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Shen J, He Y, Zhou B, Qin H, Zhang S, Huang Z, Zhang X. TFAP2C/FLT3 axis reduces ferroptosis in breast cancer cells by inhibiting mitochondrial autophagy. Int J Biochem Cell Biol 2024; 177:106691. [PMID: 39536858 DOI: 10.1016/j.biocel.2024.106691] [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: 04/16/2024] [Revised: 10/31/2024] [Accepted: 11/10/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND FMS-like tyrosine kinase 3 (FLT3), a key target protein for treating acute myeloid leukemia, has recently been found to be closely related to ferroptosis in breast cancer (BC). However, the mechanism by which FLT3 regulates ferroptosis in BC remains unknown. Whether this regulatory relationship can be exploited for BC treatment needs further exploration. METHODS This study combined analysis from The Cancer Genome Atlas database with immunohistochemistry/quantitative reverse transcription-PCR/Western blot experiments to verify the expression of FLT3 in BC. FLT3 knockdown/overexpression plasmids were used in conjunction with mitochondrial autophagy inducers to treat BC cells, analyzing the effects of FLT3 on autophagy and ferroptosis. Key transcription factors for FLT3 were determined through predictions from the KnockTF database and dual luciferase/chromatin immunoprecipitation experiments, further analyzing the impact of this regulatory axis on autophagy and ferroptosis in BC cells. RESULTS FLT3 was significantly overexpressed in BC tissues and cells. Overexpression of FLT3 could inhibit autophagy and ferroptosis in BC cells, a regulation that was restored upon the addition of mitochondrial autophagy inducers. Additionally, transcription factor AP-2 gamma (TFAP2C) could mediate the transcriptional activation of FLT3, further inhibiting ferroptosis induced by mitochondrial autophagy. CONCLUSION The TFAP2C/FLT3 axis reduced ferroptosis in BC cells by inhibiting mitochondrial autophagy. These research findings elucidated the mechanism by which FLT3 regulated ferroptosis in BC and provided potential targets for BC treatment.
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Affiliation(s)
- Jiayue Shen
- Department of General Surgery, Guangxi Hospital Division of the First Affiliated Hospital, Sun Yat-sen University, Nanning 530022, China
| | - Yali He
- Critical Care Medicine, Guangxi Hospital Division of the First Affiliated Hospital, Sun Yat-sen University, Nanning 530022, China
| | - Bingchuan Zhou
- Department of General Surgery, Guangxi Hospital Division of the First Affiliated Hospital, Sun Yat-sen University, Nanning 530022, China
| | - Huabo Qin
- Department of General Surgery, Guangxi Hospital Division of the First Affiliated Hospital, Sun Yat-sen University, Nanning 530022, China
| | - Shuai Zhang
- Department of General Surgery, Guangxi Hospital Division of the First Affiliated Hospital, Sun Yat-sen University, Nanning 530022, China
| | - Zixiang Huang
- Department of General Surgery, Guangxi Hospital Division of the First Affiliated Hospital, Sun Yat-sen University, Nanning 530022, China
| | - Xiangcheng Zhang
- Department of General Surgery, Guangxi Hospital Division of the First Affiliated Hospital, Sun Yat-sen University, Nanning 530022, China.
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2
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Zhou Z, Zhang P, Li J, Yao J, Jiang Y, Wan M, Tang W, Liu L. Autophagy and the pancreas: Healthy and disease states. Front Cell Dev Biol 2024; 12:1460616. [PMID: 39381372 PMCID: PMC11458389 DOI: 10.3389/fcell.2024.1460616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Accepted: 09/12/2024] [Indexed: 10/10/2024] Open
Abstract
Macroautophagy/autophagy is an intracellular degradation pathway that has an important effect on both healthy and diseased pancreases. It protects the structure and function of the pancreas by maintaining organelle homeostasis and removing damaged organelles. A variety of pancreas-related diseases, such as diabetes, pancreatitis, and pancreatic cancer, are closely associated with autophagy. Genetic studies that address autophagy confirm this view. Loss of autophagy homeostasis (lack or overactivation) can lead to a series of adverse reactions, such as oxidative accumulation, increased inflammation, and cell death. There is growing evidence that stimulating or inhibiting autophagy is a potential therapeutic strategy for various pancreatic diseases. In this review, we discuss the multiple roles of autophagy in physiological and pathological conditions of the pancreas, including its role as a protective or pathogenic factor.
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Affiliation(s)
- Zixian Zhou
- Department of Neurology, West China Hospital, Sichuan University, Chengdu, China
| | - Pengcheng Zhang
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
- Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu, Sichuan, China
| | - Juan Li
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Jiaqi Yao
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Yuhong Jiang
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Meihua Wan
- Department of Neurology, West China Hospital, Sichuan University, Chengdu, China
| | - Wenfu Tang
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
- Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu, Sichuan, China
| | - Ling Liu
- Department of Neurology, West China Hospital, Sichuan University, Chengdu, China
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3
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Santiago-O’Farrill JM, Blessing Bollu A, Yang H, Orellana V, Pina M, Zhang X, Liu J, Bast RC, Lu Z. Crizotinib Enhances PARP Inhibitor Efficacy in Ovarian Cancer Cells and Xenograft Models by Inducing Autophagy. Mol Cancer Res 2024; 22:840-851. [PMID: 38780897 PMCID: PMC11372360 DOI: 10.1158/1541-7786.mcr-23-0680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 04/02/2024] [Accepted: 05/20/2024] [Indexed: 05/25/2024]
Abstract
Poly (ADP-ribose) polymerase inhibitors (PARPi) can encounter resistance through various mechanisms, limiting their effectiveness. Our recent research showed that PARPi alone can induce drug resistance by promoting autophagy. Moreover, our studies have revealed that anaplastic lymphoma kinase (ALK) plays a role in regulating the survival of ovarian cancer cells undergoing autophagy. Here, we explored whether the ALK-inhibitor crizotinib could enhance the efficacy of PARPi by targeting drug-induced autophagic ovarian cancer cell and xenograft models. Our investigation demonstrates that crizotinib enhances the anti-tumor activity of PARPi across multiple ovarian cancer cells. Combination therapy with crizotinib and olaparib reduced cell viability and clonogenic growth in two-olaparib resistant cell lines. More importantly, this effect was consistently observed in patient-derived organoids. Furthermore, combined treatment with crizotinib and olaparib led to tumor regression in human ovarian xenograft models. Mechanistically, the combination resulted in increased levels of reactive oxygen species (ROS), induced DNA damage, and decreased the phosphorylation of AKT, mTOR, and ULK-1, contributing to increased olaparib-induced autophagy and apoptosis. Notably, pharmacologic, or genetic inhibition or autophagy reduced the sensitivity of ovarian cancer cell lines to olaparib and crizotinib treatment, underscoring the role of autophagy in cell death. Blocking ROS mitigated olaparib/crizotinib-induced autophagy and cell death while restoring levels of phosphorylated AKT, mTOR and ULK-1. These findings suggest that crizotinib can improve the therapeutic efficacy of olaparib by enhancing autophagy. Implications: The combination of crizotinib and PARPi presents a promising strategy, that could provide a novel approach to enhance outcomes for patients with ovarian cancer.
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Affiliation(s)
| | - Alicia Blessing Bollu
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Hailing Yang
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Vivian Orellana
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Marc Pina
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Xudong Zhang
- Department of Pathology/Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Jinsong Liu
- Department of Pathology/Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Robert C. Bast
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Zhen Lu
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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4
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Zheng S, Zhang Y, Gong X, Teng Z, Chen J. CREB1 regulates RECQL4 to inhibit mitophagy and promote esophageal cancer metastasis. J Clin Biochem Nutr 2024; 75:102-110. [PMID: 39345293 PMCID: PMC11425078 DOI: 10.3164/jcbn.23-118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 12/12/2023] [Indexed: 10/01/2024] Open
Abstract
Mitophagy plays a vital role in carcinogenesis and tumor progression. However, the research on the mechanism of mitophagy in esophageal cancer metastasis is limited. This study explored the regulatory mechanism of RECQL4 in mitophagy and affects esophageal cancer metastasis. The RECQL4 expression in esophageal cancer tissues and cells was examined by bioinformatics and qRT-PCR. Bioinformatics analysis was used to determine the upstream regulatory factor of RECQL4 and CREB1. Their binding relationship was evaluated by dual luciferase and Chromatin Immunoprecipitation assays. The effects of RECQL4 on esophageal cancer cells viability, metastasis, and mitophagy were examined using CCK-8, Transwell, immunofluorescence, and Western blot assays. The expression of RECQL4 was up-regulated in esophageal cancer tissues and cells. Overexpression of RECQL4 promoted the cells viability, invasion, migration, and epithelial-mesenchymal transition by inhibiting mitophagy. Bioinformatics analysis revealed a positive correlation between RECQL4 and CREB1, their binding relationship was validatied by dual luciferase and ChIP assays. CREB1 knockdown promoted mitophagy and prevented the metastasis of cancer cells, which could be countered by overexpressing RECQL4. In conclusion, CREB1 was found to transcriptionally activate RECQL4 to inhibit mitophagy, thereby promoting esophageal cancer metastasis. Targeting mitophagy could be an effective therapeutic approach for esophageal cancer.
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Affiliation(s)
- Shiyi Zheng
- Department of Cardiothoracic and Vascular Surgery, Guangyuan First People’s Hospital, Guangyuan 628017, China
| | - Yi Zhang
- Department of Cardiothoracic and Vascular Surgery, Guangyuan First People’s Hospital, Guangyuan 628017, China
| | - Xiaozhou Gong
- Department of Cardiothoracic and Vascular Surgery, Guangyuan First People’s Hospital, Guangyuan 628017, China
| | - Zhangyu Teng
- Department of Cardiothoracic and Vascular Surgery, Guangyuan First People’s Hospital, Guangyuan 628017, China
| | - Jun Chen
- Department of Cardiothoracic and Vascular Surgery, Guangyuan First People’s Hospital, Guangyuan 628017, China
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Liu Y, Meng Y, Zhang J, Gu L, Shen S, Zhu Y, Wang J. Pharmacology Progresses and Applications of Chloroquine in Cancer Therapy. Int J Nanomedicine 2024; 19:6777-6809. [PMID: 38983131 PMCID: PMC11232884 DOI: 10.2147/ijn.s458910] [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: 01/10/2024] [Accepted: 05/07/2024] [Indexed: 07/11/2024] Open
Abstract
Chloroquine is a common antimalarial drug and is listed in the World Health Organization Standard List of Essential Medicines because of its safety, low cost and ease of use. Besides its antimalarial property, chloroquine also was used in anti-inflammatory and antivirus, especially in antitumor therapy. A mount of data showed that chloroquine mainly relied on autophagy inhibition to exert its antitumor effects. However, recently, more and more researches have revealed that chloroquine acts through other mechanisms that are autophagy-independent. Nevertheless, the current reviews lacked a comprehensive summary of the antitumor mechanism and combined pharmacotherapy of chloroquine. So here we focused on the antitumor properties of chloroquine, summarized the pharmacological mechanisms of antitumor progression of chloroquine dependent or independent of autophagy inhibition. Moreover, we also discussed the side effects and possible application developments of chloroquine. This review provided a more systematic and cutting-edge knowledge involved in the anti-tumor mechanisms and combined pharmacotherapy of chloroquine in hope of carrying out more in-depth exploration of chloroquine and obtaining more clinical applications.
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Affiliation(s)
- Yanqing Liu
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-Di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, People's Republic of China
| | - Yuqing Meng
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-Di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, People's Republic of China
| | - Junzhe Zhang
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-Di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, People's Republic of China
| | - Liwei Gu
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-Di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, People's Republic of China
| | - Shengnan Shen
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-Di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, People's Republic of China
| | - Yongping Zhu
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-Di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, People's Republic of China
| | - Jigang Wang
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-Di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, People's Republic of China
- Department of Pharmacological Sciences, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
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6
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Ayub A, Hasan MK, Mahmud Z, Hossain MS, Kabir Y. Dissecting the multifaceted roles of autophagy in cancer initiation, growth, and metastasis: from molecular mechanisms to therapeutic applications. Med Oncol 2024; 41:183. [PMID: 38902544 DOI: 10.1007/s12032-024-02417-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 05/28/2024] [Indexed: 06/22/2024]
Abstract
Autophagy is a cytoplasmic defense mechanism that cells use to break and reprocess their intracellular components. This utilization of autophagy is regarded as a savior in nutrient-deficient and other stressful conditions. Hence, autophagy keeps contact with and responds to miscellaneous cellular tensions and diverse pathways of signal transductions, such as growth signaling and cellular death. Importantly, autophagy is regarded as an effective tumor suppressor because regular autophagic breakdown is essential for cellular maintenance and minimizing cellular damage. However, paradoxically, autophagy has also been observed to promote the events of malignancies. This review discussed the dual role of autophagy in cancer, emphasizing its influence on tumor survival and progression. Possessing such a dual contribution to the malignant establishment, the prevention of autophagy can potentially advocate for the advancement of malignant transformation. In contrast, for the context of the instituted tumor, the agents of preventing autophagy potently inhibit the advancement of the tumor. Key regulators, including calpain 1, mTORC1, and AMPK, modulate autophagy in response to nutritional conditions and stress. Oncogenic mutations like RAS and B-RAF underscore autophagy's pivotal role in cancer development. The review also delves into autophagy's context-dependent roles in tumorigenesis, metastasis, and the tumor microenvironment (TME). It also discusses the therapeutic effectiveness of autophagy for several cancers. The recent implication of autophagy in the control of both innate and antibody-mediated immune systems made it a center of attention to evaluating its role concerning tumor antigens and treatments of cancer.
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Affiliation(s)
- Afia Ayub
- Department of Biochemistry and Molecular Biology, Tejgaon College, National University, Gazipur, 1704, Bangladesh
| | - Md Kamrul Hasan
- Department of Biochemistry and Molecular Biology, Tejgaon College, National University, Gazipur, 1704, Bangladesh.
- Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main St. W., Hamilton, L8S 4K1, Canada.
- Department of Public Health, North South University, Dhaka, Bangladesh.
| | - Zimam Mahmud
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh.
| | - Md Sabbir Hossain
- Department of Biochemistry and Molecular Biology, Tejgaon College, National University, Gazipur, 1704, Bangladesh
| | - Yearul Kabir
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh.
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Kwon WA. PARP Inhibitors in the Treatment of Prostate Cancer: From Scientific Rationale to Clinical Development. World J Mens Health 2024; 42:290-303. [PMID: 37853532 PMCID: PMC10949026 DOI: 10.5534/wjmh.230177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 07/19/2023] [Indexed: 10/20/2023] Open
Abstract
Prostate cancer (PC) treatment has reached a milestone with the introduction of poly(ADP-ribose) polymerase (PARP) inhibitors. PARP inhibitors (PARPi) induce breaks in single-stranded and/or double-stranded DNA, resulting in synthetic lethality in cancer cells lacking functional homologous recombination genes. Around 20% to 25% of patients with metastatic castration-resistant prostate cancer harbor mutations in DNA damage repair genes, either somatic or germline. The success of PARPi in these patients has prompted studies exploring its potential in tumors classified as "BRCAness," which refers to tumors without germline BRCA1 or BRCA2 mutations. Additionally, there is a proposed connection between androgen receptor signaling and synthetic lethality of PARPi. The inclusion of genetic mutation tests in the treatment algorithm for PC is a significant step towards precision and personalized medicine, marking a first in the field. The objectives of this review encompass understanding the mechanism of action of PARPi in both monotherapy and combination therapy, exploring patient selection criteria, discussing pivotal studies that led to its approval, and offering future prospects. However, numerous unanswered questions remain, including the identification of the patient population that could benefit most from PARPi, determining whether to use PARPi as monotherapy or in combination, and finding the optimal timing of PARPi administration in advanced or localized disease. To address these questions, several ongoing clinical trials are being conducted.
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Affiliation(s)
- Whi-An Kwon
- Department of Urology, Myongji Hospital, Hanyang University College of Medicine, Goyang, Korea.
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Wu J, Wu Y, Chen S, Guo Q, Shao Y, Liu C, Lin K, Wang S, Zhu J, Chen X, Ju X, Xia L, Wu X. PARP1-stabilised FOXQ1 promotes ovarian cancer progression by activating the LAMB3/WNT/β-catenin signalling pathway. Oncogene 2024; 43:866-883. [PMID: 38297082 DOI: 10.1038/s41388-024-02943-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 01/03/2024] [Accepted: 01/08/2024] [Indexed: 02/02/2024]
Abstract
Metastasis is an important factor that causes ovarian cancer (OC) to become the most lethal malignancy of the female reproductive system, but its molecular mechanism is not fully understood. In this study, through bioinformatics analysis, as well as analysis of tissue samples and clinicopathological characteristics and prognosis of patients in our centre, it was found that Forkhead box Q1 (FOXQ1) was correlated with metastasis and prognosis of OC. Through cell function experiments and animal experiments, the results show that FOXQ1 can promote the progression of ovarian cancer in vivo and in vitro. Through RNA-seq, chromatin immunoprecipitation sequencing (ChIP-seq), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis (GSEA), Western blotting (WB), quantitative real-time polymerase chain reaction (qRT‒PCR), immunohistochemistry (IHC), luciferase assay, and ChIP-PCR, it was demonstrated that FOXQ1 can mediate the WNT/β-catenin pathway by targeting the LAMB promoter region. Through coimmunoprecipitation (Co-IP), mass spectrometry (MS), ubiquitination experiments, and immunofluorescence (IF), the results showed that PARP1 could stabilise FOXQ1 expression via the E3 ubiquitin ligase Hsc70-interacting protein (CHIP). Finally, the whole mechanism pathway was verified by animal drug combination experiments and clinical specimen prognosis analysis. In summary, our results suggest that PARP1 can promote ovarian cancer progression through the LAMB3/WNT/β-catenin pathway by stabilising FOXQ1 expression.
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Affiliation(s)
- Jiangchun Wu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Yong Wu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Siyu Chen
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Qinhao Guo
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Yang Shao
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Chaohua Liu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Kailin Lin
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Simin Wang
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Jun Zhu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Xiaojun Chen
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Xingzhu Ju
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Lingfang Xia
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Xiaohua Wu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China.
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Bai W, Liu D, Cheng Q, Yang X, Zhu L, Qin L, Fang J. Tetraarsenic tetrasulfide triggers ROS-induced apoptosis and ferroptosis in B-cell acute lymphoblastic leukaemia by targeting HK2. Transl Oncol 2024; 40:101850. [PMID: 38043497 PMCID: PMC10701457 DOI: 10.1016/j.tranon.2023.101850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 11/14/2023] [Accepted: 11/25/2023] [Indexed: 12/05/2023] Open
Abstract
PURPOSE Acute lymphoblastic leukemia (ALL) is the most common type of cancer diagnosed in children. Despite cure rates of higher than 85 %, refractory or relapsed ALL still exhibits a bleak prognosis indicative of the dearth of treatment modalities specific for relapsed or refractory ALL. Prior research has implicated metabolic alterations in leukemia pathogenesis, and literature on the therapeutic efficacy of arsenic compounds targeting metabolic pathways in B-cell acute lymphoblastic leukemia (B-ALL) cells is scarce. METHODS A compound extracted from realgar, tetraarsenic tetrasulfide (As4S4), and its antitumor effects on B-ALL were experimentally examined in vitro and in vivo. RESULTS As4S4 apparently targets B-ALL cells by inducing specific cellular responses, including apoptosis, G2/M arrest, and ferroptosis. Interestingly, these effects are attributed to reactive oxygen species (ROS) accumulation, and increased ROS levels have been linked to both the mitochondria-dependent caspase cascade and the activation of p53 signaling. The ROS scavenger N-acetylcysteine (NAC) can counteract the effects of As4S4 treatment on Nalm-6 and RS4;11 cells. Specifically, by targeting Hexokinase-2 (HK2), As4S4 induces alterations in mitochondrial membrane potential and disrupts glucose metabolism, leading to ROS accumulation, and was shown to inhibit B-ALL cell proliferation in vitro and in vivo. Intriguingly, overexpression of HK2 can partially desensitize B-ALL cells to As4S4 treatment. CONCLUSION Tetraarsenic tetrasulfide can regulate the Warburg effect by controlling HK2 expression, a finding that provides both new mechanistic insight into metabolic alterations and pharmacological evidence for the clinical treatment of B-ALL.
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Affiliation(s)
- Wenke Bai
- Department of Pediatrics, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, 107 Yanjiang West Road, Guangzhou, Guangdong 510120, China
| | - Diandian Liu
- Department of Pediatrics, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, 107 Yanjiang West Road, Guangzhou, Guangdong 510120, China
| | - Qianyi Cheng
- Department of Pediatrics, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, 107 Yanjiang West Road, Guangzhou, Guangdong 510120, China
| | - Xingge Yang
- Department of Pediatrics, the First Affiliated Hospital of Henan University of Science and Technology, 24 Jinghua Road Luoyang, Henan 471003, China
| | - Liwen Zhu
- Department of Pediatrics, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, 107 Yanjiang West Road, Guangzhou, Guangdong 510120, China
| | - Lijun Qin
- Department of Pediatrics, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, 107 Yanjiang West Road, Guangzhou, Guangdong 510120, China.
| | - Jianpei Fang
- Department of Pediatrics, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, 107 Yanjiang West Road, Guangzhou, Guangdong 510120, China.
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10
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Wang LH, Wei S, Yuan Y, Zhong MJ, Wang J, Yan ZX, Zhou K, Luo T, Liang L, Bian XW. KPT330 promotes the sensitivity of glioblastoma to olaparib by retaining SQSTM1 in the nucleus and disrupting lysosomal function. Autophagy 2024; 20:295-310. [PMID: 37712615 PMCID: PMC10813631 DOI: 10.1080/15548627.2023.2252301] [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: 01/04/2023] [Revised: 08/14/2023] [Accepted: 08/21/2023] [Indexed: 09/16/2023] Open
Abstract
ABBREVIATIONS AO: acridine orange; ATM: ATM serine/threonine kinase; CHEK1: checkpoint kinase 1; CHEK2: checkpoint kinase 2; CI: combination index; DMSO: dimethyl sulfoxide; DSBs: double-strand breaks; GBM: glioblastoma; HR: homologous recombination; H2AX: H2A.X variant histone; IHC: immunohistochemistry; LAPTM4B: lysosomal protein transmembrane 4 beta; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PARP: poly(ADP-ribose) polymerase; RAD51: RAD51 recombinase; SQSTM1: sequestosome 1; SSBs: single-strand breaks; RNF168: ring finger protein 168; XPO1: exportin 1.
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Affiliation(s)
- Li-Hong Wang
- Department of Pathology, School of Basic Medical Science, Southern Medical University, Guangzhou, Guangdong, China
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing400038, China
| | - Sen Wei
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing400038, China
| | - Ye Yuan
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing400038, China
| | - Ming-Jun Zhong
- Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu610000, China
| | - Jiao Wang
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing400038, China
| | - Ze-Xuan Yan
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing400038, China
| | - Kai Zhou
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Tao Luo
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing400038, China
| | - Li Liang
- Department of Pathology, School of Basic Medical Science, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiu-Wu Bian
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing400038, China
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11
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Maekawa S, Takata R, Obara W. Molecular Mechanisms of Prostate Cancer Development in the Precision Medicine Era: A Comprehensive Review. Cancers (Basel) 2024; 16:523. [PMID: 38339274 PMCID: PMC10854717 DOI: 10.3390/cancers16030523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 01/21/2024] [Accepted: 01/22/2024] [Indexed: 02/12/2024] Open
Abstract
The progression of prostate cancer (PCa) relies on the activation of the androgen receptor (AR) by androgens. Despite efforts to block this pathway through androgen deprivation therapy, resistance can occur through several mechanisms, including the abnormal activation of AR, resulting in castration-resistant PCa following the introduction of treatment. Mutations, amplifications, and splicing variants in AR-related genes have garnered attention in this regard. Furthermore, recent large-scale next-generation sequencing analysis has revealed the critical roles of AR and AR-related genes, as well as the DNA repair, PI3K, and cell cycle pathways, in the onset and progression of PCa. Moreover, research on epigenomics and microRNA has increasingly become popular; however, it has not translated into the development of effective therapeutic strategies. Additionally, treatments targeting homologous recombination repair mutations and the PI3K/Akt pathway have been developed and are increasingly accessible, and multiple clinical trials have investigated the efficacy of immune checkpoint inhibitors. In this comprehensive review, we outline the status of PCa research in genomics and briefly explore potential future developments in the field of epigenetic modifications and microRNAs.
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Affiliation(s)
- Shigekatsu Maekawa
- Department of Urology, Iwate Medical University, Iwate 028-3694, Japan; (R.T.); (W.O.)
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12
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Wang Q, Zhang M, Li A, Yao X, Chen Y. Unraveling the allosteric inhibition mechanism of PARP-1 CAT and the D766/770A mutation effects via Gaussian accelerated molecular dynamics and Markov state model. Comput Biol Med 2024; 168:107682. [PMID: 38000246 DOI: 10.1016/j.compbiomed.2023.107682] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Revised: 10/03/2023] [Accepted: 11/06/2023] [Indexed: 11/26/2023]
Abstract
PARP-1 (Poly (ADP-ribose) polymerase 1) is a nuclear enzyme and plays a key role in many cellular functions, such as DNA repair, modulation of chromatin structure, and recombination. Developing the PARP-1 inhibitors has emerged as an effective therapeutic strategy for a growing list of cancers. The catalytic structural domain (CAT) of PARP-1 upon binding the inhibitor allosterically regulates the conformational changes of helix domain (HD), affecting its identification with the damaged DNA. The typical type I (EB47) and III (veliparib) inhibitors were able to lengthening or shortening the retention time of this enzyme on DNA damage and thus regulating the cytotoxicity. Nonetheless, the basis underlying allosteric inhibition is unclear, which limits the development of novel PARP-1 inhibitors. Here, to investigate the distinct allosteric changes of EB47 and veliparib against PARP-1 CAT, each complex was simulated via classical and Gaussian accelerated molecular dynamics (cMD and GaMD). To study the reverse allosteric basis and mutation effects, the complexes PARP-1 with UKTT15 and PARP-1 D766/770A mutant with EB47 were also simulated. Importantly, the markov state models were built to identify the transition pathways of crucial substates of allosteric communication and the induction basis of PARP-1 reverse allostery. The conformational change differences of PARP-1 CAT regulated by allosteric inhibitors were concerned with to their interaction at the active site. Energy calculations suggested the energy advantage of EB47 in inhibiting the wild-type PARP-1, compared with D766/770A PARP-1. Secondary structure results showed the change of two key loops (αB-αD and αE-αF) in different systems. This work reported the basis of PARP-1 allostery from both thermodynamic and kinetic views, providing the guidance for the discovery and design of more innovative PARP-1 allosteric inhibitors.
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Affiliation(s)
- Qianqian Wang
- Chronic Disease Research Center, Medical College, Dalian University, Dalian, 116622, China.
| | - Mingyu Zhang
- Chronic Disease Research Center, Medical College, Dalian University, Dalian, 116622, China
| | - Aohan Li
- Chronic Disease Research Center, Medical College, Dalian University, Dalian, 116622, China
| | - Xiaojun Yao
- Centre for Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao, 999078, China
| | - Yingqing Chen
- Chronic Disease Research Center, Medical College, Dalian University, Dalian, 116622, China.
