|
1
|
Maguire B, Kisakol B, Prehn JHM, Burke JP. SATB2 Expression Affects Chemotherapy Metabolism and Immune Checkpoint Gene Expression in Colorectal Cancer. Clin Colorectal Cancer 2025; 24:129-134.e7. [PMID: 39794188 DOI: 10.1016/j.clcc.2024.12.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 12/04/2024] [Accepted: 12/08/2024] [Indexed: 01/13/2025]
Abstract
BACKGROUND Special AT-rich binding protein-2 (SATB2) is a nuclear matrix associated protein regulating gene expression which is normally expressed in colonic tissue. Loss of SATB2 expression in colorectal cancer (CRC) has negative implications for prognosis and has been associated with chemotherapy resistance. Furthermore, recent evidence suggests SATB2 may influence immune checkpoint (IC) expression. We hypothesized that SATB2 expression may be associated with altered expression of chemotherapy resistance associated and IC genes. METHODS Clinicopathologic and gene expression data were extracted from The Cancer Genome Atlas PanCancer Atlas. SATB2 expression was compared by clinicopathologic characteristic and by using multivariate regression analysis to explore associations with chemotherapy and IC gene expression. RESULTS About 553 patients were included for analysis. Lower quartile SATB2 expression was associated with worse disease specific survival (P = .04). MSI (P < .001) and mucinous (P < .001) tumors were associated with reduced SATB2 expression independently. SATB2 varied by consensus molecular subtype (P < .001) and was lowest in CMS1. On multivariate analysis, SATB2 was negatively associated with 5-FU related metabolism genes, while more complex but significant relationships were seen with oxaliplatin and irinotecan related genes. Low SATB2 expression was associated with increased expression of PD-1, PD-L1, TIM-3 and CTLA-4 IC genes. CONCLUSION The positive prognostic influence of SATB2 expression is reaffirmed in this study. This effect may be explained by the negative association between SATB2 and 5-FU-resistance related gene expression. Enhanced IC gene expression in SATB2 low cases suggests a potential role for IC inhibition in this setting, but further study is required.
Collapse
Affiliation(s)
- Barry Maguire
- Department of Colorectal Surgery, Beaumont Hospital, Dublin, Ireland; Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Batuhan Kisakol
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland; Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Jochen H M Prehn
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland; Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - John P Burke
- Department of Colorectal Surgery, Beaumont Hospital, Dublin, Ireland.
| |
Collapse
|
|
2
|
Li X, Zhang X, Liu T, Zhang G, Chen D, Lin S. Identification of immune characteristic biomarkers and therapeutic targets in cuproptosis for rheumatoid arthritis by integrated bioinformatics analysis and single-cell RNA sequencing analysis. Front Med (Lausanne) 2025; 12:1520400. [PMID: 40166070 PMCID: PMC11955502 DOI: 10.3389/fmed.2025.1520400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Accepted: 03/03/2025] [Indexed: 04/02/2025] Open
Abstract
Introduction Rheumatoid arthritis (RA) is a chronic autoimmune disorder intricately liked with inflammation. Cuproptosis, an emerging type of cell death, has been implicated in the initiation and development of RA. However, the exact alterations in the expression and biological function of cuproptosis-related genes (CRGs) in RA remain poorly understood. Therefore, our study aims to elucidate the potential association between CRGs and RA, with the goal of identifying novel biomarkers for the treatment and prognosis of RA. Methods In this study, we identified ten differentially expressed cuproptosis-related genes (DE-CRGs) between patients with RA and controls. Through comprehensive functional enrichment and protein-protein interaction (PPI) network analysis, we explored the functional roles of the DE-CRGs. Additionally, we investigated the correlation between DE-CRGs and immune infiltration, immune factors, diagnostic efficacy, and potential therapeutic drugs. Results Leveraging single-cell RNA sequencing data, we conducted a detailed analysis to elucidate alterations in various cell clusters associated with RA. Our study unveiled a significant association between DE-CRGs and diverse biological functions, as well as potential drug candidates. Discussion These findings provide crucial insights into the involvement of DE-CRGs in the pathogenesis of RA and shed light on potential therapeutic strategies.
Collapse
Affiliation(s)
- Xianbin Li
- School of Computer and Big Data Science, Jiujiang University, Jiujiang, China
- Department of Digital Media Technology, Hangzhou Dianzi University, Hangzhou, China
- Jiujiang Key Laboratory of Digital Technology, Jiujiang, China
| | - Xueli Zhang
- Department of Medical Technology, Zhengzhou Railway Vocational and Technical College, Zhengzhou, China
| | - Tao Liu
- School of Computer and Big Data Science, Jiujiang University, Jiujiang, China
| | - Guodao Zhang
- Department of Digital Media Technology, Hangzhou Dianzi University, Hangzhou, China
| | - Dan Chen
- Department of Rheumatology, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang, China
| | - Suxian Lin
- Department of Rheumatology, Wenzhou People’s Hospital, Wenzhou, China
| |
Collapse
|
|
3
|
Zhang C, Zhu J, Yuan X, Yan Z, Ye H, Xiong T, Xu A, Li C, Ji D, Yang S, Zhang J, Zhang Y, Wu J, Huang Z. Development of Integrated Bioorthogonal Self-Catalyzed NO Donor/Platinum(IV) Prodrugs for Synergistical Intervention against Triple-Negative Breast Cancer. J Med Chem 2024; 67:479-491. [PMID: 38110353 DOI: 10.1021/acs.jmedchem.3c01693] [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: 12/20/2023]
Abstract
The platinum(IV) prodrug strategy is attractive for the synergistic antitumor effect. High levels (>400 nM) of nitric oxide (NO) exert promising cancer inhibition effects via multiple mechanisms. Herein, we designed and synthesized a new group of integrated bioorthogonal self-catalyzed NO donor/Pt(IV) prodrugs bearing long alkyl chains to enhance the stability in circulation, while the cytoplasmic reductants trigger cascade activation to release Pt and NO in tumor cells. Specifically, compound 10c exhibited an improved stability, favorable pharmacokinetic properties (AUC(0-t) of 2210.10 h*ng/mL), potent anti-triple-negative breast cancer (TNBC) effects (71.08% tumor growth inhibition (TGI) against the MDA-MB-231 xenograft model), potent in vivo anti-TNBC lung metastasis activity, and acceptable low toxicity. Importantly, NO released from 10c leads to the S-nitrosation of metal transporters Atox1&ATP7a in TNBC cells, which increases the Pt retention and inhibits lysyl oxidase, generating synergistic tumoricidal and antimetastatic activity. These results may inspire further study on the synergistical therapy of Pt and NO for the treatment of TNBC.
