaches─such as selective inhibitors, dual inhibitors, protein-protein interaction inhibitors, and proteolysis-targeting chimeras─is expected to address these challenges. Notably, the selective inhibitor TAS-116 has already been successfully marketed. In this Perspective, we summarize the structure, biological functions, and roles of HSP90 in cancer, analyze the clinical status of HSP90 inhibitors, and highlight the latest advancements in novel strategies, offering insights into their future development.
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Affiliation(s)
- Xinqi Liang
- Department of Neurology, Laboratory of Neuro-system and Multimorbidity and Targeted Tracer Research and Development Laboratory and Institute of Respiratory Health and Frontiers Science Center for Disease-related Molecular Network and Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China
| | - Ruixian Chen
- Department of Neurology, Laboratory of Neuro-system and Multimorbidity and Targeted Tracer Research and Development Laboratory and Institute of Respiratory Health and Frontiers Science Center for Disease-related Molecular Network and Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China
- Breast Center, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China
| | - Chengdi Wang
- Department of Neurology, Laboratory of Neuro-system and Multimorbidity and Targeted Tracer Research and Development Laboratory and Institute of Respiratory Health and Frontiers Science Center for Disease-related Molecular Network and Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China
| | - Yuxi Wang
- Department of Neurology, Laboratory of Neuro-system and Multimorbidity and Targeted Tracer Research and Development Laboratory and Institute of Respiratory Health and Frontiers Science Center for Disease-related Molecular Network and Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China
- Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, 610212 Sichuan, China
| | - Jifa Zhang
- Department of Neurology, Laboratory of Neuro-system and Multimorbidity and Targeted Tracer Research and Development Laboratory and Institute of Respiratory Health and Frontiers Science Center for Disease-related Molecular Network and Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China
- Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, 610212 Sichuan, China
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2
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Chen H, Yang F, Zhao Q, Wang H, Zhu M, Li H, Ge Z, Zhang S, Guo Q, Hui H. GL-V9 synergizes with oxaliplatin of colorectal cancer via Wee1 degradation mediated by HSP90 inhibition. J Pharm Pharmacol 2024; 76:1006-1017. [PMID: 38767973 DOI: 10.1093/jpp/rgae060] [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: 02/02/2024] [Accepted: 05/02/2024] [Indexed: 05/22/2024]
Abstract
OBJECTIVES GL-V9 exhibited anti-tumour effects on various types of tumours. This study aimed to verify if GL-V9 synergized with oxaliplatin in suppressing colorectal cancer (CRC) and to explore the synergistic mechanism. METHODS The synergy effect was tested by MTT assays and the mechanism was examined by comet assay, western blotting and immunohistochemistry (IHC). Xenograft model was constructed to substantiated the synergy effect and its mechanism in vivo. RESULTS GL-V9 was verified to enhance the DNA damage effect of oxaliplatin, so as to synergistically suppress colon cancer cells in vitro and in vivo. In HCT-116 cells, GL-V9 accelerated the degradation of Wee1 and induced the abrogation of cell cycle arrest and mis-entry into mitosis, bypassing the DNA damage response caused by oxaliplatin. Our findings suggested that GL-V9 binding to HSP90 was responsible for the degradation of Wee1 and the vulnerability of colon cancer cells to oxaliplatin. Functionally, overexpression of either HSP90 or WEE1 annulled the synergistic effect of GL-V9 and oxaliplatin. CONCLUSIONS Collectively, our findings revealed that GL-V9 synergized with oxaliplatin to suppress CRC and displayed a promising strategy to improve the efficacy of oxaliplatin.
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Affiliation(s)
- Hongyu Chen
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Fan Yang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Qianying Zhao
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Hongzheng Wang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Mengyuan Zhu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Hui Li
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Zheng Ge
- Department of Hematology, Zhongda Hospital, School of Medicine, Southeast University, Institute of Hematology Southeast University, Nanjing 210009, People's Republic of China
| | - Shuai Zhang
- Department of General Thoractic Surgery, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, People's Republic of China
| | - Qinglong Guo
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Hui Hui
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, People's Republic of China
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3
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Jiang M, Wu W, Xiong Z, Yu X, Ye Z, Wu Z. Targeting autophagy drug discovery: Targets, indications and development trends. Eur J Med Chem 2024; 267:116117. [PMID: 38295689 DOI: 10.1016/j.ejmech.2023.116117] [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: 11/20/2023] [Revised: 12/30/2023] [Accepted: 12/31/2023] [Indexed: 02/25/2024]
Abstract
Autophagy plays a vital role in sustaining cellular homeostasis and its alterations have been implicated in the etiology of many diseases. Drugs development targeting autophagy began decades ago and hundreds of agents were developed, some of which are licensed for the clinical usage. However, no existing intervention specifically aimed at modulating autophagy is available. The obstacles that prevent drug developments come from the complexity of the actual impact of autophagy regulators in disease scenarios. With the development and application of new technologies, several promising categories of compounds for autophagy-based therapy have emerged in recent years. In this paper, the autophagy-targeted drugs based on their targets at various hierarchical sites of the autophagic signaling network, e.g., the upstream and downstream of the autophagosome and the autophagic components with enzyme activities are reviewed and analyzed respectively, with special attention paid to those at preclinical or clinical trials. The drugs tailored to specific autophagy alone and combination with drugs/adjuvant therapies widely used in clinical for various diseases treatments are also emphasized. The emerging drug design and development targeting selective autophagy receptors (SARs) and their related proteins, which would be expected to arrest or reverse the progression of disease in various cancers, inflammation, neurodegeneration, and metabolic disorders, are critically reviewed. And the challenges and perspective in clinically developing autophagy-targeted drugs and possible combinations with other medicine are considered in the review.