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13
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Paraghamian SE, Qiu J, Hawkins GM, Zhao Z, Sun W, Fan Y, Zhang X, Suo H, Hao T, Prabhu VV, Allen JE, Zhou C, Bae-Jump V. A novel dopamine receptor D2 antagonist (ONC206) potentiates the effects of olaparib in endometrial cancer. Cancer Biol Ther 2023; 24:2202104. [PMID: 37069726 PMCID: PMC10115124 DOI: 10.1080/15384047.2023.2202104] [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: 01/18/2023] [Accepted: 04/10/2023] [Indexed: 04/19/2023] Open
Abstract
Poly ADP-ribose polymerase (PARP) inhibitors are effective therapies for cancer patients with homologous recombination (HR) deficient tumors. The imipridone ONC206 is an orally bioavailable dopamine receptor D2 antagonist and mitochondrial protease ClpP agonist that has anti-tumorigenic effects in endometrial cancer via induction of apoptosis, activation of the integrated stress response and modulation of PI3K/AKT signaling. Both PARP inhibitors and imipridones are being evaluated in endometrial cancer clinical trials but have yet to be explored in combination. In this manuscript, we evaluated the effects of the PARP inhibitor olaparib in combination with ONC206 in human endometrioid endometrial cancer cell lines and in a genetically engineered mouse model of endometrial cancer. Our results showed that simultaneous exposure of endometrial cancer cells to olaparib and ONC206 resulted in synergistic anti-proliferative effects and increased cellular stress and apoptosis in both cell lines, compared to either drug alone. The combination treatment also decreased expression of the anti-apoptotic protein Bcl-2 and reduced phosphorylation of AKT and S6, with greater effects compared to either drug alone. In the transgenic model of endometrial cancer, the combination of olaparib and ONC206 resulted in a more significant reduction in tumor weight in obese and lean mice compared to ONC206 alone or olaparib alone, together with a considerably decreased Ki-67 and enhanced H2AX expression in obese and lean mice. These results suggest that this novel dual therapy may be worthy of further exploration in clinical trials.
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Affiliation(s)
- Sarah E. Paraghamian
- Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Jianqing Qiu
- Department of Obstetrics and Gynecology, the Second Hospital of Shandong University, Jinan, China
| | - Gabrielle M. Hawkins
- Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Ziyi Zhao
- Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Wenchuan Sun
- Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Obstetrics and Gynecology, the Second Hospital of Shandong University, Jinan, China
| | - Yali Fan
- Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Xin Zhang
- Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Hongyan Suo
- Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Tianran Hao
- Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | | | | | - Chunxiao Zhou
- Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Victoria Bae-Jump
- Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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14
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Yu Y, Wang T, Meng X, Jiang T, Zhao X. Chitosan Thermosensitive Hydrogel Based on DNA Damage Repair Inhibition and Mild Photothermal Therapy for Enhanced Antitumor Treatment. Biomacromolecules 2023; 24:3755-3766. [PMID: 37506051 DOI: 10.1021/acs.biomac.3c00430] [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: 07/30/2023]
Abstract
The DNA damage repair of tumor cells limits the effect of photothermal therapy (PTT), and high temperatures induced by PTT can damage adjacent normal tissues. To overcome these limitations, we developed a novel composite hydrogel (OLA-Au-Gel) based on chitosan (CS) and β-glycerophosphate (β-GP), which encapsulated olaparib-liposomes (OLA-lips) and CS-capped gold nanoparticles (CS-AuNPs). OLA-Au-Gel achieved the combination of mild PTT (mPTT) by CS-AuNPs and tumor DNA damage repair inhibition by OLA. The hydrogel showed good biocompatibility, injectability, and photothermal response. Under near-infrared laser irradiation, OLA-Au-Gel inhibited the proliferation of tumor cells, induced the generation of reactive oxygen species in vitro, and effectively inhibited the growth of breast tumors in vivo. OLA-Au-Gel shows a promising application prospect for inhibiting tumor development and improving the antitumor effect. Collectively, we propose a novel strategy for enhanced antitumor therapy based on the combination of mPTT and DNA damage repair inhibition.
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Affiliation(s)
- Yang Yu
- Key Laboratory of Marine Drugs, Ministry of Education, Shandong Provincial Key Laboratory of Glycoscience and Glycoengineering, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China
| | - Teng Wang
- Key Laboratory of Marine Drugs, Ministry of Education, Shandong Provincial Key Laboratory of Glycoscience and Glycoengineering, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China
| | - Xin Meng
- Key Laboratory of Marine Drugs, Ministry of Education, Shandong Provincial Key Laboratory of Glycoscience and Glycoengineering, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China
| | - Tianze Jiang
- Key Laboratory of Marine Drugs, Ministry of Education, Shandong Provincial Key Laboratory of Glycoscience and Glycoengineering, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China
| | - Xia Zhao
- Key Laboratory of Marine Drugs, Ministry of Education, Shandong Provincial Key Laboratory of Glycoscience and Glycoengineering, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China
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15
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Mize BK, Salvi A, Ren Y, Burdette JE, Fuchs JR. Discovery and development of botanical natural products and their analogues as therapeutics for ovarian cancer. Nat Prod Rep 2023; 40:1250-1270. [PMID: 37387219 PMCID: PMC10448539 DOI: 10.1039/d2np00091a] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/01/2023]
Abstract
Covering: 2015 through the end of July 2022Ovarian cancer is one of the most common cancers affecting the female reproductive organs and has the highest mortality rate among gynecological cancers. Although botanical drugs and their derivatives, namely members of the taxane and camptothecin families, represent significant therapeutics currently available for the treatment of ovarian cancer, new drugs that have alternative mechanisms of action are still needed to combat the disease. For this reason, many efforts to identify additional novel compounds from botanical sources, along with the further development of existing therapeutics, have continued to appear in the literature. This review is designed to serve as a comprehensive look at both the currently available small-molecule therapeutic options and the recently reported botanically-derived natural products currently being studied and developed as potential future therapeutics that could one day be used against ovarian cancer. Specifically, key properties, structural features, and biological data are highlighted that are important for the successful development of potential agents. Recently reported examples are specifically discussed in the context of "drug discovery attributes," including the presence of structure-activity relationship, mechanism of action, toxicity, and pharmacokinetic studies, to help indicate the potential for future development and to highlight where these compounds currently exist in the development process. The lessons learned from both the successful development of the taxanes and camptothecins, as well as the strategies currently being employed for new drug development, are expected to ultimately help guide the future development of botanical natural products for ovarian cancer.
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Affiliation(s)
- Brittney K Mize
- Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
| | - Amrita Salvi
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Yulin Ren
- Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
| | - Joanna E Burdette
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA
| | - James R Fuchs
- Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
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16
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Komarla A, Dufresne S, Towers CG. Recent Advances in the Role of Autophagy in Endocrine-Dependent Tumors. Endocr Rev 2023; 44:629-646. [PMID: 36631217 PMCID: PMC10335171 DOI: 10.1210/endrev/bnad001] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 10/31/2022] [Accepted: 01/10/2023] [Indexed: 01/13/2023]
Abstract
Autophagy plays a complex role in several cancer types, including endocrine-dependent cancers, by fueling cellular metabolism and clearing damaged substrates. This conserved recycling process has a dual function across tumor types where it can be tumor suppressive at early stages but tumor promotional in established disease. This review highlights the controversial roles of autophagy in endocrine-dependent tumors regarding cancer initiation, tumorigenesis, metastasis, and treatment response. We summarize clinical trial results thus far and highlight the need for additional mechanistic, preclinical, and clinical studies in endocrine-dependent tumors, particularly in breast cancer and prostate cancer.
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Affiliation(s)
- Anvita Komarla
- Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA
- The Cell and Molecular Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Suzanne Dufresne
- The Cell and Molecular Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Christina G Towers
- The Cell and Molecular Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
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17
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Chang X, Tamauchi S, Yoshida K, Yoshihara M, Yokoi A, Shimizu Y, Ikeda Y, Yoshikawa N, Kiyono T, Yamamoto Y, Kajiyama H. Downregulating vaccinia-related kinase 1 by luteolin suppresses ovarian cancer cell proliferation by activating the p53 signaling pathway. Gynecol Oncol 2023; 173:31-40. [PMID: 37075494 DOI: 10.1016/j.ygyno.2023.04.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 03/10/2023] [Accepted: 04/03/2023] [Indexed: 04/21/2023]
Abstract
OBJECTIVES Ovarian cancer constitutes one of the most common causes of cancer-related deaths, and preventing chemotherapy resistance and recurrence in patients with ovarian cancer remains a challenge. Herein, we aimed to identify the effect of luteolin, a novel therapeutic agent targeting vaccinia-related kinase 1 (VRK1), on high-grade serous ovarian cancer (HGSOC). METHODS Phosphokinase array, RNA sequencing, and cell cycle and apoptosis assays were conducted to determine the underlying mechanism of the effect of luteolin on HGSOC cells. The anticancer effects of oral and intraperitoneal luteolin administration were assessed in patient-derived xenograft models via several methods, including the assessment of tumor size and immunohistochemistry of phospho-p53, phosphor-HistoneH3 and cleaved caspase 3. RESULTS Luteolin reduced HGSOC cell proliferation and increased apoptosis and cell cycle arrest at G2/M. Compared with controls, several genes were dysregulated in luteolin-treated cells, and luteolin activated the p53 signaling pathway. The human phosphokinase array revealed distinct p53 upregulation in luteolin-treated cells, as confirmed by p53 phosphorylation at ser15 and ser46 using western blot analysis. In patient-derived xenograft models, oral or intraperitoneal luteolin administration substantially suppressed tumor growth. Moreover, combination treatment involving luteolin and cisplatin inhibited tumor cell proliferation, especially in cisplatin-resistant HGSOC cell lines. CONCLUSIONS Luteolin demonstrated considerable anticancer effect on HGSOC cells, reduced VRK1 expression, and activated the p53 signaling pathway, thereby inducing apoptosis and cell cycle arrest in G2/M and inhibiting cell proliferation. Furthermore, luteolin exhibited a synergistic effect with cisplatin both in vivo and in vitro. Thus, luteolin can be considered a promising cotreatment option for HGSOC.
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Affiliation(s)
- Xuboya Chang
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Satoshi Tamauchi
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
| | - Kosuke Yoshida
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Institute for Advanced Research, Nagoya University, Nagoya 464-8601, Japan
| | - Masato Yoshihara
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Akira Yokoi
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Institute for Advanced Research, Nagoya University, Nagoya 464-8601, Japan
| | - Yusuke Shimizu
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Yoshiki Ikeda
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Nobuhisa Yoshikawa
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Tohru Kiyono
- Project for Prevention of HPV-related Cancer, Exploratory Oncology Research and Clinical Trial Center, Chiba 277-8577, Japan
| | - Yusuke Yamamoto
- Laboratory of Integrative Oncology, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Hiroaki Kajiyama
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
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18
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Long LL, Ma SC, Guo ZQ, Zhang YP, Fan Z, Liu LJ, Liu L, Han DD, Leng MX, Wang J, Guo XJ, Tan JL, Cai XT, Lin Y, Pan X, Wu DH, Bai X, Dong ZY. PARP Inhibition Induces Synthetic Lethality and Adaptive Immunity in LKB1-Mutant Lung Cancer. Cancer Res 2023; 83:568-581. [PMID: 36512628 DOI: 10.1158/0008-5472.can-22-1740] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 11/02/2022] [Accepted: 12/06/2022] [Indexed: 12/15/2022]
Abstract
UNLABELLED Contradictory characteristics of elevated mutational burden and a "cold" tumor microenvironment (TME) coexist in liver kinase B1 (LKB1)-mutant non-small cell lung cancers (NSCLC). The molecular basis underlying this paradox and strategies tailored to these historically difficult to treat cancers are lacking. Here, by mapping the single-cell transcriptomic landscape of genetically engineered mouse models with Kras versus Kras/Lkb1-driven lung tumors, we detected impaired tumor-intrinsic IFNγ signaling in Kras/Lkb1-driven tumors that explains the inert immune context. Mechanistic analysis showed that mutant LKB1 led to deficiency in the DNA damage repair process and abnormally activated PARP1. Hyperactivated PARP1 attenuated the IFNγ pathway by physically interacting with and enhancing the poly(ADP-ribosyl)ation of STAT1, compromising its phosphorylation and activation. Abrogation of the PARP1-driven program triggered synthetic lethality in NSCLC on the basis of the LKB1 mutation-mediated DNA repair defect, while also restoring phosphorylated STAT1 to favor an immunologically "hot" TME. Accordingly, PARP1 inhibition restored the disrupted IFNγ signaling and thus mounted an adaptive immune response to synergize with PD-1 blockade in multiple LKB1-deficient murine tumor models. Overall, this study reveals an unexplored interplay between the DNA repair process and adaptive immune response, providing a molecular basis for dual PARP1 and PD-1 inhibition in treating LKB1-mutant NSCLC. SIGNIFICANCE Targeting PARP exerts dual effects to overcome LKB1 loss-driven immunotherapy resistance through triggering DNA damage and adaptive immunity, providing a rationale for dual PARP and PD-1 inhibition in treating LKB1-mutant lung cancers.