Collapse
Affiliation(s)
- Chen Zhang
- Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, P. R. China
| | - Jie Zhu
- Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, P. R. China
| | - Xun Yuan
- Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, P. R. China
| | - Zhengsheng Yan
- Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, P. R. China
| | - Hui Ye
- Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, P. R. China
| | - Tao Xiong
- Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, P. R. China
| | - Anning Xu
- Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, P. R. China
| | - Cunrui Li
- Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, P. R. China
| | - Duorui Ji
- Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, P. R. China
| | - Shan Yang
- Xinjiang Key Laboratory of Neurological Disorder Research, The Second Affiliated Hospital of Xinjiang Medical University, Urumqi 830028, P. R. China
| | - Juan Zhang
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, P. R. China
| | - Yihua Zhang
- Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, P. R. China
| | - Jianbing Wu
- Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, P. R. China
| | - Zhangjian Huang
- Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, P. R. China
- School of Pharmacy, Key Laboratory of Active Components of Xinjiang Natural Medicine and Drug Release Technology, Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Xinjiang Medical University, Urumqi 830054, P. R. China
| |
Collapse
|
|
4
|
Wu Z, Lv G, Xing F, Xiang W, Ma Y, Feng Q, Yang W, Wang H. Copper in hepatocellular carcinoma： A double-edged sword with therapeutic potentials. Cancer Lett 2023; 571:216348. [PMID: 37567461 DOI: 10.1016/j.canlet.2023.216348] [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: 06/13/2023] [Revised: 07/28/2023] [Accepted: 08/08/2023] [Indexed: 08/13/2023]
Abstract
Copper is a necessary cofactor vital for maintaining biological functions, as well as participating in the development of cancer. A plethora of studies have demonstrated that copper is a double-edged sword, presenting both benefits and detriments to tumors. The liver is a metabolically active organ, and an imbalance of copper homeostasis can result in deleterious consequences to the liver. Hepatocellular carcinoma (HCC), the most common primary liver cancer, is a highly aggressive malignancy with limited viable therapeutic options. As research advances, the focus has shifted towards the relationships between copper and HCC. Innovatively, cuproplasia and cuproptosis have been proposed to depict copper-related cellular growth and death, providing new insights for HCC treatment. By summarizing the constantly elucidated molecular connections, this review discusses the mechanisms of copper in the pathogenesis, progression, and potential therapeutics of HCC. Additionally, we aim to tentatively provide a theoretical foundation and gospel for HCC patients.
Collapse
Affiliation(s)
- Zixin Wu
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Second Military Medical University, Shanghai, 200438, China; National Center for Liver Cancer, Second Military Medical University, Shanghai, 201805, China
| | - Guishuai Lv
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Second Military Medical University, Shanghai, 200438, China; National Center for Liver Cancer, Second Military Medical University, Shanghai, 201805, China
| | - Fuxue Xing
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Second Military Medical University, Shanghai, 200438, China; National Center for Liver Cancer, Second Military Medical University, Shanghai, 201805, China
| | - Wei Xiang
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Second Military Medical University, Shanghai, 200438, China; National Center for Liver Cancer, Second Military Medical University, Shanghai, 201805, China
| | - Yue Ma
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Second Military Medical University, Shanghai, 200438, China; National Center for Liver Cancer, Second Military Medical University, Shanghai, 201805, China
| | - Qiyu Feng
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Second Military Medical University, Shanghai, 200438, China; National Center for Liver Cancer, Second Military Medical University, Shanghai, 201805, China.
| | - Wen Yang
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Second Military Medical University, Shanghai, 200438, China; National Center for Liver Cancer, Second Military Medical University, Shanghai, 201805, China.
| | - Hongyang Wang
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Second Military Medical University, Shanghai, 200438, China; National Center for Liver Cancer, Second Military Medical University, Shanghai, 201805, China.
| |
Collapse
|
|
5
|
Nanoplatform-based cellular reactive oxygen species regulation for enhanced oncotherapy and tumor resistance alleviation. CHINESE CHEM LETT 2023. [DOI: 10.1016/j.cclet.2023.108300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/12/2023]
|
|
6
|
Nam C, Ziman B, Sheth M, Zhao H, Lin DC. Genomic and Epigenomic Characterization of Tumor Organoid Models. Cancers (Basel) 2022; 14:4090. [PMID: 36077628 PMCID: PMC9454968 DOI: 10.3390/cancers14174090] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 08/20/2022] [Accepted: 08/22/2022] [Indexed: 11/17/2022] Open
Abstract
Tumor organoid modeling has been recognized as a state-of-the-art system for in vitro research on cancer biology and precision oncology. Organoid culture technologies offer distinctive advantages, including faithful maintenance of physiological and pathological characteristics of human disease, self-organization into three-dimensional multicellular structures, and preservation of genomic and epigenomic landscapes of the originating tumor. These features effectively position organoid modeling between traditional cell line cultures in two dimensions and in vivo animal models as a valid, versatile, and robust system for cancer research. Here, we review recent advances in genomic and epigenomic characterization of tumor organoids and the novel findings obtained, highlight significant progressions achieved in organoid modeling of gene-drug interactions and genotype-phenotype associations, and offer perspectives on future opportunities for organoid modeling in basic and clinical cancer research.
Collapse
Affiliation(s)
| | | | | | | | - De-Chen Lin
- Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA
| |
Collapse
|
|
7
|
Cuesta-Casanovas L, Delgado-Martínez J, Cornet-Masana JM, Carbó JM, Clément-Demange L, Risueño RM. Lysosome-mediated chemoresistance in acute myeloid leukemia. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2022; 5:233-244. [PMID: 35582535 PMCID: PMC8992599 DOI: 10.20517/cdr.2021.122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Despite the outstanding advances in understanding the biology underlying the pathophysiology of acute myeloid leukemia (AML) and the promising preclinical data published lastly, AML treatment still relies on a classic chemotherapy regimen largely unchanged for the past five decades. Recently, new drugs have been approved for AML, but the real clinical benefit is still under evaluation. Nevertheless, primary refractory and relapse AML continue to represent the main clinical challenge, as the majority of AML patients will succumb to the disease despite achieving a complete remission during the induction phase. As such, treatments for chemoresistant AML represent an unmet need in this disease. Although great efforts have been made to decipher the biological basis for leukemogenesis, the mechanism by which AML cells become resistant to chemotherapy is largely unknown. The identification of the signaling pathways involved in resistance may lead to new combinatory therapies or new therapeutic approaches suitable for this subset of patients. Several mechanisms of chemoresistance have been identified, including drug transporters, key secondary messengers, and metabolic regulators. However, no therapeutic approach targeting chemoresistance has succeeded in clinical trials, especially due to broad secondary effects in healthy cells. Recent research has highlighted the importance of lysosomes in this phenomenon. Lysosomes' key role in resistance to chemotherapy includes the potential to sequester drugs, central metabolic signaling role, and gene expression regulation. These results provide further evidence to support the development of new therapeutic approaches that target lysosomes in AML.