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Affiliation(s)
- Mengjia Jiang
- Department of Pharmacology and Pharmacy, China Jiliang University, China
| | - Wayne Wu
- College of Osteopathic Medicine, New York Institute of Technology, USA
| | - Zijie Xiong
- Department of Pharmacology and Pharmacy, China Jiliang University, China
| | - Xiaoping Yu
- Department of Biology, China Jiliang University, China
| | - Zihong Ye
- Department of Biology, China Jiliang University, China
| | - Zhiping Wu
- Department of Pharmacology and Pharmacy, China Jiliang University, China.
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4
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Zhang Z, Zhao Y, Wang Y, Zhao Y, Guo J. Autophagy/ferroptosis in colorectal cancer: Carcinogenic view and nanoparticle-mediated cell death regulation. ENVIRONMENTAL RESEARCH 2023; 238:117006. [PMID: 37669735 DOI: 10.1016/j.envres.2023.117006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 08/19/2023] [Accepted: 08/26/2023] [Indexed: 09/07/2023]
Abstract
The cell death mechanisms have a long history of being evaluated in diseases and pathological events. The ability of triggering cell death is considered to be a promising strategy in cancer therapy, but some mechanisms have dual functions in cancer, requiring more elucidation of underlying factors. Colorectal cancer (CRC) is a disease and malignant condition of colon and rectal that causes high mortality and morbidity. The autophagy targeting in CRC is therapeutic importance and this cell death mechanism can interact with apoptosis in inhibiting or increasing apoptosis. Autophagy has interaction with ferroptosis as another cell death pathway in CRC and can accelerate ferroptosis in suppressing growth and invasion. The dysregulation of autophagy affects the drug resistance in CRC and pro-survival autophagy can induce drug resistance. Therefore, inhibition of protective autophagy enhances chemosensitivity in CRC cells. Moreover, autophagy displays interaction with metastasis and EMT as a potent regulator of invasion in CRC cells. The same is true for ferroptosis, but the difference is that function of ferroptosis is determined and it can reduce viability. The lack of ferroptosis can cause development of chemoresistance in CRC cells and this cell death mechanism is regulated by various pathways and mechanisms that autophagy is among them. Therefore, current review paper provides a state-of-art analysis of autophagy, ferroptosis and their crosstalk in CRC. The nanoparticle-mediated regulation of cell death mechanisms in CRC causes changes in progression. The stimulation of ferroptosis and control of autophagy (induction or inhibition) by nanoparticles can impair CRC progression. The engineering part of nanoparticle synthesis to control autophagy and ferroptosis in CRC still requires more attention.
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Affiliation(s)
- Zhibin Zhang
- Chengde Medical College, College of Traditional Chinese Medicine, Chengde, Hebei, 067000, China.
| | - Yintao Zhao
- Chengde Medical College, Chengde, Hebei, 067000, China
| | - Yuman Wang
- Chengde Medical College, Chengde, Hebei, 067000, China
| | - Yutang Zhao
- Chengde Medical College, Chengde, Hebei, 067000, China
| | - Jianen Guo
- Chengde Medical College, Chengde, Hebei, 067000, China
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5
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Kang X, Zhong C, Du X, Amevor FK, Shah AM, Zhu Q, Tian Y, Shu G, Wang Y, Zhao X. Study on the role of heat shock protein 90 ( HSP90) gene in chicken preadipocytes proliferation and differentiation. Anim Biotechnol 2023; 34:1776-1785. [PMID: 35522178 DOI: 10.1080/10495398.2022.2050252] [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] [Indexed: 11/01/2022]
Abstract
In this study, we examined the effects of Heat Shock Protein 90 (HSP90) on adipocyte proliferation and differentiation in chickens. To achieve this, we constructed RNA interference (RNAi) vectors to target HSP90 and transfected the vectors into primary adipocytes. After transfection, oil red O staining was performed to determine the status of triglyceride accumulation in the cells, whereas the CCK-8 cell kit and 5-Ethynyl-2'-Deoxyuridine (EdU) assays were used to determine cell proliferation. Thereafter, the mRNA and protein expression levels of PPARγ, FAS, SREBP-1c, and HSP90 were determined, and the results showed that after the interference of HSP90, the mRNA and protein expression levels of HSP90 in the chicken adipocytes decreased significantly compared to the control and blank groups (p < 0.05). The decreased mRNA and protein expression of PPARγ, FAS, and SREBP-1c was related to adipocyte differentiation (p < 0.05). However, HSP90 interference had no effect on adipocyte proliferation (p > 0.05). Taken together, the results of this study showed that HSP90 influenced the expression of PPARγ and adipose-differentiation-related genes, thereby regulating triglyceride accumulation and adipocyte differentiation in chickens.
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Affiliation(s)
- Xincheng Kang
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Chenglin Zhong
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Xiaxia Du
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Felix Kwame Amevor
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Ali Mujtaba Shah
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Qing Zhu
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Yaofu Tian
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Gang Shu
- Department of Basic Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Yan Wang
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Xiaoling Zhao
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China
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6
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Xie X, Zhang N, Li X, Huang H, Peng C, Huang W, Foster LJ, He G, Han B. Small-molecule dual inhibitors targeting heat shock protein 90 for cancer targeted therapy. Bioorg Chem 2023; 139:106721. [PMID: 37467620 DOI: 10.1016/j.bioorg.2023.106721] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 06/21/2023] [Accepted: 07/06/2023] [Indexed: 07/21/2023]
Abstract
Heat shock protein 90, also known as Hsp90, is an extensively preserved molecular chaperone that performs a critical function in organizing various biological pathways and cellular operations. As a potential drug target, Hsp90 is closely linked to cancer. Hsp90 inhibitors are a class of drugs that have been extensively studied in preclinical models and have shown promise in a variety of diseases, especially cancer. However, Hsp90 inhibitors have encountered several challenges in clinical development, such as low efficacy, toxicity, or drug resistance, few Hsp90 small molecule inhibitors have been approved worldwide. Nonetheless, combining Hsp90 inhibitors with other tumor inhibitors, such as HDAC inhibitors, tubulin inhibitors, and Topo II inhibitors, has been shown to have synergistic antitumor effects. Consequently, the development of Hsp90 dual-target inhibitors is an effective strategy in cancer treatment, as it enhances potency while reducing drug resistance. This article provides an overview of Hsp90's domain structure and biological functions, as well as a discussion of the design, discovery, and structure-activity relationships of Hsp90 dual inhibitors, aiming to provide insights into clinical drug research from a medicinal chemistry perspective and discover novel Hsp90 dual inhibitors.