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Affiliation(s)
- Li-Li Long
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Si-Cong Ma
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Information Management and Big Data Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ze-Qin Guo
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yan-Pei Zhang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Information Management and Big Data Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhenzhen Fan
- Institute of Life and Health Engineering, Jinan University, Guangzhou, China
| | - Li-Juan Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, and Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Guangzhou, China
| | - Li Liu
- Information Management and Big Data Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Medical Quality Management, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Duan-Duan Han
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Meng-Xin Leng
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jian Wang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xue-Jun Guo
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jia-Le Tan
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiao-Ting Cai
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yan Lin
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xinghua Pan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, and Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Guangzhou, China
| | - De-Hua Wu
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xue Bai
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhong-Yi Dong
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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19
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Shi D, Pang Q, Qin Q, Yao X, Yao X, Yu Y. Discovery of novel anti-tumor compounds targeting PARP-1 with induction of autophagy through in silico and in vitro screening. Front Pharmacol 2022; 13:1026306. [PMID: 36353483 PMCID: PMC9638114 DOI: 10.3389/fphar.2022.1026306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 10/13/2022] [Indexed: 11/16/2022] Open
Abstract
Poly (ADP-ribose) polymerase 1 (PARP-1) is a critical enzyme involved in DNA damage repair and recombination, and shows great potential for drug development in the treatment of cancers with defective DNA repair. The anti-tumor activities of PARP-1 inhibitors are regulated by both inhibition activities and allosteric mechanisms of PARP-1, and may also be involved in an autophagy-mediated process. Screening PARP-1 inhibitors with potential allosteric mechanisms and induced autophagy process could achieve elevated potency toward cancer cell killing. In this study, we tried to discover novel anti-tumor compounds targeting PARP-1 by computer simulations and in vitro screening. In order to filter PARP-1 inhibitors that could affect the folding state of the helix domain (HD) on PARP-1, the free energy contribution of key residues on HD were systematically analyzed using the ligand-binding crystal structures and integrated into in silico screening workflow for the selection of 20 pick-up compounds. Four compounds (Chemdiv codes: 8012-0567, 8018-6529, 8018-7168, 8018-7603) were proved with above 40% inhibitory ratio targeting PARP-1 under 20 μM, and further performed binding mode prediction and dynamic effect evaluation by molecular dynamics simulation. Further in vitro assays showed that compounds 8018-6529 and 8018-7168 could inhibit the growth of the human colorectal cancer cell (HCT-116) with IC50 values of 4.30 and 9.29 μM and were accompanied with an induced autophagy process. Taken together, we discover two novel anti-tumor compounds that target PARP-1 with an induced autophagy process and provide potential hit compounds for the anti-cancer drug development.
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Affiliation(s)
- Danfeng Shi
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou, China
- *Correspondence: Yang Yu, ; Danfeng Shi,
| | - Qianqian Pang
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou, China
| | - Qianyu Qin
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou, China
| | - Xinsheng Yao
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou, China
| | - Xiaojun Yao
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, China
| | - Yang Yu
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou, China
- *Correspondence: Yang Yu, ; Danfeng Shi,
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20
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Xiong J, Barayan R, Louie AV, Lok BH. Novel therapeutic combinations with PARP inhibitors for small cell lung cancer: A bench-to-bedside review. Semin Cancer Biol 2022; 86:521-542. [PMID: 35917883 DOI: 10.1016/j.semcancer.2022.07.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 07/02/2022] [Accepted: 07/29/2022] [Indexed: 10/31/2022]
Abstract
Small cell lung cancer (SCLC) is treated as a monolithic disease despite the evident intra- and intertumoral heterogeneity. Non-specific DNA-damaging agents have remained the first-line treatment for decades. Recently, emerging transcriptomic and genomic profiling of SCLC tumors identified distinct SCLC subtypes and vulnerabilities towards targeted therapeutics, including inhibitors of the nuclear enzyme poly (ADP-ribose) polymerase (PARPi). SCLC cell lines and tumors exhibited an elevated level of PARP1 protein and mRNA compared to healthy lung tissues and other subtypes of lung tumors. Notable responses to PARPi were also observed in preclinical SCLC models. Clinically, PARPi monotherapy exerted variable benefits for SCLC patients. To date, research is being vigorously conducted to examine predictive biomarkers of PARPi response and various PARPi combination strategies to maximize the clinical utility of PARPi. This narrative review summarizes existing preclinical evidence supporting PARPi monotherapy, combination therapy, and respective translation to the clinic. Specifically, we covered the combination of PARPi with DNA-damaging chemotherapy (cisplatin, etoposide, temozolomide), thoracic radiotherapy, immunotherapy (immune checkpoint inhibitors), and many other novel therapeutic agents that target DNA damage response, tumor microenvironment, epigenetic modulation, angiogenesis, the ubiquitin-proteasome system, or autophagy. Putative biomarkers, such as SLFN11 expression, MGMT methylation, E2F1 expression, and platinum sensitivity, which may be predictive of response to distinct therapeutic combinations, were also discussed. The future of SCLC treatment is undergoing rapid change with a focus on tailored and personalized treatment strategies. Further development of cancer therapy with PARPi will immensely benefit at least a subset of biomarker-defined SCLC patients.
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Affiliation(s)
- Jiaqi Xiong
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Ranya Barayan
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Alexander V Louie
- Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada; Odette Cancer Centre - Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
| | - Benjamin H Lok
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.
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21
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Li H, Liu H, Chen K. Living biobank-based cancer organoids: prospects and challenges in cancer research. Cancer Biol Med 2022; 19:j.issn.2095-3941.2021.0621. [PMID: 35856555 PMCID: PMC9334762 DOI: 10.20892/j.issn.2095-3941.2021.0621] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 03/28/2022] [Indexed: 11/24/2022] Open
Abstract
Biobanks bridge the gap between basic and translational research. Traditional cancer biobanks typically contain normal and tumor tissues, and matched blood. However, biospecimens in traditional biobanks are usually nonrenewable. In recent years, increased interest has focused on establishing living biobanks, including organoid biobanks, for the collection and storage of viable and functional tissues for long periods of time. The organoid model is based on a 3D in vitro cell culture system, is highly similar to primary tissues and organs in vivo, and can recapitulate the phenotypic and genetic characteristics of target organs. Publications on cancer organoids have recently increased, and many types of cancer organoids have been used for modeling cancer processes, as well as for drug discovery and screening. On the basis of the current research status, more exploration of cancer organoids through technical advancements is required to improve reproducibility and scalability. Moreover, given the natural characteristics of organoids, greater attention must be paid to ethical considerations. Here, we summarize recent advances in cancer organoid biobanking research, encompassing rectal, gastric, pancreatic, breast, and glioblastoma cancers. Living cancer biobanks that contain cancerous tissues and matched organoids with different genetic backgrounds, subtypes, and individualized characteristics will eventually contribute to the understanding of cancer and ultimately facilitate the development of innovative treatments.
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Affiliation(s)
- Haixin Li
- Cancer Biobank, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Molecular Cancer Epidemiology of Tianjin, Tianjin 300060, China
| | - Hongkun Liu
- Cancer Biobank, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Molecular Cancer Epidemiology of Tianjin, Tianjin 300060, China
| | - Kexin Chen
- Department of Epidemiology and Biostatistics, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Molecular Cancer Epidemiology of Tianjin, Tianjin 300060, China
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22
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Ortiz M, Wabel E, Mitchell K, Horibata S. Mechanisms of chemotherapy resistance in ovarian cancer. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2022; 5:304-316. [PMID: 35800369 PMCID: PMC9255249 DOI: 10.20517/cdr.2021.147] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 03/09/2022] [Accepted: 03/17/2022] [Indexed: 12/13/2022]
Abstract
Ovarian cancer is one of the most lethal gynecologic cancers. The standard therapy for ovarian cancer has been the same for the past two decades, a combination treatment of platinum with paclitaxel. Recently, the FDA approved three new therapeutic drugs, two poly (ADP-ribose) polymerase inhibitors (olaparib and niraparib) and one vascular endothelial growth factor inhibitor (bevacizumab) as maintenance therapies for ovarian cancer. In this review, we summarize the resistance mechanisms for conventional platinum-based chemotherapy and for the newly FDA-approved drugs.
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Affiliation(s)
- Mylena Ortiz
- Precision Health Program, Michigan State University,766 Service Road, East Lansing, MI 48824, USA.,Authors contributed equally
| | - Emma Wabel
- Precision Health Program, Michigan State University,766 Service Road, East Lansing, MI 48824, USA.,Department of Pharmacology and Toxicology, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA.,Authors contributed equally
| | - Kerry Mitchell
- Precision Health Program, Michigan State University,766 Service Road, East Lansing, MI 48824, USA.,Authors contributed equally
| | - Sachi Horibata
- Precision Health Program, Michigan State University,766 Service Road, East Lansing, MI 48824, USA.,Department of Pharmacology and Toxicology, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA
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23
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Uddin MH, Zhou JY, Pimentel J, Patrick SM, Kim S, Shekhar MP, Wu GS. Proteomic Analysis Identifies p62/SQSTM1 as a Critical Player in PARP Inhibitor Resistance. Front Oncol 2022; 12:908603. [PMID: 35847859 PMCID: PMC9277186 DOI: 10.3389/fonc.2022.908603] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 05/27/2022] [Indexed: 02/04/2023] Open
Abstract
Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) are currently being used for treating breast cancer patients with deleterious or suspected deleterious germline BRCA-mutated, HER2-negative locally advanced or metastatic diseases. Despite durable responses, almost all patients receiving PARPis ultimately develop resistance and succumb to their illness, but the mechanism of PARPi resistance is not fully understood. To better understand the mechanism of PARPi resistance, we established two olaparib-resistant SUM159 and MDA468 cells by chronically exposing olaparib-sensitive SUM159 and MDA468 cells to olaparib. Olaparib-resistant SUM159 and MDA468 cells displayed 5-fold and 7-fold more resistance over their corresponding counterparts. Despite defects in PARPi-induced DNA damage, these olaparib-resistant cells are sensitive to cisplatin-induced cell death. Using an unbiased proteomic approach, we identified 6 447 proteins, of which 107 proteins were differentially expressed between olaparib-sensitive and -resistant cells. Ingenuity pathway analysis (IPA) revealed a number of pathways that are significantly altered, including mTOR and ubiquitin pathways. Among these differentially expressed proteins, p62/SQSTM1 (thereafter p62), a scaffold protein, plays a critical role in binding to and delivering the ubiquitinated proteins to the autophagosome membrane for autophagic degradation, was significantly downregulated in olaparib-resistant cells. We found that autophagy inducers rapamycin and everolimus synergistically sensitize olaparib-resistant cells to olaparib. Moreover, p62 protein expression was correlated with better overall survival in estrogen receptor-negative breast cancer. Thus, these findings suggest that PARPi-sensitive TNBC cells hyperactivate autophagy as they develop acquired resistance and that pharmacological stimulation of excessive autophagy could lead to cell death and thus overcome PARPi resistance.
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Affiliation(s)
- Mohammed Hafiz Uddin
- Molecular Therapeutics Program, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, United States
| | - Jun-Ying Zhou
- Molecular Therapeutics Program, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, United States
| | - Julio Pimentel
- Cancer Biology Program, Wayne State University School of Medicine, Detroit, MI, United States
| | - Steve M. Patrick
- Molecular Therapeutics Program, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, United States,Cancer Biology Program, Wayne State University School of Medicine, Detroit, MI, United States,Department of Oncology, Wayne State University School of Medicine, Detroit, MI, United States
| | - Seongho Kim
- Cancer Biology Program, Wayne State University School of Medicine, Detroit, MI, United States,Department of Oncology, Wayne State University School of Medicine, Detroit, MI, United States
| | - Malathy P. Shekhar
- Molecular Therapeutics Program, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, United States,Cancer Biology Program, Wayne State University School of Medicine, Detroit, MI, United States,Department of Oncology, Wayne State University School of Medicine, Detroit, MI, United States
| | - Gen Sheng Wu
- Molecular Therapeutics Program, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, United States,Cancer Biology Program, Wayne State University School of Medicine, Detroit, MI, United States,Department of Oncology, Wayne State University School of Medicine, Detroit, MI, United States,*Correspondence: Gen Sheng Wu,
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24
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Chen J, Wei Z, Fu K, Duan Y, Zhang M, Li K, Guo T, Yin R. Non-apoptotic cell death in ovarian cancer: Treatment, resistance and prognosis. Biomed Pharmacother 2022; 150:112929. [PMID: 35429741 DOI: 10.1016/j.biopha.2022.112929] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 04/02/2022] [Accepted: 04/05/2022] [Indexed: 11/19/2022] Open
Abstract
Ovarian cancer is mostly diagnosed at an advanced stage due to the absence of effective screening methods and specific symptoms. Repeated chemotherapy resistance and recurrence before PARPi are used as maintenance therapies, lead to low survival rates and poor prognosis. Apoptotic cell death plays a crucial role in ovarian cancer, which is proved by current researches. With the ongoing development of targeted therapy, non-apoptotic cell death has shown substantial potential in tumor prevention and treatment, including autophagy, ferroptosis, necroptosis, immunogenic cell death, pyroptosis, alkaliptosis, and other modes of cell death. We systematically reviewed the research progress on the role of non-apoptotic cell death in the onset, development, and outcome of ovarian cancer. This review provides a more theoretical basis for exploring therapeutic targets, reversing drug resistance in refractory ovarian cancer, and establishing risk prediction models that help realize the clinical transformation of vital drugs.
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Affiliation(s)
- Jinghong Chen
- Department of Obstetrics and Gynaecology, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Zhichen Wei
- The Second Clinical Medical College, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Kaiyu Fu
- Department of Obstetrics and Gynaecology, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yuanqiong Duan
- Department of Obstetrics and Gynaecology, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Mengpei Zhang
- Department of Obstetrics and Gynaecology, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Kemin Li
- Department of Obstetrics and Gynaecology, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Tao Guo
- Department of Obstetrics and Gynaecology, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Rutie Yin
- Department of Obstetrics and Gynaecology, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China.