Collapse
Affiliation(s)
- Laia Cuesta-Casanovas
- Josep Carreras Leukaemia Research Institute (IJC), Barcelona 08916, Spain
- Faculty of Biosciences, Autonomous University of Barcelona, Bellaterra (Cerdanyola del Vallès) 08193, Spain
| | - Jennifer Delgado-Martínez
- Josep Carreras Leukaemia Research Institute (IJC), Barcelona 08916, Spain
- Faculty of Pharmacy, University of Barcelona, Barcelona 08028, Spain
| | | | - José M. Carbó
- Leukos Biotech, Muntaner, 383, Barcelona 08036, Spain
| | | | - Ruth M. Risueño
- Josep Carreras Leukaemia Research Institute (IJC), Barcelona 08916, Spain
| |
Collapse
|
|
8
|
Ghoneum A, Almousa S, Warren B, Abdulfattah AY, Shu J, Abouelfadl H, Gonzalez D, Livingston C, Said N. Exploring the clinical value of tumor microenvironment in platinum-resistant ovarian cancer. Semin Cancer Biol 2021; 77:83-98. [PMID: 33476723 PMCID: PMC8286277 DOI: 10.1016/j.semcancer.2020.12.024] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 12/20/2020] [Accepted: 12/30/2020] [Indexed: 12/13/2022]
Abstract
Platinum resistance in epithelial ovarian cancer (OvCa) is rising at an alarming rate, with recurrence of chemo-resistant high grade serous OvCa (HGSC) in roughly 75 % of all patients. Additionally, HGSC has an abysmal five-year survival rate, standing at 39 % and 17 % for FIGO stages III and IV, respectively. Herein we review the crucial cellular interactions between HGSC cells and the cellular and non-cellular components of the unique peritoneal tumor microenvironment (TME). We highlight the role of the extracellular matrix (ECM), ascitic fluid as well as the mesothelial cells, tumor associated macrophages, neutrophils, adipocytes and fibroblasts in platinum-resistance. Moreover, we underscore the importance of other immune-cell players in conferring resistance, including natural killer cells, myeloid-derived suppressive cells (MDSCs) and T-regulatory cells. We show the clinical relevance of the key platinum-resistant markers and their correlation with the major pathways perturbed in OvCa. In parallel, we discuss the effect of immunotherapies in re-sensitizing platinum-resistant patients to platinum-based drugs. Through detailed analysis of platinum-resistance in HGSC, we hope to advance the development of more effective therapy options for this aggressive disease.
Collapse
Affiliation(s)
- Alia Ghoneum
- Departments of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC, 27157, USA
| | - Sameh Almousa
- Departments of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC, 27157, USA
| | - Bailey Warren
- Departments of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC, 27157, USA
| | - Ammar Yasser Abdulfattah
- Departments of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC, 27157, USA; Alexandria University School of Medicine, Alexandria, Egypt
| | - Junjun Shu
- Departments of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC, 27157, USA; The Third Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Hebatullah Abouelfadl
- Departments of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC, 27157, USA; Department of Genetics, Animal Health Research Institute, Dokki, Egypt
| | - Daniela Gonzalez
- Departments of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC, 27157, USA
| | - Christopher Livingston
- Departments of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC, 27157, USA
| | - Neveen Said
- Departments of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC, 27157, USA; Departments of Urology, Wake Forest University School of Medicine, Winston Salem, NC, 27157, USA; Comprehensive Cancer Center, Winston Salem, NC, 27157, USA.
| |
Collapse
|
|
9
|
Pasquariello KZ, Dey JM, Sprowl JA. Current Understanding of Membrane Transporters as Regulators or Targets for Cisplatin-Induced Hearing Loss. Mol Pharmacol 2021; 100:348-355. [PMID: 34330821 PMCID: PMC8626641 DOI: 10.1124/molpharm.121.000274] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 07/22/2021] [Indexed: 11/22/2022] Open
Abstract
Cisplatin is a platinum-based drug, which remains among the most efficacious anticancer treatment options. Unfortunately, use of cisplatin is hindered by dose-limiting toxicities, including irreversible hearing loss, which can grossly affect patient quality of life. Cisplatin-induced ototoxicity is the result of cochlear hair cell damage through a mechanism that is poorly understood. However, cisplatin cytotoxicity is reliant on intracellular accumulation, a process that is largely dependent on the presence of particular membrane transporters. This review will provide an update on our current understanding of the various transporters known to be involved in the disposition and cytotoxicity of platinum drugs or their metabolites, as well as their role in mediating cisplatin-induced hearing loss. We also provide a summary of the successes and opportunities in therapeutically targeting membrane transporters to alleviate platinum-induced hearing loss. Moreover, we describe how this approach could be used to reduce the severity or onset of other adverse events associated with exposure to various forms of platinum drugs, without diminishing antitumor efficacy. SIGNIFICANCE STATEMENT: Cisplatin-induced hearing loss is a dose-limiting and irreversible adverse event with no current preventative or curative treatment measures. Pharmacological targeting of membrane transporters that regulate platinum uptake into cochlear hair cells, if conducted appropriately, may alleviate this devastating side effect and could be applied to alleviate other platinum-induced toxicities.
Collapse
Affiliation(s)
- Kyle Z Pasquariello
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York
| | - Jason M Dey
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York
| | - Jason A Sprowl
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York
| |
Collapse
|
|
10
|
O'Connell E, Reynolds IS, Salvucci M, McNamara DA, Burke JP, Prehn JHM. Mucinous and non-mucinous colorectal cancers show differential expression of chemotherapy metabolism and resistance genes. THE PHARMACOGENOMICS JOURNAL 2021; 21:510-519. [PMID: 33731881 DOI: 10.1038/s41397-021-00229-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 01/22/2021] [Accepted: 02/18/2021] [Indexed: 01/31/2023]
Abstract
Previous research has identified differences in mutation frequency in genes implicated in chemotherapy resistance between mucinous and non-mucinous colorectal cancers (CRC). We hypothesized that outcomes in mucinous and non-mucinous CRC may be influenced by expression of genes responsible for chemotherapy resistance. Gene expression data from primary tumor samples were extracted from The Cancer Genome Atlas PanCancer Atlas. The distribution of clinical, pathological, and gene expression variables was compared between 74 mucinous and 521 non-mucinous CRCs. Predictors of overall survival (OS) were assessed in a multivariate analysis. Kaplan-Meier curves were constructed to compare survival according to gene expression using the log rank test. The median expression of 5-FU-related genes TYMS, TYMP, and DYPD was significantly higher in mucinous CRC compared to non-mucinous CRC (p < 0.001, p = 0.003, p < 0.001, respectively). The median expression of oxaliplatin-related genes ATP7B and SRPK1 was significantly reduced in mucinous versus non-mucinous CRC (p = 0.004, p = 0.007, respectively). At multivariate analysis, age (odds ratio (OR) = 0.96, p < 0.001), node positive disease (OR = 0.49, p = 0.005), and metastatic disease (OR = 0.32, p < 0.001) remained significant negative predictors of OS, while high SRPK1 remained a significant positive predictor of OS (OR = 1.59, p = 0.037). Subgroup analysis of rectal cancers demonstrated high SRPK1 expression was associated with significantly longer OS compared to low SRPK1 expression (p = 0.011). This study highlights that the molecular differences in mucinous CRC and non-mucinous CRC extend to chemotherapy resistance gene expression. SRPK1 gene expression was associated with OS, with a prognostic role identified in rectal cancers.