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Affiliation(s)
- Xin Xie
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, College of Medical Technology and School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Michael Smith Laboratories, University of British Columbia, Vancouver V6T 1Z4, Canada
| | - Nan Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, College of Medical Technology and School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Dermatology & Venereology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xiang Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, College of Medical Technology and School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - He Huang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, College of Medical Technology and School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, College of Medical Technology and School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Wei Huang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, College of Medical Technology and School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Leonard J Foster
- Michael Smith Laboratories, University of British Columbia, Vancouver V6T 1Z4, Canada.
| | - Gu He
- Department of Dermatology & Venereology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Bo Han
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, College of Medical Technology and School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
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7
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Zeng XY, Qiu XZ, Wu JN, Liang SM, Huang JA, Liu SQ. Interaction mechanisms between autophagy and ferroptosis: Potential role in colorectal cancer. World J Gastrointest Oncol 2023; 15:1135-1148. [PMID: 37546557 PMCID: PMC10401467 DOI: 10.4251/wjgo.v15.i7.1135] [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: 02/03/2023] [Revised: 03/28/2023] [Accepted: 04/23/2023] [Indexed: 07/12/2023] Open
Abstract
Colorectal cancer (CRC) is a common malignancy that has the second highest incidence and mortality rate. Although there are many personalized treatment options for CRC, the therapeutic effects are ultimately limited by drug resistance. Studies have aimed to block the initiation and progression of CRC by inducing cell death to overcome this obstacle. Substantial evidence has indicated that both autophagy and ferroptosis play important regulatory roles in CRC. Autophagy, a lysosome-dependent process by which cellular proteins and organelles are degraded, is the basic mechanism for maintaining cell homeostasis. The duality and complexity of autophagy in cancer therapy is a hot topic of discussion. Ferroptosis, a regulated cell death pathway, is associated with iron accumulation-induced lipid peroxidation. The activation of ferroptosis can suppress CRC proliferation, invasion and drug resistance. Furthermore, recent studies have suggested an interaction between autophagy and ferroptosis. Autophagy can selectively degrade certain cellular contents to provide raw materials for ferroptosis, ultimately achieving antitumor and anti-drug resistance. Therefore, exploring the interaction between autophagy and ferroptosis could reveal novel ideas for the treatment of CRC. In this review, we describe the mechanisms of autophagy and ferroptosis, focusing on their roles in CRC and the crosstalk between them.
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Affiliation(s)
- Xin-Ya Zeng
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530000, Guangxi Zhuang Autonomous Region, China
| | - Xin-Ze Qiu
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530000, Guangxi Zhuang Autonomous Region, China
| | - Jiang-Ni Wu
- Department of Pathology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530000, Guangxi Zhuang Autonomous Region, China
| | - Sheng-Mei Liang
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530000, Guangxi Zhuang Autonomous Region, China
| | - Jie-An Huang
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530000, Guangxi Zhuang Autonomous Region, China
| | - Shi-Quan Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530000, Guangxi Zhuang Autonomous Region, China
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8
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Dai Q, Sun Q, Ouyang X, Liu J, Jin L, Liu A, He B, Fan T, Jiang Y. Antitumor Activity of s-Triazine Derivatives: A Systematic Review. Molecules 2023; 28:molecules28114278. [PMID: 37298753 DOI: 10.3390/molecules28114278] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 05/15/2023] [Accepted: 05/19/2023] [Indexed: 06/12/2023] Open
Abstract
1,3,5-triazine derivatives, also called s-triazines, are a series of containing-nitrogen heterocyclic compounds that play an important role in anticancer drug design and development. To date, three s-triazine derivatives, including altretamine, gedatolisib, and enasidenib, have already been approved for refractory ovarian cancer, metastatic breast cancer, and leukemia therapy, respectively, demonstrating that the s-triazine core is a useful scaffold for the discovery of novel anticancer drugs. In this review, we mainly focus on s-triazines targeting topoisomerases, tyrosine kinases, phosphoinositide 3-kinases, NADP+-dependent isocitrate dehydrogenases, and cyclin-dependent kinases in diverse signaling pathways, which have been extensively studied. The medicinal chemistry of s-triazine derivatives as anticancer agents was summarized, including discovery, structure optimization, and biological applications. This review will provide a reference to inspire new and original discoveries.