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25
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Dihydropyrazole-Carbohydrazide Derivatives with Dual Activity as Antioxidant and Anti-Proliferative Drugs on Breast Cancer Targeting the HDAC6. Pharmaceuticals (Basel) 2022; 15:ph15060690. [PMID: 35745608 PMCID: PMC9230091 DOI: 10.3390/ph15060690] [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: 04/02/2022] [Revised: 05/20/2022] [Accepted: 05/26/2022] [Indexed: 12/24/2022] Open
Abstract
Breast cancer (BC) is the most frequently diagnosed cancer and is the second-most common cause of death in women worldwide. Because of this, the search for new drugs and targeted therapy to treat BC is an urgent and global need. Histone deacetylase 6 (HDAC6) is a promising anti-BC drug target associated with its development and progression. In the present work, the design and synthesis of a new family of dihydropyrazole-carbohydrazide derivatives (DPCH) derivatives focused on HDAC6 inhibitory activity is presented. Computational chemistry approaches were employed to rationalize the design and evaluate their physicochemical and toxic-biological properties. The new family of nine DPCH was synthesized and characterized. Compounds exhibited optimal physicochemical and toxicobiological properties for potential application as drugs to be used in humans. The in silico studies showed that compounds with –Br, –Cl, and –OH substituents had good affinity with the catalytic domain 2 of HDAC6 like the reference compounds. Nine DPCH derivatives were assayed on MCF-7 and MDA-MB-231 BC cell lines, showing antiproliferative activity with IC50 at μM range. Compound 2b showed, in vitro, an IC50 value of 12 ± 3 µM on human HDAC6. The antioxidant activity of DPCH derivatives showed that all the compounds exhibit antioxidant activity similar to that of ascorbic acid. In conclusion, the DPCH derivatives are promising drugs with therapeutic potential for the epigenetic treatment of BC, with low cytotoxicity towards healthy cells and important antioxidant activity.
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26
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Experimental models for ovarian cancer research. Exp Cell Res 2022; 416:113150. [DOI: 10.1016/j.yexcr.2022.113150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 03/30/2022] [Accepted: 04/05/2022] [Indexed: 11/23/2022]
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Resveratrol sensitizes breast cancer to PARP inhibitor, talazoparib through dual inhibition of AKT and autophagy flux. Biochem Pharmacol 2022; 199:115024. [PMID: 35367197 DOI: 10.1016/j.bcp.2022.115024] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 02/15/2022] [Accepted: 03/24/2022] [Indexed: 12/18/2022]
Abstract
The efficacy of poly (ADP-ribose) polymerase inhibitors (PARPi) is largely limited to the homologous recombination (HR) deficient cancers. Therefore, there is a necessity to explore novel drug combinations with PARPi to enhance its anti-cancer activity in HR-proficient cancers. By analysing the patient data in cBioPortal, we found copy number amplification of PARP1 in ∼ 22.8% of breast cancers. PARP1 upregulation has been correlated with unfavourable outcome with PARPi treatment. To overcome this adversity, we explored the effect of resveratrol, a natural molecule chemosensitizer, in enhancing the effects of the third generation PARPi, talazoparib (BMN673), against breast adenocarcinoma. Our results show that resveratrol effectively sensitized talazoparib induced cell death in HR proficient and BRCA wild-type breast cancer cells in vitro. Mechanistically, resveratrol caused dysregulation of cell cycle and enhanced talazoparib-induced double strand breaks (DSBs), leading to abnormal mitotic progression culminating in mitotic catastrophe. Intriguingly, our results showed potential of resveratrol in dual-inhibition of AKT-signalling and autophagy flux to impair HR-mediated DSB-repair in breast cancer cells. By using EGFP-LC3 and tf-LC3 (mRFP-EGFP-LC3) expressing breast cancer cells, we found that resveratrol attenuates fusion of autophagosome and lysosome though induction of lysosomal-membrane-permeabilization (LMP). The combination of resveratrol and talazoparib effectively reduced cell proliferation in the high-density cell proliferation assay and also led to tumour volume reduction in vivo pre-clinical SCID-mice model. The combination caused no or minimal cytotoxicity in three different normal cell lines in vitro. Taken together, our work proposes the usage of resveratrol as a chemosensitizer along with talazoparib for targeting HR-proficient breast cancers in clinical settings.
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28
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Patient-derived tumor models are attractive tools to repurpose drugs for ovarian cancer treatment: Pre-clinical updates. Oncotarget 2022; 13:553-575. [PMID: 35359749 PMCID: PMC8959092 DOI: 10.18632/oncotarget.28220] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 03/08/2022] [Indexed: 11/29/2022] Open
Abstract
Despite advances in understanding of ovarian cancer biology, the progress in translation of research findings into new therapies is still slow. It is associated in part with limitations of commonly used cancer models such as cell lines and genetically engineered mouse models that lack proper representation of diversity and complexity of actual human tumors. In addition, the development of de novo anticancer drugs is a lengthy and expensive process. A promising alternative to new drug development is repurposing existing FDA-approved drugs without primary oncological purpose. These approved agents have known pharmacokinetics, pharmacodynamics, and toxicology and could be approved as anticancer drugs quicker and at lower cost. To successfully translate repurposed drugs to clinical application, an intermediate step of pre-clinical animal studies is required. To address challenges associated with reliability of tumor models for pre-clinical studies, there has been an increase in development of patient-derived xenografts (PDXs), which retain key characteristics of the original patient’s tumor, including histologic, biologic, and genetic features. The expansion and utilization of clinically and molecularly annotated PDX models derived from different ovarian cancer subtypes could substantially aid development of new therapies or rapid approval of repurposed drugs to improve treatment options for ovarian cancer patients.
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29
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Eshraghi M, Ahmadi M, Afshar S, Lorzadeh S, Adlimoghaddam A, Rezvani Jalal N, West R, Dastghaib S, Igder S, Torshizi SRN, Mahmoodzadeh A, Mokarram P, Madrakian T, Albensi BC, Łos MJ, Ghavami S, Pecic S. Enhancing autophagy in Alzheimer's disease through drug repositioning. Pharmacol Ther 2022; 237:108171. [PMID: 35304223 DOI: 10.1016/j.pharmthera.2022.108171] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 02/18/2022] [Accepted: 03/08/2022] [Indexed: 02/07/2023]
Abstract
Alzheimer's disease (AD) is one of the biggest human health threats due to increases in aging of the global population. Unfortunately, drugs for treating AD have been largely ineffective. Interestingly, downregulation of macroautophagy (autophagy) plays an essential role in AD pathogenesis. Therefore, targeting autophagy has drawn considerable attention as a therapeutic approach for the treatment of AD. However, developing new therapeutics is time-consuming and requires huge investments. One of the strategies currently under consideration for many diseases is "drug repositioning" or "drug repurposing". In this comprehensive review, we have provided an overview of the impact of autophagy on AD pathophysiology, reviewed the therapeutics that upregulate autophagy and are currently used in the treatment of other diseases, including cancers, and evaluated their repurposing as a possible treatment option for AD. In addition, we discussed the potential of applying nano-drug delivery to neurodegenerative diseases, such as AD, to overcome the challenge of crossing the blood brain barrier and specifically target molecules/pathways of interest with minimal side effects.
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Affiliation(s)
- Mehdi Eshraghi
- Department of Human Anatomy and Cell Science, University of Manitoba College of Medicine, Winnipeg, MB R3E 0V9, Canada
| | - Mazaher Ahmadi
- Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran; Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saeid Afshar
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Shahrokh Lorzadeh
- Department of Human Anatomy and Cell Science, University of Manitoba College of Medicine, Winnipeg, MB R3E 0V9, Canada
| | - Aida Adlimoghaddam
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; St. Boniface Hospital Albrechtsen Research Centre, Division of Neurodegenerative Disorders, Winnipeg, MB R2H2A6, Canada
| | | | - Ryan West
- Department of Chemistry and Biochemistry, California State University, Fullerton, United States of America
| | - Sanaz Dastghaib
- Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz Iran
| | - Somayeh Igder
- Department of Clinical Biochemistry, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | | | - Amir Mahmoodzadeh
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran
| | - Pooneh Mokarram
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Tayyebeh Madrakian
- Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran; Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Benedict C Albensi
- St. Boniface Hospital Albrechtsen Research Centre, Division of Neurodegenerative Disorders, Winnipeg, MB R2H2A6, Canada; Nova Southeastern Univ. College of Pharmacy, Davie, FL, United States of America; University of Manitoba, College of Medicine, Winnipeg, MB R3E 0V9, Canada
| | - Marek J Łos
- Biotechnology Center, Silesian University of Technology, 44-100 Gliwice, Poland
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, University of Manitoba College of Medicine, Winnipeg, MB R3E 0V9, Canada; Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Research Institutes of Oncology and Hematology, Cancer Care Manitoba-University of Manitoba, Winnipeg, MB R3E 0V9, Canada; Biology of Breathing Theme, Children Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB R3E 0V9, Canada; Faculty of Medicine in Zabrze, University of Technology in Katowice, Academia of Silesia, 41-800 Zabrze, Poland
| | - Stevan Pecic
- Department of Chemistry and Biochemistry, California State University, Fullerton, United States of America.
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Liu T, Shen J, He Q, Xu S. Identification of a Novel Immune-Related lncRNA CTD-2288O8.1 Regulating Cisplatin Resistance in Ovarian Cancer Based on Integrated Analysis. Front Genet 2022; 13:814291. [PMID: 35237300 PMCID: PMC8884246 DOI: 10.3389/fgene.2022.814291] [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: 11/13/2021] [Accepted: 01/17/2022] [Indexed: 11/13/2022] Open
Abstract
Ovarian cancer (OC) is the most lethal gynecological malignancy, in which chemoresistance is a crucial factor leading to the poor prognosis. Recently, immunotherapy has brought new light for the treatment of solid tumors. Hence, as a kind of immunologically active cancer, it is reasonably necessary to explore the potential mechanism between immune characteristics and cisplatin resistance in OC. Our study focused on the important role of cisplatin resistance-related lncRNAs on mediating the OC tumor immune microenvironment (TIME) using an integrative analysis based on the Cancer Genome Atlas (TCGA) database. First, the cisplatin resistance-related differentially expressed lncRNAs (DELs) and mRNAs (DEMs) were preliminarily screened to construct a DEL–DEM co-expression network. Next, the protein–protein interaction (PPI) network and pivot analysis were performed to reveal the relevance of these lncRNAs with tumor immune response. Second, the novel lncRNA CTD-2288O8.1 was identified as a key gene for the OC cisplatin resistance formation by qRT-PCR and survival analysis. Gain- and loss-of-function assays (Cell Counting Kit-8 (CCK-8) assay, wound-healing scratch assay, transwell assay, and colony formation assay) further verified the activity of CTD-2288O8.1 in OC progression as well. Third, gene set enrichment analysis (GSEA) was applied along with the correlation analyses of CTD-2288O8.1 with ImmuneScore, tumor-infiltrating immune cells (TICs), and immune inhibitory checkpoint molecules, illustrating that CTD-2288O8.1 was strongly associated with the TIME and has the potential to predict the effect of OC immunotherapy. In addition, basic experiments demonstrated that the expression of CTD-2288O8.1 impacted the EGFR/AKT signal pathway activity of OC tumor cells. Of greater significance, it promoted the M2 polarization of macrophage, which is a type of the most important components of the TIME in solid tumor. Taking together, our study revealed cisplatin resistance-related lncRNAs closely linked with tumor immunity in OC, underscoring the potential mechanism of the TIME in conferring cisplatin resistance, which provided the research basis for further clinical treatment. CTD-2288O8.1 was identified to mediate cisplatin resistance and affect the response of immunotherapy, which could serve as a promising biomarker for guiding clinical treatment and improving prognosis in OC.
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Affiliation(s)
- Tingwei Liu
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jiacheng Shen
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Qizhi He
- Department of Pathology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
- *Correspondence: Qizhi He, ; Shaohua Xu,
| | - Shaohua Xu
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
- *Correspondence: Qizhi He, ; Shaohua Xu,
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Zhou Y, Zhao X, Zhang L, Xia Q, Peng Y, Zhang H, Yan D, Yang Z, Li J. Iron overload inhibits cell proliferation and promotes autophagy via PARP1/SIRT1 signaling in endometriosis and adenomyosis. Toxicology 2022; 465:153050. [PMID: 34826546 DOI: 10.1016/j.tox.2021.153050] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 11/10/2021] [Accepted: 11/20/2021] [Indexed: 10/19/2022]
Abstract
Emerging evidence suggests that excess iron accumulates in endometriotic and adenomyotic lesions. However, the role iron overload plays in the pathogenesis of endometriosis or adenomyosis remains unknown. Primary human eutopic endometrial stromal cells (EuESCs) from endometriosis or adenomyosis patients were used as the in vitro model of endometriosis or adenomyosis in this study. We found that iron, manifesting as ferric ammonium citrate (FAC; 0.05-4.8 mM), significantly inhibited cell growth, induced oxidative stress through the Fenton reaction, and functionally activated autophagy in EuESCs, as measured by 5-ethynyl-2'-deoxyuridine incorporation assay, MitoSOX™ Red staining, LC3 turnover assay, and tandem mCherry-eGFP-LC3B fluorescence microscopy. Immunohistochemistry analysis of Ki67 expression in proliferative-phase endometrial tissues revealed that cell proliferation in ectopic tissues was dramatically compromised, suggesting that iron overload may play a role in cell growth inhibition in vivo. We observed that autophagy may alleviate the FAC-induced inhibition of endometrial stromal cell proliferation. Furthermore, sequential FAC (0.8 mM, 24 h) and hydrogen peroxide (H2O2; 300 μM, 2 h) treatment successfully induced the Fenton reaction in EuESCs and caused extensive apoptosis, whereas the disruption of autophagy by the knockdown of BECN1 further aggravated cell death. MitoSOX™ Red staining showed that autophagy may promote the survival of EuESCs by decreasing of the Fenton reaction-induced reactive oxygen species generation. In addition, we observed that the Fenton reaction-induced oxidative stress significantly suppressed iron overload-induced autophagy. Moreover, we found that FAC treatment impaired poly(ADP-ribose)-polymerase 1 (PARP1) expression while simultaneously upregulating SIRT1 expression in EuESCs. Our data further showed that PARP1 expression decreased in endometriotic lesions, which may partially result from iron overload. We also found that PARP1 inhibition aggravated iron overload-induced cell growth suppression, and was implicated in iron overload-induced autophagy. In addition, SIRT1 silencing alleviated iron overload-induced PARP1 downregulation and autophagy activation. Overall, our data suggest that iron overload in endometrial stromal cells of endometriotic or adenomyotic lesions may be involved in the inhibition of cell proliferation, simultaneously with the activation of protective autophagy via PARP1/SIRT1 signaling.