Collapse
Affiliation(s)
- E O'Connell
- Department of Colorectal Surgery, Beaumont Hospital, Dublin 9, Ireland.,Department of Surgery, Royal College of Surgeons in Ireland, Dublin 2, Ireland
| | - I S Reynolds
- Department of Colorectal Surgery, Beaumont Hospital, Dublin 9, Ireland.,Department of Surgery, Royal College of Surgeons in Ireland, Dublin 2, Ireland
| | - M Salvucci
- Department of Surgery, Royal College of Surgeons in Ireland, Dublin 2, Ireland
| | - D A McNamara
- Department of Colorectal Surgery, Beaumont Hospital, Dublin 9, Ireland.,Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland
| | - J P Burke
- Department of Colorectal Surgery, Beaumont Hospital, Dublin 9, Ireland
| | - J H M Prehn
- Department of Surgery, Royal College of Surgeons in Ireland, Dublin 2, Ireland. .,Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
| |
Collapse
|
|
11
|
de Witte CJ, Espejo Valle-Inclan J, Hami N, Lõhmussaar K, Kopper O, Vreuls CPH, Jonges GN, van Diest P, Nguyen L, Clevers H, Kloosterman WP, Cuppen E, Snippert HJG, Zweemer RP, Witteveen PO, Stelloo E. Patient-Derived Ovarian Cancer Organoids Mimic Clinical Response and Exhibit Heterogeneous Inter- and Intrapatient Drug Responses. Cell Rep 2021; 31:107762. [PMID: 32553164 DOI: 10.1016/j.celrep.2020.107762] [Citation(s) in RCA: 180] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 03/26/2020] [Accepted: 05/21/2020] [Indexed: 01/19/2023] Open
Abstract
There remains an unmet need for preclinical models to enable personalized therapy for ovarian cancer (OC) patients. Here we evaluate the capacity of patient-derived organoids (PDOs) to predict clinical drug response and functional consequences of tumor heterogeneity. We included 36 whole-genome-characterized PDOs from 23 OC patients with known clinical histories. OC PDOs maintain the genomic features of the original tumor lesion and recapitulate patient response to neoadjuvant carboplatin/paclitaxel combination treatment. PDOs display inter- and intrapatient drug response heterogeneity to chemotherapy and targeted drugs, which can be partially explained by genetic aberrations. PDO drug screening identifies high responsiveness to at least one drug for 88% of patients. PDOs are valuable preclinical models that can provide insights into drug response for individual patients with OC, complementary to genetic testing. Generating PDOs of multiple tumor locations can improve clinical decision making and increase our knowledge of genetic and drug response heterogeneity.
Collapse
Affiliation(s)
- Chris Jenske de Witte
- Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands; Oncode Institute, Jaarbeursplein 6, 3521 AL Utrecht, the Netherlands
| | - Jose Espejo Valle-Inclan
- Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands; Oncode Institute, Jaarbeursplein 6, 3521 AL Utrecht, the Netherlands
| | - Nizar Hami
- Oncode Institute, Jaarbeursplein 6, 3521 AL Utrecht, the Netherlands; Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands
| | - Kadi Lõhmussaar
- Oncode Institute, Jaarbeursplein 6, 3521 AL Utrecht, the Netherlands; Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands
| | - Oded Kopper
- Oncode Institute, Jaarbeursplein 6, 3521 AL Utrecht, the Netherlands; Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands
| | - Celien Philomena Henrieke Vreuls
- Department of Pathology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
| | - Geertruida Nellie Jonges
- Department of Pathology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
| | - Paul van Diest
- Department of Pathology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
| | - Luan Nguyen
- Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands; Oncode Institute, Jaarbeursplein 6, 3521 AL Utrecht, the Netherlands
| | - Hans Clevers
- Oncode Institute, Jaarbeursplein 6, 3521 AL Utrecht, the Netherlands; Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands
| | - Wigard Pieter Kloosterman
- Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands
| | - Edwin Cuppen
- Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands; Oncode Institute, Jaarbeursplein 6, 3521 AL Utrecht, the Netherlands; Hartwig Medical Foundation, Science Park 408, 1098 XH Amsterdam, the Netherlands
| | - Hugo Johannes Gerhardus Snippert
- Oncode Institute, Jaarbeursplein 6, 3521 AL Utrecht, the Netherlands; Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands
| | - Ronald Peter Zweemer
- Division of Imaging and Oncology, Department of Gynecological Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
| | - Petronella Oda Witteveen
- Department of Medical Oncology, Cancer Center, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
| | - Ellen Stelloo
- Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands; Oncode Institute, Jaarbeursplein 6, 3521 AL Utrecht, the Netherlands.
| |
Collapse
|
|
12
|
Interference between copper transport systems and platinum drugs. Semin Cancer Biol 2021; 76:173-188. [PMID: 34058339 DOI: 10.1016/j.semcancer.2021.05.023] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 05/17/2021] [Indexed: 01/06/2023]
Abstract
Cisplatin, or cis-diamminedichloridoplatinum(II) cis-[PtCl2(NH3)2], is a platinum-based anticancer drug largely used for the treatment of various types of cancers, including testicular, ovarian and colorectal carcinomas, sarcomas, and lymphomas. Together with other platinum-based drugs, cisplatin triggers malignant cell death by binding to nuclear DNA, which appears to be the ultimate target. In addition to passive diffusion across the cell membrane, other transport systems, including endocytosis and some active or facilitated transport mechanisms, are currently proposed to play a pivotal role in the uptake of platinum-based drugs. In this review, an updated view of the current literature regarding the intracellular transport and processing of cisplatin will be presented, with special emphasis on the plasma membrane copper permease CTR1, the Cu-transporting ATPases, ATP7A and ATP7B, located in the trans-Golgi network, and the soluble copper chaperone ATOX1. Their role in eliciting cisplatin efficacy and their exploitation as pharmacological targets will be addressed.
Collapse
|
|
13
|
Wei G, Gu Z, Gu J, Yu J, Huang X, Qin F, Li L, Ding R, Huo J. Platinum accumulation in oxaliplatin-induced peripheral neuropathy. J Peripher Nerv Syst 2021; 26:35-42. [PMID: 33462873 PMCID: PMC7986112 DOI: 10.1111/jns.12432] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 10/29/2020] [Accepted: 10/30/2020] [Indexed: 12/16/2022]
Abstract
Oxaliplatin-induced peripheral neuropathy (OIPN) is a common and dose-limiting toxic effect that markedly limits the use of oxaliplatin and affects the quality of life. Although it is common, the underlying mechanisms of OIPN remain ambiguous. Recent studies have shown that the platinum accumulation in peripheral nervous system, especially in dorsal root ganglion, is a significant mechanism of OIPN. Several specific transporters, including organic cation transporters, high-affinity copper uptake protein1 (CTR1), ATPase copper transporting alpha (ATP7A) and multidrug and toxin extrusion protein 1 (MATE1), could be associated with this mechanism. This review summarizes the current research progress about the relationship between platinum accumulation and OIPN, as well as suggests trend for the future research.
Collapse
Affiliation(s)
- Guoli Wei
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Graduate schoolNanjing University of Chinese MedicineNanjingChina
- Department of OncologyJiangsu Province Academy of Traditional Chinese MedicineNanjingChina
| | - Zhancheng Gu
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Graduate schoolNanjing University of Chinese MedicineNanjingChina
| | - Jialin Gu
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Graduate schoolNanjing University of Chinese MedicineNanjingChina
| | - Jialin Yu
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Department of OncologyJiangsu Province Academy of Traditional Chinese MedicineNanjingChina
| | - Xiaofei Huang
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Graduate schoolNanjing University of Chinese MedicineNanjingChina
- Department of OncologyJiangsu Province Academy of Traditional Chinese MedicineNanjingChina
| | - Fengxia Qin
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Graduate schoolNanjing University of Chinese MedicineNanjingChina
- Department of OncologyJiangsu Province Academy of Traditional Chinese MedicineNanjingChina
| | - Lingchang Li
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Department of OncologyJiangsu Province Academy of Traditional Chinese MedicineNanjingChina
| | - Rong Ding
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Department of OncologyJiangsu Province Academy of Traditional Chinese MedicineNanjingChina
| | - Jiege Huo
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Department of OncologyJiangsu Province Academy of Traditional Chinese MedicineNanjingChina
| |
Collapse
|
|
14
|
Shimizu T, Fujii T, Sakai H. The Relationship Between Actin Cytoskeleton and Membrane Transporters in Cisplatin Resistance of Cancer Cells. Front Cell Dev Biol 2020; 8:597835. [PMID: 33195280 PMCID: PMC7655133 DOI: 10.3389/fcell.2020.597835] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Accepted: 10/05/2020] [Indexed: 12/13/2022] Open
Abstract
Cisplatin [cis-diamminedichloroplatinum (II)] is a platinum-based anticancer drug widely used for the treatment of various cancers. It forms interstrand and intrastrand cross-linking with DNA and block DNA replication, resulting in apoptosis. On the other hand, intrinsic and acquired cisplatin resistance restricts its therapeutic effects. Although some studies suggest that dramatic epigenetic alternations are involved in the resistance triggered by cisplatin, the mechanism is complicated and remains poorly understood. Recent studies reported that cytoskeletal structures regulate cisplatin sensitivity and that activities of membrane transporters contribute to the development of resistance to cisplatin. Therefore, we focus on the roles of actin filaments and membrane transporters in cisplatin-induced apoptosis. In this review, we summarize the relationship between actin cytoskeleton and membrane transporters in the cisplatin resistance of cancer cells.