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Affiliation(s)
- Qiuzi Dai
- The Hunan Provincial University Key Laboratory of the Fundamental and Clinical Research on Functional Nucleic Acid, Hunan Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha 410219, China
| | - Qinsheng Sun
- State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen 518055, China
| | - Xiaorong Ouyang
- The Hunan Provincial University Key Laboratory of the Fundamental and Clinical Research on Functional Nucleic Acid, Hunan Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha 410219, China
| | - Jinyang Liu
- The Hunan Provincial University Key Laboratory of the Fundamental and Clinical Research on Functional Nucleic Acid, Hunan Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha 410219, China
| | - Liye Jin
- The Hunan Provincial University Key Laboratory of the Fundamental and Clinical Research on Functional Nucleic Acid, Hunan Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha 410219, China
| | - Ahao Liu
- The Hunan Provincial University Key Laboratory of the Fundamental and Clinical Research on Functional Nucleic Acid, Hunan Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha 410219, China
| | - Binsheng He
- The Hunan Provincial University Key Laboratory of the Fundamental and Clinical Research on Functional Nucleic Acid, Hunan Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha 410219, China
| | - Tingting Fan
- Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen 518132, China
| | - Yuyang Jiang
- State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen 518055, China
- Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen 518132, China
- School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China
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9
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Dong G, Jiang Y, Zhang F, Zhu F, Liu J, Xu Z. Recent updates on 1,2,3-, 1,2,4-, and 1,3,5-triazine hybrids (2017-present): The anticancer activity, structure-activity relationships, and mechanisms of action. Arch Pharm (Weinheim) 2023; 356:e2200479. [PMID: 36372519 DOI: 10.1002/ardp.202200479] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 10/17/2022] [Accepted: 10/20/2022] [Indexed: 11/15/2022]
Abstract
Cancer is one of the leading causes of death across the world, and the prevalence and mortality rates of cancer will continue to grow. Chemotherapeutics play a critical role in cancer therapy, but drug resistance and side effects are major hurdles to effective treatment, evoking an immediate need for the discovery of new anticancer agents. Triazines including 1,2,3-, 1,2,4-, and 1,3,5-triazine have occupied a propitious place in drug design and development due to their excellent pharmacological profiles. Mechanistically, triazine derivatives could interfere with various signaling pathways to induce cancer cell death. Hence, triazine derivatives possess potential in vitro and in vivo efficacy against diverse cancers. In particular, triazine hybrids are able to overcome drug resistance and reduce side effects. Moreover, several triazine hybrids such as brivanib (indole-containing pyrrolo[2,1-f][1,2,4]triazine), gedatolisib (1,3,5-triazine-urea hybrid), and enasidenib (1,3,5-triazine-pyridine hybrid) have already been available in the market. Accordingly, triazine hybrids are useful scaffolds for the discovery of novel anticancer chemotherapeutics. This review focuses on the anticancer activity of 1,2,3-, 1,2,4-, and 1,3,5-triazine hybrids, together with the structure-activity relationships and mechanisms of action developed from 2017 to the present. The enriched structure-activity relationships may be useful for further rational drug development of triazine hybrids as potential clinical candidates.
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Affiliation(s)
- Gaoli Dong
- School of Chemistry and Pharmaceutical Engineering, Huanghuai University, Zhumadian, China
| | - Yingchun Jiang
- College of Medicine, Huanghuai University, Zhumadian, China
| | - Feng Zhang
- School of Chemistry and Pharmaceutical Engineering, Huanghuai University, Zhumadian, China
| | - Fengyun Zhu
- College of Biology and Food Engineering, Huanghuai University, Zhumadian, China
| | - Junna Liu
- Industry Innovation & Research and Development Institute of Zhumadian, Huanghuai University, Zhumadian, China
| | - Zhi Xu
- Industry Innovation & Research and Development Institute of Zhumadian, Huanghuai University, Zhumadian, China
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10
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Hong Y, Xu WQ, Feng J, Lou H, Liu H, Wang L, Cui H, Jiang LT, Xu RC, Xu HH, Xie MZ, Li Y, Kopylov P, Wang Q, Zhang Y. Nitidine chloride induces cardiac hypertrophy in mice by targeting autophagy-related 4B cysteine peptidase. Acta Pharmacol Sin 2023; 44:561-572. [PMID: 35986213 PMCID: PMC9388977 DOI: 10.1038/s41401-022-00968-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 07/25/2022] [Indexed: 11/09/2022]
Abstract
Nitidine chloride (NC) is a standard active component from the traditional Chinese medicine Zanthoxylum nitidum (Roxb.) DC. (ZN). NC has shown a variety of pharmacological activities including anti-tumor activity. As a number of anti-tumor drugs cause cardiotoxicity, herein we investigated whether NC exerted a cardiotoxic effect and the underlying mechanism. Aqueous extract of ZN (ZNE) was intraperitoneally injected into rats, while NC was injected into beagles and mice once daily for 4 weeks. Cardiac function was assessed using echocardiography. We showed that both ZNE administered in rats and NC administered in mice induced dose-dependent cardiac hypertrophy and dysfunction, whereas administration of NC at the middle and high dose caused death in Beagles. Consistently, we observed a reduction of cardiac autophagy levels in NC-treated mice and neonatal mouse cardiomyocytes. Furthermore, we demonstrated that autophagy-related 4B cysteine peptidase (ATG4B) may be a potential target of NC, since overexpression of ATG4B reversed the cardiac hypertrophy and reduced autophagy levels observed in NC-treated mice. We conclude that NC induces cardiac hypertrophy via ATG4B-mediated downregulation of autophagy in mice. Thus, this study provides guidance for the safe clinical application of ZN and the use of NC as an anti-tumor drug.