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Affiliation(s)
- Yingying Zhou
- Department of Laboratory Medicine, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China
| | - Xiumin Zhao
- Department of Obstetrics and Gynecology, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China
| | - Lingmin Zhang
- Department of Laboratory Medicine, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China
| | - Qingqing Xia
- Department of Laboratory Medicine, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China
| | - Yangying Peng
- Department of Obstetrics and Gynecology, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China
| | - Huiping Zhang
- Department of Obstetrics and Gynecology, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China
| | - Dewen Yan
- Department of Obstetrics and Gynecology, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China
| | - Zaixing Yang
- Department of Laboratory Medicine, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China.
| | - Jie Li
- Department of Laboratory Medicine, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China.
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Kanakkanthara A, Hou X, Ekstrom TL, Zanfagnin V, Huehls AM, Kelly RL, Ding H, Larson MC, Vasmatzis G, Oberg AL, Kaufmann SH, Mansfield AS, John Weroha S, Karnitz LM. Repurposing Ceritinib Induces DNA Damage and Enhances PARP Inhibitor Responses in High-Grade Serous Ovarian Carcinoma. Cancer Res 2022; 82:307-319. [PMID: 34810199 PMCID: PMC8770599 DOI: 10.1158/0008-5472.can-21-0732] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 08/05/2021] [Accepted: 11/15/2021] [Indexed: 12/14/2022]
Abstract
PARP inhibitors (PARPi) have activity in homologous recombination (HR) repair-deficient, high-grade serous ovarian cancers (HGSOC). However, even responsive tumors develop PARPi resistance, highlighting the need to delay or prevent the appearance of PARPi resistance. Here, we showed that the ALK kinase inhibitor ceritinib synergizes with PARPis by inhibiting complex I of the mitochondrial electron transport chain, which increases production of reactive oxygen species (ROS) and subsequent induction of oxidative DNA damage that is repaired in a PARP-dependent manner. In addition, combined treatment with ceritinib and PARPi synergized in HGSOC cell lines irrespective of HR status, and a combination of ceritinib with the PARPi olaparib induced tumor regression more effectively than olaparib alone in HGSOC patient-derived xenograft (PDX) models. Notably, the ceritinib and olaparib combination was most effective in PDX models with preexisting PARPi sensitivity and was well tolerated. These findings unveil suppression of mitochondrial respiration, accumulation of ROS, and subsequent induction of DNA damage as novel effects of ceritinib. They also suggest that the ceritinib and PARPi combination warrants further investigation as a means to enhance PARPi activity in HGSOC, particularly in tumors with preexisting HR defects. SIGNIFICANCE: The kinase inhibitor ceritinib synergizes with PARPi to induce tumor regression in ovarian cancer models, suggesting that ceritinib combined with PARPi may be an effective strategy for treating ovarian cancer.
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Affiliation(s)
- Arun Kanakkanthara
- Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA,Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA,To whom correspondence should be addressed: Larry M. Karnitz, Department of Oncology, Gonda 19-300, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Telephone: 507-284-3124; .; S. John Weroha, Department of Oncology, Guggenheim 13-01C, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Telephone: 507-284-3731; ; Arun Kanakkanthara, Department of Oncology, Gonda 19-300, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Telephone: 507-266-0268;
| | - Xiaonan Hou
- Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA
| | | | | | | | - Rebecca L. Kelly
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA
| | - Husheng Ding
- Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA
| | - Melissa C. Larson
- Department of Quantitative Health Sciences, Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, Minnesota, USA
| | - George Vasmatzis
- Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Ann L. Oberg
- Department of Quantitative Health Sciences, Division of Computational Biology, Mayo Clinic, Rochester, Minnesota, USA
| | - Scott H. Kaufmann
- Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA,Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA
| | | | - S. John Weroha
- Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA,To whom correspondence should be addressed: Larry M. Karnitz, Department of Oncology, Gonda 19-300, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Telephone: 507-284-3124; .; S. John Weroha, Department of Oncology, Guggenheim 13-01C, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Telephone: 507-284-3731; ; Arun Kanakkanthara, Department of Oncology, Gonda 19-300, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Telephone: 507-266-0268;
| | - Larry M. Karnitz
- Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA,Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA,To whom correspondence should be addressed: Larry M. Karnitz, Department of Oncology, Gonda 19-300, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Telephone: 507-284-3124; .; S. John Weroha, Department of Oncology, Guggenheim 13-01C, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Telephone: 507-284-3731; ; Arun Kanakkanthara, Department of Oncology, Gonda 19-300, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Telephone: 507-266-0268;
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Bustos SO, Leal Santos N, Chammas R, Andrade LNDS. Secretory Autophagy Forges a Therapy Resistant Microenvironment in Melanoma. Cancers (Basel) 2022; 14:234. [PMID: 35008395 PMCID: PMC8749976 DOI: 10.3390/cancers14010234] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 12/22/2021] [Accepted: 12/28/2021] [Indexed: 12/12/2022] Open
Abstract
Melanoma is the most aggressive skin cancer characterized by high mutational burden and large heterogeneity. Cancer cells are surrounded by a complex environment, critical to tumor establishment and progression. Thus, tumor-associated stromal components can sustain tumor demands or impair cancer cell progression. One way to manage such processes is through the regulation of autophagy, both in stromal and tumor cells. Autophagy is a catabolic mechanism that provides nutrients and energy, and it eliminates damaged organelles by degradation and recycling of cellular elements. Besides this primary function, autophagy plays multiple roles in the tumor microenvironment capable of affecting cell fate. Evidence demonstrates the existence of novel branches in the autophagy system related to cytoplasmic constituent's secretion. Hence, autophagy-dependent secretion assembles a tangled network of signaling that potentially contributes to metabolism reprogramming, immune regulation, and tumor progression. Here, we summarize the current awareness regarding secretory autophagy and the intersection with exosome biogenesis and release in melanoma and their role in tumor resistance. In addition, we present and discuss data from public databases concerning autophagy and exosome-related genes as important mediators of melanoma behavior. Finally, we will present the main challenges in the field and strategies to translate most of the pre-clinical findings to clinical practice.
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Affiliation(s)
- Silvina Odete Bustos
- Center for Translational Research in Oncology (LIM24), Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Sao Paulo 01246-000, Brazil; (N.L.S.); (R.C.)
| | | | | | - Luciana Nogueira de Sousa Andrade
- Center for Translational Research in Oncology (LIM24), Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Sao Paulo 01246-000, Brazil; (N.L.S.); (R.C.)
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Stat1 confers sensitivity to radiation in cervical cancer cells by controlling Parp1 levels: a new perspective for Parp1 inhibition. Cell Death Dis 2021; 12:933. [PMID: 34642300 PMCID: PMC8511191 DOI: 10.1038/s41419-021-04229-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 09/15/2021] [Accepted: 09/27/2021] [Indexed: 01/15/2023]
Abstract
Cervical cancer (CC) is the fourth most common cause of cancer-related death in women. According to international guidelines, a standard treatment for locally advanced cervical cancer (LACC) consists of exclusive concurrent chemoradiation treatment (CRT). However, chemoradioresistance and subsequent relapse and metastasis of cancer occur in many patients, and survival for these women has generally remained poor. Therefore, strategies to overcome resistance are urgently needed. We have recently reported a radiosensitizing effect of the signal transducer and activator of transcription 1 (STAT1) in CC, associated with the control of [Poly(ADP-ribose) polymerase −1] PARP1 levels, a key factor in cell response to DNA damage induced by radiation. Here, we sought to decipher the underlying mechanism of STAT1-mediated control of PARP1, elucidating its role as a radiosensitizer in CC. Functional and molecular biology studies demonstrated that STAT1 may act at both transcriptional and posttranscriptional levels to modulate PARP1 expression in CC cells. In light of these results, we tested the effect of Olaparib in sensitizing CC cells to radiation and investigated signaling pathways involved in the activity observed. Results showed that PARP1 inhibition, at clinically achievable doses, may indeed selectively improve the sensitivity of resistant CC cells to DNA-damaging treatment. The translational relevance of our findings was supported by preliminary results in a limited patient cohort, confirming that higher PARP1 levels are significantly associated with a radioresistant phenotype. Finally, bioinformatics analysis of GEPIA and TCGA databases, demonstrated that PARP1 mRNA is higher in CC than in normal tissues and that increased PARP1 mRNA expression levels are associated with poor prognosis of LACC patients. Overall, our data open new opportunities for the development of personalized treatments in women diagnosed with CC.
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Zhou L, Xiang J, He Y. Research progress on the association between environmental pollutants and the resistance mechanism of PARP inhibitors in ovarian cancer. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:49491-49506. [PMID: 34370190 DOI: 10.1007/s11356-021-15852-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Accepted: 08/03/2021] [Indexed: 06/13/2023]
Abstract
The occurrence and progression of ovarian cancer are closely related to genetics and environmental pollutants. Poly(ADP-ribose) polymerase (PARP) inhibitors have been a major breakthrough in the history of ovarian cancer treatment. PARP is an enzyme responsible for post-translational modification of proteins and repair of single-stranded DNA damage. PARP inhibitors can selectively inhibit PARP function, resulting in a synthetic lethal effect on tumor cells defective in homologous recombination repair. However, with large-scale application, drug resistance also inevitably appears. For PARP inhibitors, the diversity and complexity of drug resistance mechanisms have always been difficult problems in clinical treatment. Herein, we mainly summarized the research progress of DNA damage repair and drug resistance mechanisms related to PARP inhibitors and the impact of environmental pollutants on DNA damage repair to aid the development prospects and highlight urgent problems to be solved.
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Affiliation(s)
- Lina Zhou
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080, People's Republic of China
| | - Jiangdong Xiang
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080, People's Republic of China
| | - Yinyan He
- Department of Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 200092, People's Republic of China.
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Ninfole E, Pinto C, Benedetti A, Marzioni M, Maroni L. Role of autophagy in cholangiocarcinoma: Pathophysiology and implications for therapy. World J Clin Cases 2021; 9:6234-6243. [PMID: 34434990 PMCID: PMC8362566 DOI: 10.12998/wjcc.v9.i22.6234] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/26/2021] [Accepted: 06/28/2021] [Indexed: 02/06/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a malignant tumour of the biliary system that originates from the neoplastic transformation of cholangiocytes. CCA is characterized by late diagnosis and poor outcome, with surgery considered as the last option for management. Autophagy is a physiological lysosomal degradation process, essential for cellular homeostasis and ubiquitous in all eukaryotic cells. Several studies have reported a potential involvement of autophagy in cancer, but it remains unclear whether activation of this process represents a survival mechanism of cancer cells. In the present review, we examine the autophagic process and summarize the current knowledge about the involvement of autophagy in the progression of cancer. The link between autophagy and chemoresistance and the use of autophagic markers in diagnosis are also considered in detail. Preliminary evidence shows that the combination of autophagy modulators (activators or inhibitors) with conventional chemotherapeutic agents offers a possible treatment option against signalling pathways that are hyperactivated or altered in CCA. In vitro evidence suggests that combination of chemotherapy agents, such as cisplatin, under activation or inhibition of autophagic processes, in two different CCA cell lines, may improve chemosensitivity and reduce cell survival, respectively. A deeper understanding of these pathways, in both cancer and non-cancer cells, could unveil possible therapeutic targets to treat CCA patients.
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Affiliation(s)
- Elisabetta Ninfole
- Department of Gastroenterology and Hepatology, Università Politecnica delle Marche, Ancona 60126, Italy
| | - Claudio Pinto
- Department of Gastroenterology and Hepatology, Università Politecnica delle Marche, Ancona 60126, Italy
| | - Antonio Benedetti
- Department of Gastroenterology and Hepatology, Università Politecnica delle Marche, Ancona 60126, Italy
| | - Marco Marzioni
- Department of Gastroenterology, Università Politecnica delle Marche, Ancona 60126, Italy
| | - Luca Maroni
- Department of Gastroenterology and Hepatology, Università Politecnica delle Marche, Ancona 60126, Italy
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Wang H, Fu Y. NR1D1 suppressed the growth of ovarian cancer by abrogating the JAK/STAT3 signaling pathway. BMC Cancer 2021; 21:871. [PMID: 34330232 PMCID: PMC8323274 DOI: 10.1186/s12885-021-08597-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 07/06/2021] [Indexed: 11/10/2022] Open
Abstract
Background Nuclear receptor subfamily 1 group D member 1 (NR1D1), a nuclear receptor associated with a variety of physiological processes, has a low level in ovarian cancer tissues compared with adjacent normal tissues. However, its role in ovarian cancer remains unclear. Methods The level of NR1D1 in ovarian cancer cells was determined by quantitative real-time PCR. Its role in ovarian cancer was explored through gain-of-function and lose-of-function. Cell growth was evaluated by CCK8 assay, immunofluorescence and flow cytometry. Western blot was conducted to assess the activation of JAK/STAT3 signaling pathway. A xenograft model of ovarian cancer was established to explore the role of NR1D1 in vivo. Results Up-regulation of NR1D1 repressed the ovarian cancer cell proliferation and induced cell cycle arrest and apoptosis, while silencing NR1D1 promoted their proliferation and G1/S transition. In addition, the JAK/STAT3 signaling pathway, an intracellular signal transduction closely associated with cancer progression, was inhibited by NR1D1. Consistently, xenografts with NR1D1 over-expression grew more slowly in vivo than the controls. Furthermore, NR1D1 up-regulated the expression of suppressor of cytokine signaling 3 (SOCS3), an inhibitor of the JAK/STAT3 signaling pathway. Whereas, SOCS3 silencing abolished the function of NR1D1 over-expression on ovarian cancer growth and JAK/STAT3 signaling pathway. Conclusions NR1D1 up-regulated the expression of SOCS3, resulting in suppression of the JAK/STAT3 signaling pathway, thus retarding the growth of ovarian cancer cells. This study highlights a profound role of NR1D1 in the treatment of ovarian cancer. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08597-8.