Collapse
Affiliation(s)
- Takahiro Shimizu
- Department of Pharmaceutical Physiology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Takuto Fujii
- Department of Pharmaceutical Physiology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Hideki Sakai
- Department of Pharmaceutical Physiology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| |
Collapse
|
|
15
|
Gallenito MJ, Qasim TS, Tutol JN, Prakash V, Dodani SC, Meloni G. A recombinant platform to characterize the role of transmembrane protein hTMEM205 in Pt(II)-drug resistance and extrusion. Metallomics 2020; 12:1542-1554. [PMID: 32789331 DOI: 10.1039/d0mt00114g] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Platinum-coordination complexes are among the most effective chemotherapeutic drugs used in clinics for the treatment of cancer. Despite their efficacy, cancer cells can develop drug resistance leading to treatment failure and relapse. Cellular uptake and extrusion of Pt(ii)-complexes mediated by transmembrane proteins are critical in controlling the intracellular concentration of Pt(ii)-drugs and in developing pre-target resistance. TMEM205 is a human transmembrane protein (hTMEM205) overexpressed in cancer cells that are resistant to cisplatin, but its molecular function underlying - resistance remains elusive. We developed a low-cost and high-throughput recombinant expression platform coupled to in vivo functional resistance assays to study the molecular mechanism by which the orphan hTMEM205 protects against Pt(ii)-complex toxicity. Based on the original observation by the Rosenberg group, which led to the discovery of cisplatin, we performed quantitative analysis of the effects of Pt(ii)-coordination complexes on cellular growth and filamentation in E. coli cells expressing hTMEM205. By coupling our methods with Pt quantification and cellular profiling in control and hTMEM205-expressing cells, we demonstrate that hTMEM205 mediates Pt(ii)-drug export selectively towards cisplatin and oxaliplatin but not carboplatin. By mutation analysis, we reveal that hTMEM205 recognizes and allows Pt(ii)-extrusion by a putative sulfur-based translocation mechanism, thereby resulting in pre-target resistance. Thus, hTMEM205 represents a new potential target that can be exploited to reduce cellular resistance towards Pt(ii)-drugs.
Collapse
Affiliation(s)
- Marc J Gallenito
- Department of Chemistry and Biochemistry, The University of Texas at Dallas, Richardson, TX 75080, USA.
| | - Tahir S Qasim
- Department of Chemistry and Biochemistry, The University of Texas at Dallas, Richardson, TX 75080, USA.
| | - Jasmine N Tutol
- Department of Chemistry and Biochemistry, The University of Texas at Dallas, Richardson, TX 75080, USA.
| | - Ved Prakash
- Imaging and Histology Core and Olympus Discovery Center, Office of Research, The University of Texas at Dallas, Richardson, TX 75080, USA
| | - Sheel C Dodani
- Department of Chemistry and Biochemistry, The University of Texas at Dallas, Richardson, TX 75080, USA.
| | - Gabriele Meloni
- Department of Chemistry and Biochemistry, The University of Texas at Dallas, Richardson, TX 75080, USA.
| |
Collapse
|
|
16
|
Copper transporter 1 affinity as a delivery strategy to improve the cytotoxic profile of rationally designed copper(II) complexes for cancer treatment. Toxicol In Vitro 2020; 67:104922. [PMID: 32590028 DOI: 10.1016/j.tiv.2020.104922] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 05/30/2020] [Accepted: 06/17/2020] [Indexed: 12/20/2022]
Abstract
Cisplatin is widely used to treat different types of cancer, but its severe side effects are the major disadvantage of this treatment. Therefore, other metals are currently the subject of research in the rational development of anticancer drugs, such as copper, that has been demonstrated to be promising in this scenario. Here, we evaluated the effects of two novel copper complexes against breast cancer cell lines, and also examined the influence of overexpressing copper transporter 1 (CTR1) on the cytotoxicity of these complexes. Complex (1) [Cu(sdmx-)2(phen)] showed low IC50 values, induced intense cell morphological changes and arrested the cell cycle at the sub-G1 phase in cancer cells. Complex (1) was tested in transfected cells overexpressing the CTR1 receptor in order to compare its steric effects with a less bulky ligand and more labile complex (2) [CuCl2(impy)]. A significant reduction of IC50 value was observed in CTR1 overexpressing cells for complex (2) (32 μM to 20 μM) as compared to (1) (2.78 μM to 3.41 μM), evidencing a possible uptake through copper reduction (Cu+2 → Cu+1) mediated by CTR1. Thus, considering that CTR1 is a mediator of metallodrugs uptake, the development of strategies that use rational drug design is important in order to improve the therapeutic efficacy through greater specificity and consecutive reduction of side effects. Here we show the example for the case of copper(II) complexes.
Collapse
|
|
17
|
Zhou J, Kang Y, Chen L, Wang H, Liu J, Zeng S, Yu L. The Drug-Resistance Mechanisms of Five Platinum-Based Antitumor Agents. Front Pharmacol 2020; 11:343. [PMID: 32265714 PMCID: PMC7100275 DOI: 10.3389/fphar.2020.00343] [Citation(s) in RCA: 274] [Impact Index Per Article: 54.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 03/09/2020] [Indexed: 01/17/2023] Open
Abstract
Platinum-based anticancer drugs, including cisplatin, carboplatin, oxaliplatin, nedaplatin, and lobaplatin, are heavily applied in chemotherapy regimens. However, the intrinsic or acquired resistance severely limit the clinical application of platinum-based treatment. The underlying mechanisms are incredibly complicated. Multiple transporters participate in the active transport of platinum-based antitumor agents, and the altered expression level, localization, or activity may severely decrease the cellular platinum accumulation. Detoxification components, which are commonly increasing in resistant tumor cells, can efficiently bind to platinum agents and prevent the formation of platinum–DNA adducts, but the adducts production is the determinant step for the cytotoxicity of platinum-based antitumor agents. Even if adequate adducts have formed, tumor cells still manage to survive through increased DNA repair processes or elevated apoptosis threshold. In addition, autophagy has a profound influence on platinum resistance. This review summarizes the critical participators of platinum resistance mechanisms mentioned above and highlights the most potential therapeutic targets or predicted markers. With a deeper understanding of the underlying resistance mechanisms, new solutions would be produced to extend the clinical application of platinum-based antitumor agents largely.