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Affiliation(s)
- Yang Hong
- grid.410736.70000 0001 2204 9268Department of Pharmacology (the State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081 China
| | - Wan-qing Xu
- grid.410736.70000 0001 2204 9268Department of Pharmacology (the State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081 China
| | - Jing Feng
- grid.410736.70000 0001 2204 9268Department of Pharmacology (the State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081 China
| | - Han Lou
- grid.410736.70000 0001 2204 9268Department of Pharmacology (the State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081 China
| | - Heng Liu
- grid.410736.70000 0001 2204 9268Department of Pharmacology (the State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081 China
| | - Lei Wang
- grid.410736.70000 0001 2204 9268Department of Pharmacology (the State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081 China
| | - Hao Cui
- grid.410736.70000 0001 2204 9268Department of Pharmacology (the State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081 China
| | - Lin-tong Jiang
- grid.410736.70000 0001 2204 9268Department of Pharmacology (the State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081 China
| | - Ran-chen Xu
- grid.410736.70000 0001 2204 9268Department of Pharmacology (the State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081 China
| | - Heng-hui Xu
- grid.410736.70000 0001 2204 9268Department of Pharmacology (the State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081 China
| | - Min-zhen Xie
- grid.410736.70000 0001 2204 9268Department of Medicinal Chemistry and Natural Medicinal Chemistry, College of Pharmacy, Harbin Medical University, Harbin, 150081 China
| | - Yang Li
- grid.410736.70000 0001 2204 9268Department of Pharmaceutical Analysis, College of Pharmacy, Harbin Medical University, Harbin, 150081 China
| | - Philipp Kopylov
- grid.448878.f0000 0001 2288 8774Department of Preventive and Emergency Cardiology, Sechenov First Moscow State Medical University, Moscow, 101-135 Russian Federation
| | - Qi Wang
- Department of Medicinal Chemistry and Natural Medicinal Chemistry, College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
| | - Yong Zhang
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China. .,Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical Sciences, Harbin, 150081, China. .,Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Harbin, 150086, China.
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11
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Evaluation of the Heat Shock Protein 90 Inhibitor Ganetespib as a Sensitizer to Hyperthermia-Based Cancer Treatments. Cancers (Basel) 2022; 14:cancers14215250. [PMID: 36358669 PMCID: PMC9654690 DOI: 10.3390/cancers14215250] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/17/2022] [Accepted: 10/17/2022] [Indexed: 11/24/2022] Open
Abstract
Simple Summary Hyperthermia boosts the effects of radio- and chemotherapy regimens, but its clinical potential is hindered by the ability of (cancer) cells to activate a protective mechanism known as the heat stress response. Strategies that inhibit its activation or functions have the potential, therefore, to improve the overall efficacy of hyperthermia-based treatments. In this study, we evaluated the efficacy of the HSP90 inhibitor ganetespib in promoting the effects of radiotherapy or cisplatin combined with hyperthermia in vitro and in a cervix cancer mouse model. Abstract Hyperthermia is being used as a radio- and chemotherapy sensitizer for a growing range of tumor subtypes in the clinic. Its potential is limited, however, by the ability of cancer cells to activate a protective mechanism known as the heat stress response (HSR). The HSR is marked by the rapid overexpression of molecular chaperones, and recent advances in drug development make their inhibition an attractive option to improve the efficacy of hyperthermia-based therapies. Our previous in vitro work showed that a single, short co-treatment with a HSR (HSP90) inhibitor ganetespib prolongs and potentiates the effects of hyperthermia on DNA repair, enhances hyperthermic sensitization to radio- and chemotherapeutic agents, and reduces thermotolerance. In the current study, we first validated these results using an extended panel of cell lines and more robust methodology. Next, we examined the effects of hyperthermia and ganetespib on global proteome changes. Finally, we evaluated the potential of ganetespib to boost the efficacy of thermo-chemotherapy and thermo-radiotherapy in a xenograft murine model of cervix cancer. Our results revealed new insights into the effects of HSR inhibition on cellular responses to heat and show that ganetespib could be employed to increase the efficacy of hyperthermia when combined with radiation.
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12
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Heterocyclic Compounds as Hsp90 Inhibitors: A Perspective on Anticancer Applications. Pharmaceutics 2022; 14:pharmaceutics14102220. [PMID: 36297655 PMCID: PMC9610671 DOI: 10.3390/pharmaceutics14102220] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 10/10/2022] [Accepted: 10/17/2022] [Indexed: 11/22/2022] Open
Abstract
Heat shock proteins (Hsps) have garnered special attention in cancer therapy as molecular chaperones with regulatory/mediatory effects on folding, maintenance/stability, maturation, and conformation of proteins as well as their effects on prevention of protein aggregation. Hsp90 ensures the stability of various client proteins needed for the growth of cells or the survival of tumor cells; therefore, they are overexpressed in tumor cells and play key roles in carcinogenesis. Accordingly, Hsp90 inhibitors are recognized as attractive therapeutic agents for investigations pertaining to tumor suppression. Natural Hsp90 inhibitors comprising geldanamycin (GM), reclaimed analogs of GM including 17-AAG and DMAG, and radicicol, a natural macrocyclic antifungal, are among the first potent Hsp90 inhibitors. Herein, recently synthesized heterocyclic compounds recognized as potent Hsp90 inhibitors are reviewed along with the anticancer effects of heterocyclic compounds, comprising purine, pyrazole, triazine, quinolines, coumarin, and isoxazoles molecules.