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Affiliation(s)
- Huailin Wang
- Department of Gynecology, the First Hospital of Jilin University, 71 Xinmin Avenue, Changchun, 130021, China
| | - Yan Fu
- Department of Gynecology, the First Hospital of Jilin University, 71 Xinmin Avenue, Changchun, 130021, China.
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Chen X, Lan H, He D, Wang Z, Xu R, Yuan J, Xiao M, Zhang Y, Gong L, Xiao S, Cao K. Analysis of Autophagy-Related Signatures Identified Two Distinct Subtypes for Evaluating the Tumor Immune Microenvironment and Predicting Prognosis in Ovarian Cancer. Front Oncol 2021; 11:616133. [PMID: 34041016 PMCID: PMC8141647 DOI: 10.3389/fonc.2021.616133] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Accepted: 04/19/2021] [Indexed: 12/26/2022] Open
Abstract
Ovarian cancer (OC) is one of the most lethal gynecologic malignant tumors. The interaction between autophagy and the tumor immune microenvironment has clinical importance. Hence, it is necessary to explore reliable biomarkers associated with autophagy-related genes (ARGs) for risk stratification in OC. Here, we obtained ARGs from the MSigDB database and downloaded the expression profile of OC from TCGA database. The k-means unsupervised clustering method was used for clustering, and two subclasses of OC (cluster A and cluster B) were identified. SsGSEA method was used to quantify the levels of infiltration of 24 subtypes of immune cells. Metascape and GSEA were performed to reveal the differential gene enrichment in signaling pathways and cellular processes of the subtypes. We found that patients in cluster A were significantly associated with higher immune infiltration and immune-associated signaling pathways. Then, we established a risk model by LASSO Cox regression. ROC analysis and Kaplan-Meier analysis were applied for evaluating the efficiency of the risk signature, patients with low-risk got better outcomes than those with high-risk in overall survival. Finally, ULK2 and GABARAPL1 expression was further validated in clinical samples. In conclusion, Our study constructed an autophagy-related prognostic indicator, and identified two promising targets in OC.
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Affiliation(s)
- Xingyu Chen
- Department of Oncology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Hua Lan
- Department of Obstetrics and Gynecology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Dong He
- The Second People's Hospital of Hunan Province, Hunan University of Chinese Medicine, Changsha, China
| | - Zhanwang Wang
- Department of Oncology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Runshi Xu
- Medical School, Hunan University of Chinese Medicine, Changsha, China
| | - Jing Yuan
- Department of Obstetrics and Gynecology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Mengqing Xiao
- Department of Oncology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Yao Zhang
- Department of Oncology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Lian Gong
- Department of Oncology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Songshu Xiao
- Department of Obstetrics and Gynecology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Ke Cao
- Department of Oncology, Third Xiangya Hospital of Central South University, Changsha, China
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Long noncoding RNA GAS8-AS1: A novel biomarker in human diseases. Biomed Pharmacother 2021; 139:111572. [PMID: 33838502 DOI: 10.1016/j.biopha.2021.111572] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 03/21/2021] [Accepted: 03/31/2021] [Indexed: 12/16/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) represent a group of ncRNAs with more than 200 nucleotides. These RNAs can specifically regulate gene expression at both the transcriptional and the post-transcriptional levels, and increasing evidence indicates that they play vital roles in a variety of disease-related cellular processes. The lncRNA GAS8 antisense RNA 1 (GAS8-AS1, also known as C16orf3) is located in the second intron of GAS8 and has been reported to be both abnormally expressed in several diseases and closely correlated with many clinical characteristics. GAS8-AS1 has been shown to affect many biological functions, including cell proliferation, migration, invasiveness, and autophagy using several signaling pathways. In this review, we have summarized current studies on GAS8-AS1 roles in disease and discuss its potential clinical utility. GAS8-AS1 may be a promising biomarker for both diagnoses and prognoses, and a novel target for many disease therapies.
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Golan T, Atias D, Stossel C, Raitses-Gurevich M. Patient-derived xenograft models of BRCA-associated pancreatic cancers. Adv Drug Deliv Rev 2021; 171:257-265. [PMID: 33617901 DOI: 10.1016/j.addr.2021.02.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 02/04/2021] [Accepted: 02/10/2021] [Indexed: 12/20/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease. The majority of patients diagnosed at an advanced, metastatic stage, and poor overall survival rates. The most clinically meaningful subtype obtained from PDAC genomic classification is represented by unstable genomes, and co-segregated with inactivation of DNA damage repair genes, e.g., Breast cancer 1/2 (BRCA1/2). The FDA and EMA has recently approved olaparib, a Poly (ADP-ribose) polymerase (PARP) inhibitor, as a maintenance strategy for platinum-sensitive advanced PDAC patients with BRCA mutations. However, susceptibility to treatment varies, and resistance may develop. Resistance can be defined as innate or acquired resistance to platinum/PARP-inhibition. Patient-derived xenograft (PDX) models have been utilized in cancer research for many years. We generated a unique PDX model, obtained from BRCA-associated PDAC patients at distinct time points of the disease recapitulating the different clinical scenario. In this review we discuss the relevant PDX-derived models for investigating BRCA-associated PDAC and drug development.
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Affiliation(s)
- Talia Golan
- Institute of Oncology, Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel.
| | - Dikla Atias
- Institute of Oncology, Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel
| | - Chani Stossel
- Institute of Oncology, Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel
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Chan CY, Tan KV, Cornelissen B. PARP Inhibitors in Cancer Diagnosis and Therapy. Clin Cancer Res 2021; 27:1585-1594. [PMID: 33082213 DOI: 10.1158/1078-0432.ccr-20-2766] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 09/07/2020] [Accepted: 10/14/2020] [Indexed: 11/16/2022]
Abstract
Targeting of PARP enzymes has emerged as an effective therapeutic strategy to selectively target cancer cells with deficiencies in homologous recombination signaling. Currently used to treat BRCA-mutated cancers, PARP inhibitors (PARPi) have demonstrated improved outcome in various cancer types as single agents. Ongoing efforts have seen the exploitation of PARPi combination therapies, boosting patient responses as a result of drug synergisms. Despite great successes using PARPi therapy, selecting those patients who will benefit from single agent or combination therapy remains one of the major challenges. Numerous reports have demonstrated that the presence of a BRCA mutation does not always result in synthetic lethality with PARPi therapy in treatment-naïve tumors. Cancer cells can also develop resistance to PARPi therapy. Hence, combination therapy may significantly affect the treatment outcomes. In this review, we discuss the development and utilization of PARPi in different cancer types from preclinical models to clinical trials, provide a current overview of the potential uses of PARP imaging agents in cancer therapy, and discuss the use of radiolabeled PARPi as radionuclide therapies.
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Affiliation(s)
- Chung Ying Chan
- MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, United Kingdom
| | - Kel Vin Tan
- Department of Diagnostic Radiology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Bart Cornelissen
- MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, United Kingdom.
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Li N, Wang J, Zang X, Wang Z, Zhang T, Zhao B, Miao J, Lin Z. H 2S probe CPC inhibits autophagy and promotes apoptosis by inhibiting glutathionylation of Keap1 at Cys434. Apoptosis 2021; 26:111-131. [PMID: 33389358 DOI: 10.1007/s10495-020-01652-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/11/2020] [Indexed: 12/18/2022]
Abstract
H2S is actual an endogenous signaling gas molecule and involved in a range of cell physiological processes. However, the mechanism of endogenous H2S regulating autophagy and apoptosis has not been thoroughly investigated. Here, we try to address this issue by using a H2S probe, (E)-2-(4-(4-(7-(diethylamino)-2-oxo-2H-chromene-3-carbonyl)-piperazin-1-yl)-styryl)-1, 3, 3-trimethyl-3H-indol-1-ium iodide (CPC), which could react with endogenous H2S. Herein, we reported that CPC inhibited autophagy and decreased the expression and activity of NF-E2-related factor 2 (Nrf2), then induced cell apoptosis. CPC inhibited autophagy and promoted apoptosis by inhibiting Nrf2 activation, which was H2S dependent. Furthermore, we found that CPC inhibited Nrf2 nucleus translocation by inhibiting glutathionylation of Kelch-like ECH-associated protein 1 (Keap1) at the Cys434 residue. CPC also inhibited various cancer cell growth, but had no effect on normal cell growth in vitro, and inhibited A549 cancer growth, but did not affect normal angiogenesis in vivo. Therefore, we not only found a new inhibitor of autophagy and Nrf2, but also suggested a novel mechanism that endogenous H2S could regulate autophagy, apoptosis and Nrf2 activity through regulating glutathionylation of Keap1 at the Cys434 residue.
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Affiliation(s)
- Na Li
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Qingdao, 266237, People's Republic of China
| | - JuYuan Wang
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Qingdao, 266237, People's Republic of China
| | - XiaoLing Zang
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, People's Republic of China
| | - ZhaoYang Wang
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Qingdao, 266237, People's Republic of China
| | - Tao Zhang
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Qingdao, 266237, People's Republic of China
| | - BaoXiang Zhao
- Institute of Organic Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, People's Republic of China.
| | - JunYing Miao
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Qingdao, 266237, People's Republic of China.
| | - ZhaoMin Lin
- Institute of Medical Science, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033, People's Republic of China.
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The Dual Role of Autophagy in Cancer Development and a Therapeutic Strategy for Cancer by Targeting Autophagy. Int J Mol Sci 2020; 22:ijms22010179. [PMID: 33375363 PMCID: PMC7795059 DOI: 10.3390/ijms22010179] [Citation(s) in RCA: 100] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 12/23/2020] [Accepted: 12/24/2020] [Indexed: 02/07/2023] Open
Abstract
Autophagy is a delicate intracellular degradation process that occurs due to diverse stressful conditions, including the accumulation of damaged proteins and organelles as well as nutrient deprivation. The mechanism of autophagy is initiated by the creation of autophagosomes, which capture and encapsulate abnormal components. Afterward, autophagosomes assemble with lysosomes to recycle or remove degradative cargo. The regulation of autophagy has bipolar roles in cancer suppression and promotion in diverse cancers. Furthermore, autophagy modulates the features of tumorigenesis, cancer metastasis, cancer stem cells, and drug resistance against anticancer agents. Some autophagy regulators are used to modulate autophagy for anticancer therapy but the dual roles of autophagy limit their application in anticancer therapy, and present as the main reason for therapy failure. In this review, we summarize the mechanisms of autophagy, tumorigenesis, metastasis, cancer stem cells, and resistance against anticancer agents. Finally, we discuss whether targeting autophagy is a promising and effective therapeutic strategy in anticancer therapy.
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Tamauchi S, Suzuki S, Xuboya C, Yoshihara M, Yoshida K, Ikeda Y, Yoshikawa N, Kajiyama H, Kikkawa F. Establishment of a patient-derived xenograft model and cell line of malignant transformation of mature cystic teratoma of the ovary. J Obstet Gynaecol Res 2020; 47:713-719. [PMID: 33300248 DOI: 10.1111/jog.14596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 09/09/2020] [Accepted: 11/29/2020] [Indexed: 11/29/2022]
Abstract
AIM Malignant transformation of mature cystic teratoma (MTMCT) of the ovary is a rare gynecological malignancy and commonly arises in women older than 50 years of age. The most common histological type of MTMCT is squamous cell carcinoma (SCC), and the prognosis is extremely poor. Patient-derived xenograft (PDX) models are promising animal models for preclinical drug screening. Here, we report the generation of a new PDX model of MTMCT, and a new cell line established from the tumors of PDX model animals. METHODS Tumor tissue was obtained from a 32-year-old patient with MTMCT. To generate PDX, NSG (NOD.Cg-Prkdcscid Il2rgtm1Wjl /SzJ) mice, a strain of super-immunodeficient mice, were used. Tumor-bearing mice were sacrificed, followed by the collection of these tumors and re-transplantation into new NSG mice (in vivo passage). Tumor samples were also cultured in vitro. Adherent cells were continuously cultured and passaged, a cell line was established. RESULTS In the primary PDX mouse, tumor engraftment was confirmed 30 days after tumor implantation. After three times in vivo passage, we confirmed that the cryopreserved tumors could be engrafted even when transplanted into BALB/c nude mice. Using the tumor tissue at the time of the first in vivo passage, a new cell line NOSCC1 was established. PDX tumors and cell-line derived xenograft tumors exhibited similar morphology of SCC. CONCLUSION We established a new PDX model of MTMCT and a new cell line of it, which may be important tools for the development of new therapies and the elucidation of the carcinogenic mechanisms of MTMCT.