Collapse
Affiliation(s)
- Jiabei Zhou
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Yu Kang
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Lu Chen
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Hua Wang
- Department of Urology, Cancer Hospital of Zhejiang Province, Hangzhou, China
| | - Junqing Liu
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Su Zeng
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Lushan Yu
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| |
Collapse
|
|
18
|
Perde-Schrepler M, Fischer-Fodor E, Virag P, Brie I, Cenariu M, Pop C, Valcan A, Gurzau E, Maniu A. The expression of copper transporters associated with the ototoxicity induced by platinum-based chemotherapeutic agents. Hear Res 2020; 388:107893. [PMID: 32006874 DOI: 10.1016/j.heares.2020.107893] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 12/17/2019] [Accepted: 01/07/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Antitumor agents based on platinum have gained a well-established place in the treatment of several forms of cancer. Their efficiency is hampered by serious toxic effects against healthy tissues as well. Ototoxicity is a serious side effect leading to hearing impairment and represents an important issue affecting the patients' quality of life. The currently used platinum chemotherapeutics exert different toxicity towards cochlear cells. The aim of our study was to answer some questions regarding the differential uptake and cellular pharmacodynamics of Cisplatin (CDDP), Carboplatin (CBDCA) and Oxaliplatin (L-OHP) in the HEI-OC1 cochlear cell line. METHODS We studied the expression of copper transporters CTR1, ATP7A and ATP7B which are presumably involved in the uptake, cellular transport and efflux of platinum compounds by immunofluorescence microscopy and flow-cytometry. The cellular uptake of the compounds was evaluated through the determination of intracellular platinum concentration by atomic absorption spectroscopy. The effects of the treatment of HEI-OC1 cells with platinum compounds were also evaluated: cytotoxicity with the Cell Titer Blue viability test, formation of reactive oxygen species with 2',7' -dichlorofluorescein diacetate, genotoxicity with the comet assay and apoptosis with the cleaved PARP ELISA test. RESULTS CTR1, ATP7A and ATP7B were all expressed by HEI-OC1 cells. The treatment with the platinum compounds led to a modulation of their expression, manifested in a differential platinum uptake. Treatment with Cisplatin led to the highest intracellular concentration of platinum compared to Oxaliplatin and Carboplatin at the same dose. Treatment with CuSO4 reduced platinum uptake of all the compounds, significantly in the case of Cisplatin and Carboplatin. CDDP was the most cytotoxic against HEI-OC1 cells, with an IC50 = 65.79 μM, compared to 611.7 μM for L-OHP and 882.9 μM for CBDCA, at the same molar concentration. The production of ROS was the most intense after CDDP, followed by L-OHP and CBDCA. In the comet assay, at the 100 μM concentration, L-OHP and CBDCA induced DNA adducts while CDDP induced adducts as well as DNA strand breaks. CBDCA and L-OHP lead to a significant increase of cleaved PARP at 24h (p < 0.001), suggesting an important apoptotic process induced by these compounds at the used concentrations. CONCLUSIONS The results obtained in the current study suggest that the modulation of copper transporters locally may represent a new strategy against platinum drugs ototoxicity.
Collapse
Affiliation(s)
| | | | - Piroska Virag
- "Ion Chiricuta" Oncology Institute Cluj-Napoca, Romania
| | - Ioana Brie
- "Ion Chiricuta" Oncology Institute Cluj-Napoca, Romania
| | - Mihai Cenariu
- University of Agricultural Science and Veterinary Medicine Cluj-Napoca, Romania
| | - Cristian Pop
- Environment and Health Centre Cluj-Napoca, Romania
| | | | - Eugen Gurzau
- Environment and Health Centre Cluj-Napoca, Romania
| | - Alma Maniu
- Department of Otorhynolaryngology, "Iuliu Hatieganu" University of Medicine and Pharmacy Cluj-Napoca, Romania
| |
Collapse
|
|
19
|
Abstract
The organic cation transporters (OCTs) OCT1, OCT2, OCT3, novel OCT (OCTN)1, OCTN2, multidrug and toxin exclusion (MATE)1, and MATE kidney-specific 2 are polyspecific transporters exhibiting broadly overlapping substrate selectivities. They transport organic cations, zwitterions, and some uncharged compounds and operate as facilitated diffusion systems and/or antiporters. OCTs are critically involved in intestinal absorption, hepatic uptake, and renal excretion of hydrophilic drugs. They modulate the distribution of endogenous compounds such as thiamine, L-carnitine, and neurotransmitters. Sites of expression and functions of OCTs have important impact on energy metabolism, pharmacokinetics, and toxicity of drugs, and on drug-drug interactions. In this work, an overview about the human OCTs is presented. Functional properties of human OCTs, including identified substrates and inhibitors of the individual transporters, are described. Sites of expression are compiled, and data on regulation of OCTs are presented. In addition, genetic variations of OCTs are listed, and data on their impact on transport, drug treatment, and diseases are reported. Moreover, recent data are summarized that indicate complex drug-drug interaction at OCTs, such as allosteric high-affinity inhibition of transport and substrate dependence of inhibitor efficacies. A hypothesis about the molecular mechanism of polyspecific substrate recognition by OCTs is presented that is based on functional studies and mutagenesis experiments in OCT1 and OCT2. This hypothesis provides a framework to imagine how observed complex drug-drug interactions at OCTs arise. Finally, preclinical in vitro tests that are performed by pharmaceutical companies to identify interaction of novel drugs with OCTs are discussed. Optimized experimental procedures are proposed that allow a gapless detection of inhibitory and transported drugs.
Collapse
Affiliation(s)
- Hermann Koepsell
- Institute of Anatomy and Cell Biology and Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute, University of Würzburg, Würzburg, Germany
| |
Collapse
|
|
20
|
Reynolds IS, O’Connell E, Fichtner M, McNamara DA, Kay EW, Prehn JHM, Furney SJ, Burke JP. Mucinous adenocarcinoma is a pharmacogenomically distinct subtype of colorectal cancer. THE PHARMACOGENOMICS JOURNAL 2019; 20:524-532. [DOI: 10.1038/s41397-019-0137-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 11/22/2019] [Accepted: 11/26/2019] [Indexed: 02/07/2023]
|
|
21
|
Systematic chemical screening identifies disulfiram as a repurposed drug that enhances sensitivity to cisplatin in bladder cancer: a summary of preclinical studies. Br J Cancer 2019; 121:1027-1038. [PMID: 31673101 PMCID: PMC6964684 DOI: 10.1038/s41416-019-0609-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 09/24/2019] [Accepted: 10/02/2019] [Indexed: 12/14/2022] Open
Abstract
Background Since the standard gemcitabine and cisplatin (GC) chemotherapy for advanced bladder cancer yields limited therapeutic effect due to chemoresistance, it is a clinical challenge to enhance sensitivity to GC. Methods We performed high-throughput screening by using a library of known chemicals and repositionable drugs. A total of 2098 compounds were administered alone or with GC to human bladder cancer cells, and chemicals that enhanced GC effects were screened. Results Disulfiram (DSF), an anti-alcoholism drug, was identified as a candidate showing synergistic effects with cisplatin but not with gemcitabine in multiple cell lines. Co-administration of DSF with GC affected cellular localisation of a cisplatin efflux transporter ATP7A, increased DNA–platinum adducts and promoted apoptosis. Micellar DSF nanoparticles (DSF-NP) that stabilised DSF in vivo, enhanced the inhibitory effect of cisplatin in patient-derived and cell-based xenograft models without severe adverse effects. A drug susceptibility evaluation system by using cancer tissue-originated spheroid culture showed promise in identifying cases who would benefit from DSF with cisplatin. Conclusions The present study highlighted the advantage of drug repurposing to enhance the efficacy of anticancer chemotherapy. Repurposing of DSF to a chemotherapy sensitiser may provide additional efficacy with less expense by using an available drug with a well-characterised safety profile.