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13
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Peng F, Liao M, Qin R, Zhu S, Peng C, Fu L, Chen Y, Han B. Regulated cell death (RCD) in cancer: key pathways and targeted therapies. Signal Transduct Target Ther 2022; 7:286. [PMID: 35963853 PMCID: PMC9376115 DOI: 10.1038/s41392-022-01110-y] [Citation(s) in RCA: 411] [Impact Index Per Article: 137.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 07/04/2022] [Accepted: 07/05/2022] [Indexed: 02/07/2023] Open
Abstract
Regulated cell death (RCD), also well-known as programmed cell death (PCD), refers to the form of cell death that can be regulated by a variety of biomacromolecules, which is distinctive from accidental cell death (ACD). Accumulating evidence has revealed that RCD subroutines are the key features of tumorigenesis, which may ultimately lead to the establishment of different potential therapeutic strategies. Hitherto, targeting the subroutines of RCD with pharmacological small-molecule compounds has been emerging as a promising therapeutic avenue, which has rapidly progressed in many types of human cancers. Thus, in this review, we focus on summarizing not only the key apoptotic and autophagy-dependent cell death signaling pathways, but the crucial pathways of other RCD subroutines, including necroptosis, pyroptosis, ferroptosis, parthanatos, entosis, NETosis and lysosome-dependent cell death (LCD) in cancer. Moreover, we further discuss the current situation of several small-molecule compounds targeting the different RCD subroutines to improve cancer treatment, such as single-target, dual or multiple-target small-molecule compounds, drug combinations, and some new emerging therapeutic strategies that would together shed new light on future directions to attack cancer cell vulnerabilities with small-molecule drugs targeting RCD for therapeutic purposes.
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Affiliation(s)
- Fu Peng
- West China School of Pharmacy, State Key Laboratory of Biotherapy and Cancer Center, Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Minru Liao
- West China School of Pharmacy, State Key Laboratory of Biotherapy and Cancer Center, Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Rui Qin
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Shiou Zhu
- West China School of Pharmacy, State Key Laboratory of Biotherapy and Cancer Center, Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Leilei Fu
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China.
| | - Yi Chen
- West China School of Pharmacy, State Key Laboratory of Biotherapy and Cancer Center, Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Bo Han
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
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14
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Zhang L, Zhu Y, Zhang J, Zhang L, Chen L. Inhibiting Cytoprotective Autophagy in Cancer Therapy: An Update on Pharmacological Small-Molecule Compounds. Front Pharmacol 2022; 13:966012. [PMID: 36034776 PMCID: PMC9403721 DOI: 10.3389/fphar.2022.966012] [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: 06/10/2022] [Accepted: 06/21/2022] [Indexed: 12/02/2022] Open
Abstract
Autophagy is a self-degradation process in which damaged proteins and organelles are engulfed into autophagosomes for digestion and eventually recycled for cellular metabolism to maintain intracellular homeostasis. Accumulating studies have reported that autophagy has the Janus role in cancer as a tumor suppressor or an oncogenic role to promote the growth of established tumors and developing drug resistance. Importantly, cytoprotective autophagy plays a prominent role in many types of human cancers, thus inhibiting autophagy, and has been regarded as a promising therapeutic strategy for cancer therapy. Here, we focus on summarizing small-molecule compounds inhibiting the autophagy process, as well as further discuss other dual-target small-molecule compounds, combination strategies, and other strategies to improve potential cancer therapy. Therefore, these findings will shed new light on exploiting more small-molecule compounds inhibiting cytoprotective autophagy as candidate drugs for fighting human cancers in the future.
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Affiliation(s)
- Lijuan Zhang
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yuxuan Zhu
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Jiahui Zhang
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China
- School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
| | - Lan Zhang
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China
- *Correspondence: Lan Zhang, ; Lu Chen,
| | - Lu Chen
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- *Correspondence: Lan Zhang, ; Lu Chen,
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15
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Peinado-Ruiz IC, Burgos-Molina AM, Sendra-Portero F, Ruiz-Gómez MJ. Relationship between heat shock proteins and cellular resistance to drugs and ageing. Exp Gerontol 2022; 167:111896. [PMID: 35870754 DOI: 10.1016/j.exger.2022.111896] [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: 01/17/2022] [Revised: 07/06/2022] [Accepted: 07/12/2022] [Indexed: 11/04/2022]
Abstract
BACKGROUND AND AIMS Ageing is a multifactorial degenerative process which causes a decrease in the cellular capacity for repair and adaptation to external stressors. In this way, it is important to maintain the proper balance of the proteome. Heat shock proteins (HSP) will intervene in this balance, which are responsible for the correct assembly, folding and translocation of other proteins when cells are subjected to stressors. This type of protein is overexpressed in human tumor cells, while its deficit, both in function and quantity, contributes to ageing processes. The present work aims to analyze the response of cells from studies carried out in normal and tumor cells that are subjected to stressors. METHODS AND RESULTS A PubMed search was performed using the keywords "cell ageing, cell longevity, resistance, HSP, heat shock proteins, thermal shock proteins". This search generated 212 articles. Subsequently, a series of inclusion and exclusion criteria were applied to select the articles of interest to be evaluated. Normal cells subjected to external stressors at low doses increase the number of HSP, causing them to become more resistant. In addition, tumor cells expressing high levels of HSP show greater resistance to treatment and increased cell replication. HSP intervene in the cellular resistance of both normal and tumor cells. CONCLUSIONS In the case of normal cells, the increase in HSP levels makes them respond effectively to an external stressor, increasing their resistance and not causing cell death. In the case of tumor cells, there is an increase in resistance to treatment.
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Affiliation(s)
- Isabel C Peinado-Ruiz
- Departamento de Radiología y Medicina Física, Facultad de Medicina, Universidad de Málaga, Málaga, Spain
| | - Antonio M Burgos-Molina
- Departamento de Especialidades Quirúrgicas, Bioquímica e Inmunología, Facultad de Medicina, Universidad de Málaga, Málaga, Spain
| | - Francisco Sendra-Portero
- Departamento de Radiología y Medicina Física, Facultad de Medicina, Universidad de Málaga, Málaga, Spain
| | - Miguel J Ruiz-Gómez
- Departamento de Radiología y Medicina Física, Facultad de Medicina, Universidad de Málaga, Málaga, Spain.