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Affiliation(s)
- Satoshi Tamauchi
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shiro Suzuki
- Department of Gynecologic Oncology, Aichi Cancer Center, Nagoya, Japan
| | - Chang Xuboya
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masato Yoshihara
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kosuke Yoshida
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshiki Ikeda
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Nobuhisa Yoshikawa
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroaki Kajiyama
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Fumitaka Kikkawa
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Zhong K, Chen D, Wu Z, Wang X, Pan B, Chen N, Zhong W. [Effect of small interfering RNA-mediated BIRC6 silencing on apoptosis and autophagy of renal cancer 786-O cells]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2020; 40:1651-1655. [PMID: 33243730 DOI: 10.12122/j.issn.1673-4254.2020.11.18] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
OBJECTIVE To study the expression of BIRC6 in renal cancer tissues and investigate the effect of BIRC6 silencing on apoptosis and autophagy of 786-O cells. METHODS Twenty surgical specimens of renal cancer tissues and adjacent renal tissues were collected from Meizhou People's Hospital between February, 2016 and December, 2018 for detection of BIRC6 protein expression using immunohistochemistry. Renal cancer 786-O cells were transfected with a control small interfering RNA (siRNA) or BIRC6 siRNA via lipofectamine 2000, and the changes in cell proliferation and apoptosis following 5-FU treatment were assessed using CCK8 assay and flow cytometry; the expressions of autophagy-related proteins Beclin and LC3A/B were detected by Western blotting. RESULTS The expression of BIRC6 protein was significantly higher in renal cancer tissues than in the adjacent renal tissues. Western blotting showed that siRNA-mediated silencing of BIRC6 significantly lowered the expression of BIRC6 in 786-O cells. In the cells with BIRC6 silencing, treatment with 12.5, 25, 50, 100 and 200 μg/mL 5-FU resulted in significantly higher proliferation inhibition rates than in the cells transfected with the control siRNA (P < 0.01). BIRC6 silencing also significantly increased the apoptosis rate of 786-O cells following 5-FU treatment (P < 0.01). The results of Western blotting showed that BIRC6 silencing significantly lowered the protein expressions of Beclin and LC3A/B in 786-O cells. CONCLUSIONS Interference of BIRC6 mediated by siRNA can inhibit autophagy and promote 5-FU-induced apoptosis to enhance the sensitivity of 786-O cells to 5-FU.
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Affiliation(s)
- Kaihua Zhong
- Department of Urology, Meizhou People's Hospital, Meizhou 514031, China
| | - Dong Chen
- Department of Urology, Sun Yat-sen Cancer Center, Guangzhou 510060, China
| | - Zhiming Wu
- Department of Urology, Sun Yat-sen Cancer Center, Guangzhou 510060, China
| | - Xiaohong Wang
- Department of Nephrology, Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China
| | - Bin Pan
- Department of Urology, First Affiliated Hospital of Jinan University, Guangzhou 510630, China
| | - Nanhui Chen
- Department of Urology, Meizhou People's Hospital, Meizhou 514031, China
| | - Weifeng Zhong
- Department of Urology, Meizhou People's Hospital, Meizhou 514031, China.,Department of Urology, Sun Yat-sen Cancer Center, Guangzhou 510060, China
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王 丽, 张 璇, 王 亮, 王 蓓, 张 競, 李 玉. [IL-17A/lL-17RA reduces cisplatin sensitivity of ovarian cancer SKOV3 cells by regulating autophagy]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2020; 40:1550-1556. [PMID: 33243748 PMCID: PMC7704378 DOI: 10.12122/j.issn.1673-4254.2020.11.03] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Indexed: 11/24/2022]
Abstract
OBJECTIVE To investigate the effect of interleukin-17A (IL-17A) on chemosensitivity of ovarian cancer cells to cisplatin (DDP) and explore the mechanism in light of autophagy regulation. METHODS Ovarian cancer SKOV3 cells cultured in vitro were treated with different concentrations of DDP (1-20 μg/mL). MTT assay was used to observe the changes in proliferation of the treated cells and the effect of treatment with 100 ng/mL IL-17A for 24 h on DDP-induced apoptosis of SKOV3 cells. We then examined the expression of IL-17A receptor (IL-17RA) in SKOV3 cells using flow cytometry. Annexin V-FITC/PI double staining was used to detect the cell apoptosis rate, and early apoptosis of the cells was detected with JC-1 assay. A neutralizing monoclonal antibody (mAb) against IL-17RA was used to block IL-17RA. We also observed the effects of IL-17RA silencing mediated by a siRNA targeting IL-17RA (siRNA-IL-17RA) and treatment with 3-methyladenine (3-MA) for inhibiting autophagy on DDP-induced apoptosis of SKOV3 cells. The expressions of apoptosis-related proteins (Bcl-2, Bax, and cleaved caspase-3) and autophagy-related proteins (P62 and Beclin-1) in the treated cells were detected using Western blotting. RESULTS DDP increased the expression of IL-17RA in ovarian cancer SKOV3 cells. Treatment with IL-17A significantly reduced the susceptibility of SKOV3 cells to cisplatin-induced apoptosis (P < 0.05). DDP obviously augmented the expression of Beclin-1 and reduced the autophagy degradation substrate P62 protein in the cells (P < 0.05). IL-17A/IL-17RA strongly enhanced the DDPinducted autophagy of the cells (P < 0.05). Blocking autophagy with 3-MA significantly increased DDP- induced apoptosis of SKOV3 cells with IL-17RA silencing, lowered the expression of Bcl-2 and enhanced Bax expression in the cells (P < 0.05). CONCLUSIONS IL-17A/IL-17RA can decrease chemosensitivity of SKOV3 cells to DDP by upregulating DDP-induced autophagy.
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Affiliation(s)
- 丽华 王
- />蚌埠医学院第一附属医院肿瘤妇科，安徽 蚌埠 233004Department of Gynecology, First Affiliated Hospital of Bengbu Medical College, Bengbu 233004, China
| | - 璇 张
- />蚌埠医学院第一附属医院肿瘤妇科，安徽 蚌埠 233004Department of Gynecology, First Affiliated Hospital of Bengbu Medical College, Bengbu 233004, China
| | - 亮亮 王
- />蚌埠医学院第一附属医院肿瘤妇科，安徽 蚌埠 233004Department of Gynecology, First Affiliated Hospital of Bengbu Medical College, Bengbu 233004, China
| | - 蓓蓓 王
- />蚌埠医学院第一附属医院肿瘤妇科，安徽 蚌埠 233004Department of Gynecology, First Affiliated Hospital of Bengbu Medical College, Bengbu 233004, China
| | - 競 张
- />蚌埠医学院第一附属医院肿瘤妇科，安徽 蚌埠 233004Department of Gynecology, First Affiliated Hospital of Bengbu Medical College, Bengbu 233004, China
| | - 玉芝 李
- />蚌埠医学院第一附属医院肿瘤妇科，安徽 蚌埠 233004Department of Gynecology, First Affiliated Hospital of Bengbu Medical College, Bengbu 233004, China
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Yang Y, Yu Y, Chen H, Meng X, Ma W, Yu M, Li Z, Li C, Liu H, Zhang X, Xiao H, Yu Z. Illuminating Platinum Transportation while Maximizing Therapeutic Efficacy by Gold Nanoclusters via Simultaneous Near-Infrared-I/II Imaging and Glutathione Scavenging. ACS NANO 2020; 14:13536-13547. [PMID: 32924505 DOI: 10.1021/acsnano.0c05541] [Citation(s) in RCA: 157] [Impact Index Per Article: 31.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Killing tumor cells with a visualized system is a promising strategy in tumor therapy to achieve minimal side effects and high efficiency. Herein, a theranostic nanomedicine (AuNCs-Pt) is developed based on nanocarrier gold nanoclusters (AuNCs) with bifunctions of both NIR-I/NIR-II imaging and glutathione-scavenging abilities. AuNCs-Pt possesses NIR-II imaging capability on a fatal high-grade serous ovarian cancer (HGSOC) model in the deep abdomen, thus facilitating it to be a promising tool for monitoring platinum transportation. Meanwhile, AuNCs-Pt depletes intracellular glutathione to minimize platinum detoxification, effectively maximizing the chemotherapeutic efficacy of platinum. AuNCs-Pt is used to eradicate the tumor burden in this study on a HGSOC model and a patient-derived tumor xenograft model of hepatocellular carcinoma, suggesting great potential for clinical visualized therapy and platinum drug sensitization.
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Affiliation(s)
- Yuanyuan Yang
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, No. 1023, South Shatai Road, Guangzhou 510515, China
| | - Yingjie Yu
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, No. 1023, South Shatai Road, Guangzhou 510515, China
- Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics and Chemistry Institute of Chemistry, Chinese Academy of Sciences, No. 2, Zhongguancun Road, Beijing 100190, China
| | - Hao Chen
- Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, No. 15, North Third Ring Road, Beijing 100029, China
| | - Xiangxi Meng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, No. 52, Fucheng Road, Beijing 100142, China
| | - Wen Ma
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, No. 1023, South Shatai Road, Guangzhou 510515, China
| | - Meng Yu
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, No. 1023, South Shatai Road, Guangzhou 510515, China
| | - Ziyuan Li
- Department of Biomedical Engineering, College of Engineering, Peking University, No. 5, Yiheyuan Road, Beijing 100871, China
| | - Changhui Li
- Department of Biomedical Engineering, College of Engineering, Peking University, No. 5, Yiheyuan Road, Beijing 100871, China
| | - Haile Liu
- Department of Physics and Tianjin Key Laboratory of Low Dimensional Materials Physics and Preparing Technology, School of Science, Tianjin University, No. 135, Yaguan Road, Tianjin 300354, China
| | - Xiaodong Zhang
- Department of Physics and Tianjin Key Laboratory of Low Dimensional Materials Physics and Preparing Technology, School of Science, Tianjin University, No. 135, Yaguan Road, Tianjin 300354, China
| | - Haihua Xiao
- Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics and Chemistry Institute of Chemistry, Chinese Academy of Sciences, No. 2, Zhongguancun Road, Beijing 100190, China
| | - Zhiqiang Yu
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, No. 1023, South Shatai Road, Guangzhou 510515, China
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Development of synthetic lethality in cancer: molecular and cellular classification. Signal Transduct Target Ther 2020; 5:241. [PMID: 33077733 PMCID: PMC7573576 DOI: 10.1038/s41392-020-00358-6] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 09/02/2020] [Accepted: 09/03/2020] [Indexed: 12/27/2022] Open
Abstract
Recently, genetically targeted cancer therapies have been a topic of great interest. Synthetic lethality provides a new approach for the treatment of mutated genes that were previously considered unable to be targeted in traditional genotype-targeted treatments. The increasing researches and applications in the clinical setting made synthetic lethality a promising anticancer treatment option. However, the current understandings on different conditions of synthetic lethality have not been systematically assessed and the application of synthetic lethality in clinical practice still faces many challenges. Here, we propose a novel and systematic classification of synthetic lethality divided into gene level, pathway level, organelle level, and conditional synthetic lethality, according to the degree of specificity into its biological mechanism. Multiple preclinical findings of synthetic lethality in recent years will be reviewed and classified under these different categories. Moreover, synthetic lethality targeted drugs in clinical practice will be briefly discussed. Finally, we will explore the essential implications of this classification as well as its prospects in eliminating existing challenges and the future directions of synthetic lethality.
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An olaparib window-of-opportunity trial in patients with early-stage endometrial carcinoma: POLEN study. Gynecol Oncol 2020; 159:721-731. [PMID: 32988624 DOI: 10.1016/j.ygyno.2020.09.013] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 09/07/2020] [Indexed: 11/23/2022]
Abstract
OBJECTIVE Olaparib is a potent inhibitor of poly(ADP-ribose) polymerase (PARP)-1, 2, and 3 with potential activity in endometrial cancer (EC). METHODS In this window-of-opportunity trial, women with operable type 1 EC received olaparib oral tablets (300mg) twice daily for 28days before surgery. The primary objective was to evaluate the effects of olaparib on EC in tissue samples taken at baseline and at treatment completion. Signal of activity was defined as significant changes in the expression of the cell cycle-related proteins cyclin D1, Ki67, and cleaved caspase-3. RESULTS A total of 31 patients were included in the biomarker analysis. The median time of olaparib exposure was 24 days (1-39). Significant inhibition was found for cyclin D1 (p < 0.01), but not for Ki67 and active caspase 3 immunostaining. PARP-1 levels positively correlated with cyclin D1 levels (rho = 0.661, p = 0.0001). Both PARP-1 and cyclin D1 levels were significantly lower (p = 0.022 and p = 0.004, respectively) in patients with ARID1A[-] tumors than ARID1A[+] tumors. A significant relationship between plasma olaparib concentrations and decreased GLUT1 activity was observed (r = -0.5885; p < 0.05). Drug-related toxicity consisted mostly of gastrointestinal and grade 1 or 2 adverse events. CONCLUSIONS Olaparib reduced expression of cyclin D1, which positively correlated with PARP-1 levels. This effect was more evident in ARID1A-deficient tumors. Olaparib further induced inhibition of GLUT1 plasma activity. Our findings could have noteworthy implications in predicting which patients with EC would benefit from olaparib-based strategies.
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Jiang W, Xie S, Liu Y, Zou S, Zhu X. The Application of Patient-Derived Xenograft Models in Gynecologic Cancers. J Cancer 2020; 11:5478-5489. [PMID: 32742495 PMCID: PMC7391187 DOI: 10.7150/jca.46145] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 06/14/2020] [Indexed: 02/07/2023] Open
Abstract
Recently, due to the limitations of cell line models and animal models in the preclinical research with insufficient reflecting the physiological situation of humans, patient-derived xenograft (PDX) models of many cancers have been widely developed because of their better representation of the tumor heterogeneity and tumor microenvironment with retention of the cellular complexity, cytogenetics, and stromal architecture. PDX models now have been identified as a powerful tool for determining cancer characteristics, developing new treatment, and predicting drug efficacy. An increase in attempts to generate PDX models in gynecologic cancers has emerged in recent years to understand tumorigenesis. Hence, this review summarized the generation of PDX models and engraftment success of PDX models in gynecologic cancers. Furthermore, we illustrated the similarity between PDX model and original tumor, and described preclinical utilization of PDX models in gynecologic cancers. It would help supply better personalized therapy for gynecologic cancer patients.
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Affiliation(s)
- Wenxiao Jiang
- Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China
| | - Shangdan Xie
- Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China
| | - Yi Liu
- Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China
| | - Shuangwei Zou
- Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China
| | - Xueqiong Zhu
- Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China
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