Collapse
|
|
22
|
Purkait K, Ruturaj, Mukherjee A, Gupta A. ATP7B Binds Ruthenium(II) p-Cymene Half-Sandwich Complexes: Role of Steric Hindrance and Ru-I Coordination in Rescuing the Sequestration. Inorg Chem 2019; 58:15659-15670. [PMID: 31657924 DOI: 10.1021/acs.inorgchem.9b02780] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Ruthenium(II/III) complexes are predicted to be efficient alternatives to platinum drug-resistant cancers but have never been investigated for sequestration and efflux by Cu-ATPases (ATP7A or ATP7B) overexpressed in resistant cancer cells, although a major cause of platinum drug resistance is found to be sequestration of platinum chemotherapeutic agents by thiol donors glutathione (GSH) or the Cys-X-X-Cys (CXXC) motifs in the Cu-ATPases in cytosol. Here, we show for the first time that ATP7B efficiently sequesters ruthenium(II) η6-p-cymene complexes. We present seven complexes, [RuII(η6-p-cym)(L)X](PF6) (1-7; L = L1-L3, X = Cl, Br, and I), out of which two resists deactivation by the cellular thiol, glutathione (GSH). The results show that Ru-I coordination and a moderate steric factor increase resistance to GSH and the CXXC motif. RuII-I-coordinated 3 and 7 showed resistance to sequestration by ATP7B. 3 displays highest resistance against GSH and does not trigger ATP7B trafficking in the liver cancer cell line. It escapes ATP7B-mediated sequestration and triggers apoptosis. Thus, with a suitable bidentate ligand and iodido leaving group, RuII(η6-p-cym) complexes may display strong kinetic inertness to inhibit the ATP7B detoxification pathway. Inductively coupled plasma mass spectrometry data show higher retention of 3 and 7 inside the cell with time compared to 4, supporting ATP7B-mediated sequestration.
Collapse
|
|
23
|
Petruzzelli R, Polishchuk RS. Activity and Trafficking of Copper-Transporting ATPases in Tumor Development and Defense against Platinum-Based Drugs. Cells 2019; 8:E1080. [PMID: 31540259 PMCID: PMC6769697 DOI: 10.3390/cells8091080] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 09/10/2019] [Accepted: 09/12/2019] [Indexed: 02/06/2023] Open
Abstract
Membrane trafficking pathways emanating from the Golgi regulate a wide range of cellular processes. One of these is the maintenance of copper (Cu) homeostasis operated by the Golgi-localized Cu-transporting ATPases ATP7A and ATP7B. At the Golgi, these proteins supply Cu to newly synthesized enzymes which use this metal as a cofactor to catalyze a number of vitally important biochemical reactions. However, in response to elevated Cu, the Golgi exports ATP7A/B to post-Golgi sites where they promote sequestration and efflux of excess Cu to limit its potential toxicity. Growing tumors actively consume Cu and employ ATP7A/B to regulate the availability of this metal for oncogenic enzymes such as LOX and LOX-like proteins, which confer higher invasiveness to malignant cells. Furthermore, ATP7A/B activity and trafficking allow tumor cells to detoxify platinum (Pt)-based drugs (like cisplatin), which are used for the chemotherapy of different solid tumors. Despite these noted activities of ATP7A/B that favor oncogenic processes, the mechanisms that regulate the expression and trafficking of Cu ATPases in malignant cells are far from being completely understood. This review summarizes current data on the role of ATP7A/B in the regulation of Cu and Pt metabolism in malignant cells and outlines questions and challenges that should be addressed to understand how ATP7A and ATP7B trafficking mechanisms might be targeted to counteract tumor development.
Collapse
Affiliation(s)
- Raffaella Petruzzelli
- Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078 Pozzuoli (NA), Italy.
| | - Roman S Polishchuk
- Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078 Pozzuoli (NA), Italy.
| |
Collapse
|
|
24
|
Lasorsa A, Nardella MI, Rosato A, Mirabelli V, Caliandro R, Caliandro R, Natile G, Arnesano F. Mechanistic and Structural Basis for Inhibition of Copper Trafficking by Platinum Anticancer Drugs. J Am Chem Soc 2019; 141:12109-12120. [DOI: 10.1021/jacs.9b05550] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Alessia Lasorsa
- Department of Chemistry, University of Bari “Aldo Moro”, via Orabona, 4, 70125 Bari, Italy
| | - Maria I. Nardella
- Department of Chemistry, University of Bari “Aldo Moro”, via Orabona, 4, 70125 Bari, Italy
| | - Antonio Rosato
- Department of Chemistry, University of Bari “Aldo Moro”, via Orabona, 4, 70125 Bari, Italy
| | | | - Rosanna Caliandro
- Bioorganic Chemistry and Bio-Crystallography laboratory (B(2)Cl), Faculty of Science and Technology, Free University of Bolzano, Piazza Università 5, 39100 Bolzano, Italy
- Institute of Crystallography, CNR, Area Science Park Basovizza, 34149 Trieste, Italy
| | - Rocco Caliandro
- Institute of Crystallography, CNR, via Amendola, 122/o, 70126 Bari, Italy
| | - Giovanni Natile
- Department of Chemistry, University of Bari “Aldo Moro”, via Orabona, 4, 70125 Bari, Italy
| | - Fabio Arnesano
- Department of Chemistry, University of Bari “Aldo Moro”, via Orabona, 4, 70125 Bari, Italy
| |
Collapse
|
|
25
|
The modulatory effect of green tea catechin on drug resistance in human ovarian cancer cells. Med Chem Res 2019. [DOI: 10.1007/s00044-019-02324-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
|
|
26
|
Myint K, Biswas R, Li Y, Jong N, Jamieson S, Liu J, Han C, Squire C, Merien F, Lu J, Nakanishi T, Tamai I, McKeage M. Identification of MRP2 as a targetable factor limiting oxaliplatin accumulation and response in gastrointestinal cancer. Sci Rep 2019; 9:2245. [PMID: 30783141 PMCID: PMC6381153 DOI: 10.1038/s41598-019-38667-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Accepted: 12/21/2018] [Indexed: 01/05/2023] Open
Abstract
Oxaliplatin is important for the clinical treatment of colorectal cancer and other gastrointestinal malignancies, but tumour resistance is limiting. Several oxaliplatin transporters were previously identified but their relative contributions to determining oxaliplatin tumour responses and gastrointestinal tumour cell sensitivity to oxaliplatin remains unclear. We studied clinical associations between tumour expression of oxaliplatin transporter candidate genes and patient response to oxaliplatin, then experimentally verified associations found with MRP2 in models of human gastrointestinal cancer. Among 18 oxaliplatin transporter candidate genes, MRP2 was the only one to be differentially expressed in the tumours of colorectal cancer patients who did or did not respond to FOLFOX chemotherapy. Over-expression of MRP2 (endogenously in HepG2 and PANC-1 cells, or induced by stable transfection of HEK293 cells) decreased oxaliplatin accumulation and cytotoxicity but those deficits were reversed by inhibition of MRP2 with myricetin or siRNA knockdown. Mice bearing subcutaneous HepG2 tumour xenografts were sensitised to oxaliplatin antitumour activity by concurrent myricetin treatment with little or no increase in toxicity. In conclusion, MRP2 limits oxaliplatin accumulation and response in human gastrointestinal cancer. Screening tumour MRP2 expression levels, to select patients for treatment with oxaliplatin-based chemotherapy alone or in combination with a MRP2 inhibitor, could improve treatment outcomes.