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16
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Li Z, Si W, Jin W, Yuan Z, Chen Y, Fu L. Targeting autophagy in colorectal cancer: An update on pharmacological small-molecule compounds. Drug Discov Today 2022; 27:2373-2385. [PMID: 35589015 DOI: 10.1016/j.drudis.2022.05.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 03/09/2022] [Accepted: 05/11/2022] [Indexed: 02/05/2023]
Abstract
Autophagy, an evolutionarily highly conserved cellular degradation process, plays the Janus role (either cytoprotective or death-promoting) in colorectal cancer, so the targeting of several key autophagic pathways with small-molecule compounds may be a new therapeutic strategy. In this review, we discuss autophagy-associated cell death pathways and key cytoprotective autophagy pathways in colorectal cancer. Moreover, we summarize a series of small-molecule compounds that have the potential to modulate autophagy-associated cell death or cytoprotective autophagy for therapeutic purposes. Taken together, these findings demonstrate the Janus role of autophagy in colorectal cancer, and shed new light on the exploitation of a growing number of small-molecule compounds to target autophagy in future cancer drug discovery.
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Affiliation(s)
- Zixiang Li
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Wen Si
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Chinese Academy of Sciences Limited, Hong Kong Special Administrative Region; Department of Neuroscience, City University of Hong Kong, Kowloon Tong, Hong Kong Special Administrative Region
| | - Wenke Jin
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Zhaoxin Yuan
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Yi Chen
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Leilei Fu
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China.
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17
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Pan B, Xia Y, Gao Z, Zhao G, Wang L, Fang S, Liu L, Yan S. Cinnamomi Ramulus inhibits the growth of colon cancer cells via Akt/ERK signaling pathways. Chin Med 2022; 17:36. [PMID: 35264225 PMCID: PMC8905814 DOI: 10.1186/s13020-022-00588-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 02/26/2022] [Indexed: 12/24/2022] Open
Abstract
Background Colon cancer (CC) ranks the second highest mortality rate among malignant tumors worldwide, and the current mainstream treatment regimens are not very effective. The unique efficacy of Chinese herb medicine (CHM) for cancer has recently attracted increasing attention. Cinnamomi Ramulus (CR), as a classic CHM, has been widely used in the treatment of a variety of diseases for hundreds of years in China, but its specific pharmacological mechanism against CC needs to be fully evaluated. Methods TCMSP and China National Knowledge Infrastructure database were utilized to predict the candidate ingredients of CR, and TCMSP and SwissTargetPrediction database were also employed to predict the drug targets of the candidate ingredients from CR. We subsequently evaluated the therapeutic effect of CR by orally administrating it on CC-bearing mice. Next, we further identified the potential CC-related targets by using Gene Expression Omnibus (GEO) database. Based on these obtained targets, the drug/disease-target PPI networks were constructed using Bisogenet plugin of Cytoscape. The potential core therapeutic targets were then identified through topological analysis using CytoNCA plugin. GO and KEGG enrichment analyses were performed to predict the underlying mechanism of CR against CC. Furthermore, these in silico analysis results were validated by a series of cellular functional and molecular biological assays. UPLC–MS/MS method and molecular docking analysis were employed to identify the potential key components from CR. Results In this study, we firstly found that CR has potential therapeutic effect on cancer. Then, oral administration of CR could inhibit the growth of CC cells in C57BL/6 mice, while inhibiting the viability and motility of CC cells in vitro. We obtained 111 putative core therapeutic targets of CR. Subsequent enrichment analysis on these targets showed that CR could induce apoptosis and cell cycle arrest in CC cells by blocking Akt/ERK signaling pathways, which was further experimentally verified. We identified 5 key components from the crude extract of CR, among which taxifolin was found most likely to be the key active component against CC. Conclusions Our results show that CR as well as its active component taxifolin holds great potential in treatment of CC. Supplementary Information The online version contains supplementary material available at 10.1186/s13020-022-00588-6.
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Affiliation(s)
- Boyu Pan
- Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, ITCWM Hospital, Tianjin University, No.92 Weijin Road, Nankai District, Tianjin, 300072, China.,Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Huanhuxi Road, Hexi District, Tianjin, 300060, China
| | - Yafei Xia
- Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, ITCWM Hospital, Tianjin University, No.92 Weijin Road, Nankai District, Tianjin, 300072, China
| | - Zilu Gao
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Gang Zhao
- Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Huanhuxi Road, Hexi District, Tianjin, 300060, China
| | - Liangjiao Wang
- Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Huanhuxi Road, Hexi District, Tianjin, 300060, China
| | - Senbiao Fang
- School of Information Science and Engineering, Central South University, Yuelu District, Changsha, 410006, Hunan, China.
| | - Liren Liu
- Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Huanhuxi Road, Hexi District, Tianjin, 300060, China.
| | - Shu Yan
- Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, ITCWM Hospital, Tianjin University, No.92 Weijin Road, Nankai District, Tianjin, 300072, China.
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18
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Mathien S, Tesnière C, Meloche S. Regulation of Mitogen-Activated Protein Kinase Signaling Pathways by the Ubiquitin-Proteasome System and Its Pharmacological Potential. Pharmacol Rev 2021; 73:263-296. [PMID: 34732541 DOI: 10.1124/pharmrev.120.000170] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Mitogen-activated protein kinase (MAPK) cascades are evolutionarily conserved signaling pathways that play essential roles in transducing extracellular environmental signals into diverse cellular responses to maintain homeostasis. These pathways are classically organized into an architecture of three sequentially acting protein kinases: a MAPK kinase kinase that phosphorylates and activates a MAPK kinase, which in turn phosphorylates and activates the effector MAPK. The activity of MAPKs is tightly regulated by phosphorylation of their activation loop, which can be modulated by positive and negative feedback mechanisms to control the amplitude and duration of the signal. The signaling outcomes of MAPK pathways are further regulated by interactions of MAPKs with scaffolding and regulatory proteins. Accumulating evidence indicates that, in addition to these mechanisms, MAPK signaling is commonly regulated by ubiquitin-proteasome system (UPS)-mediated control of the stability and abundance of MAPK pathway components. Notably, the biologic activity of some MAPKs appears to be regulated mainly at the level of protein turnover. Recent studies have started to explore the potential of targeted protein degradation as a powerful strategy to investigate the biologic functions of individual MAPK pathway components and as a new therapeutic approach to overcome resistance to current small-molecule kinase inhibitors. Here, we comprehensively review the mechanisms, physiologic importance, and pharmacological potential of UPS-mediated protein degradation in the control of MAPK signaling. SIGNIFICANCE STATEMENT: Accumulating evidence highlights the importance of targeted protein degradation by the ubiquitin-proteasome system in regulating and fine-tuning the signaling output of mitogen-activated protein kinase (MAPK) pathways. Manipulating protein levels of MAPK cascade components may provide a novel approach for the development of selective pharmacological tools and therapeutics.
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Affiliation(s)
- Simon Mathien
- Institute for Research in Immunology and Cancer, Montreal, Quebec, Canada (S.Ma., C.T., S.Me.); and Molecular Biology Program, Faculty of Medicine (C.T., S.Me.) and Department of Pharmacology and Physiology (S.Me.), Université de Montréal, Montreal, Quebec, Canada
| | - Chloé Tesnière
- Institute for Research in Immunology and Cancer, Montreal, Quebec, Canada (S.Ma., C.T., S.Me.); and Molecular Biology Program, Faculty of Medicine (C.T., S.Me.) and Department of Pharmacology and Physiology (S.Me.), Université de Montréal, Montreal, Quebec, Canada
| | - Sylvain Meloche
- Institute for Research in Immunology and Cancer, Montreal, Quebec, Canada (S.Ma., C.T., S.Me.); and Molecular Biology Program, Faculty of Medicine (C.T., S.Me.) and Department of Pharmacology and Physiology (S.Me.), Université de Montréal, Montreal, Quebec, Canada
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Zeng T, Xu M, Zhang W, Gu X, Zhao F, Liu X, Zhang X. Autophagy inhibition and microRNA‑199a‑5p upregulation in paclitaxel‑resistant A549/T lung cancer cells. Oncol Rep 2021; 46:149. [PMID: 34080652 PMCID: PMC8185510 DOI: 10.3892/or.2021.8100] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Accepted: 04/27/2021] [Indexed: 12/15/2022] Open
Abstract
Multidrug resistance (MDR) is one of the major reasons for the clinical failure of cancer chemotherapy. Autophagy activation serves a crucial role in MDR. However, the specific molecular mechanism linking autophagy with MDR remains unknown. The results of the present study demonstrated that autophagy was inhibited and microRNA (miR)-199a-5p levels were upregulated in MDR model lung cancer cells (A549/T and H1299/T) compared with those in the parental cell lines. Paclitaxel (PTX) treatment increased the expression levels of miR-199a-5p in parental lung cancer cells compared with those in PTX-untreated cells, and these expression levels were negatively correlated with PTX sensitivity of the cells. miR-199a-5p knockdown in A549/T cells induced autophagy and resensitized cells to multiple chemotherapeutic drugs including PTX, taxotere, topotecan, SN38, oxaliplatin and vinorelbine. By contrast, miR-199a-5p overexpression in A549 cells suppressed autophagy and desensitized cells to these chemotherapeutic drugs. Mechanistically, the results of the present study demonstrated that miR-199a-5p blocked autophagy by activating the PI3K/Akt/mTOR signaling pathway and inhibiting the protein expression of autophagy-related 5. Furthermore, p62 protein was identified as a direct target of miR-199a-5p; miR-199a-5p bound to p62 mRNA to decrease its mRNA and protein expression levels. In conclusion, the results of the present study suggested that miR-199a-5p may contribute to MDR development in lung cancer cells by inhibiting autophagy and targeting p62. The regulatory effect of miR-199a-5p on autophagy may provide novel insights for future multidrug-resistant lung cancer chemotherapy.
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Affiliation(s)
- Tianjiao Zeng
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, P.R. China
| | - Mingshi Xu
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, P.R. China
| | - Wanli Zhang
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, P.R. China
| | - Xiaofan Gu
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, P.R. China
| | - Fangqing Zhao
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, P.R. China
| | - Xuan Liu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| | - Xiongwen Zhang
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, P.R. China
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20
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Autophagy Modulators in Cancer Therapy. Int J Mol Sci 2021; 22:ijms22115804. [PMID: 34071600 PMCID: PMC8199315 DOI: 10.3390/ijms22115804] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 05/24/2021] [Indexed: 02/06/2023] Open
Abstract
Autophagy is a process of self-degradation that plays an important role in removing damaged proteins, organelles or cellular fragments from the cell. Under stressful conditions such as hypoxia, nutrient deficiency or chemotherapy, this process can also become the strategy for cell survival. Autophagy can be nonselective or selective in removing specific organelles, ribosomes, and protein aggregates, although the complete mechanisms that regulate aspects of selective autophagy are not fully understood. This review summarizes the most recent research into understanding the different types and mechanisms of autophagy. The relationship between apoptosis and autophagy on the level of molecular regulation of the expression of selected proteins such as p53, Bcl-2/Beclin 1, p62, Atg proteins, and caspases was discussed. Intensive studies have revealed a whole range of novel compounds with an anticancer activity that inhibit or activate regulatory pathways involved in autophagy. We focused on the presentation of compounds strongly affecting the autophagy process, with particular emphasis on those that are undergoing clinical and preclinical cancer research. Moreover, the target points, adverse effects and therapeutic schemes of autophagy inhibitors and activators are presented.
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