Collapse
Affiliation(s)
- Khine Myint
- Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand
| | - Riya Biswas
- AUT-Roche Diagnostics Laboratory, School of Science, Auckland University of Technology, Auckland, New Zealand
| | - Yan Li
- AUT-Roche Diagnostics Laboratory, School of Science, Auckland University of Technology, Auckland, New Zealand.,School of Interprofessional Health Studies, Auckland University of Technology, Auckland, New Zealand
| | - Nancy Jong
- Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand
| | - Stephen Jamieson
- Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand.,Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand
| | - Johnson Liu
- Department of Pharmacology, School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia
| | - Catherine Han
- Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand.,Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand
| | - Christopher Squire
- School of Biological Sciences, University of Auckland, Auckland, New Zealand
| | - Fabrice Merien
- AUT-Roche Diagnostics Laboratory, School of Science, Auckland University of Technology, Auckland, New Zealand
| | - Jun Lu
- AUT-Roche Diagnostics Laboratory, School of Science, Auckland University of Technology, Auckland, New Zealand.,School of Interprofessional Health Studies, Auckland University of Technology, Auckland, New Zealand
| | - Takeo Nakanishi
- Department of Membrane Transport and Biopharmaceutics, Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan
| | - Ikumi Tamai
- Department of Membrane Transport and Biopharmaceutics, Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan
| | - Mark McKeage
- Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand. .,Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand.
| |
Collapse
|
|
27
|
Fujita S, Hirota T, Sakiyama R, Baba M, Ieiri I. Identification of drug transporters contributing to oxaliplatin-induced peripheral neuropathy. J Neurochem 2018; 148:373-385. [PMID: 30295925 DOI: 10.1111/jnc.14607] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Revised: 06/19/2018] [Accepted: 10/01/2018] [Indexed: 12/23/2022]
Abstract
Oxaliplatin is widely used as a key drug in the treatment of colorectal cancer. However, its administration is associated with the dose-limiting adverse effect, peripheral neuropathy. Platinum accumulation in the dorsal root ganglion (DRG) is the major mechanism responsible for oxaliplatin-induced neuropathy. Some drug transporters have been identified as platinum complex transporters in kidney or tumor cells, but not yet in DRG. In the present study, we investigated oxaliplatin transporters and their contribution to peripheral neuropathy. We identified 12 platinum transporters expressed in DRG with real-time PCR, and their transiently overexpressing cells were established. After exposure to oxaliplatin, the accumulation of platinum in these overexpressing cells was evaluated using a coupled plasma mass spectrometer. Octn1/2- and Mate1-expressing cells showed the intracellular accumulation of oxaliplatin. In an animal study, peripheral neuropathy developed after the administration of oxaliplatin (4 mg/kg, intravenously, twice a week) to siRNA-injected rats (0.5 nmol, intrathecally, once a week) was demonstrated with the von Frey test. The knockdown of Octn1 in DRG ameliorated peripheral neuropathy, and decreased platinum accumulation in DRG, whereas the knockdown of Octn2 did not. Mate1 siRNA-injected rats developed more severe neuropathy than control rats. These results indicate that Octn1 and Mate1 are involved in platinum accumulation at DRG and oxaliplatin-induced peripheral neuropathy.
Collapse
Affiliation(s)
- Shunsuke Fujita
- Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Takeshi Hirota
- Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Ryo Sakiyama
- Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Misaki Baba
- Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Ichiro Ieiri
- Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| |
Collapse
|
|
28
|
Ding D, Jiang H, Zhang J, Xu X, Qi W, Shi H, Yin S, Salvi R. Cisplatin-induced vestibular hair cell lesion-less damage at high doses. J Otol 2018; 13:115-121. [PMID: 30671086 PMCID: PMC6335437 DOI: 10.1016/j.joto.2018.08.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 08/10/2018] [Accepted: 08/20/2018] [Indexed: 12/04/2022] Open
Abstract
Cisplatin, a widely used anticancer drug, damages hair cells in cochlear organotypic cultures at low doses, but paradoxically causes little damage at high doses resulting in a U-shaped dose-response function. To determine if the cisplatin dose-response function for vestibular hair cells follows a similar pattern, we treated vestibular organotypic cultures with doses of cisplatin ranging from 10 to 1000 μM. Vestibular hair cell lesions progressively increased as the dose of cisplatin increased with maximum damage occurring around 50–100 μM, but the lesions progressively decreased at higher doses resulting in little hair cell loss at 1000 μM. The U-shaped dose-response function for cisplatin-treated vestibular hair cells in culture appears to be regulated by copper transporters, Ctr1, ATP7A and ATP7B, that dose-dependently regulate the uptake, sequestration and extrusion of cisplatin.
Collapse
Affiliation(s)
- Dalian Ding
- Center for Hearing and Deafness, University at Buffalo, USA.,Department of Otolaryngology Head and Neck Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Haiyan Jiang
- Center for Hearing and Deafness, University at Buffalo, USA
| | - Jianhui Zhang
- Department of Otolaryngology Head and Neck Surgery, The Third People's Hospital of Chengdu, China
| | | | - Weidong Qi
- Department of Otolaryngology Head and Neck Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Haibo Shi
- Department of Otorhinolaryngology, Affiliated Sixth People's Hospital of Shanghai Jiaotong University, Shanghai, China
| | - Shankai Yin
- Department of Otorhinolaryngology, Affiliated Sixth People's Hospital of Shanghai Jiaotong University, Shanghai, China
| | - Richard Salvi
- Center for Hearing and Deafness, University at Buffalo, USA.,Department of Audiology and Speech-Language Pathology, Asia University, China
| |
Collapse
|
|
29
|
Xiao F, Li Y, Wan Y, Xue M. MircroRNA-139 sensitizes ovarian cancer cell to cisplatin-based chemotherapy through regulation of ATP7A/B. Cancer Chemother Pharmacol 2018; 81:935-947. [PMID: 29594361 DOI: 10.1007/s00280-018-3548-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Accepted: 02/20/2018] [Indexed: 12/11/2022]
Abstract
PURPOSE Ovarian cancer remains a most malignant female cancer nowadays. The acquisition of chemoresistance to common-used cisplatin-based chemotherapy results in a decreased overall patient survival. The present study is aimed to investigate the role and mechanism by which miR-139/ ATPases7A/B axis modulates the chemoresistance of ovarian cancer to cisplatin-based chemotherapy. METHODS The expression of miR-139 in cisplatin-sensitive (n = 23) and cisplatin-resistant (n = 14) ovarian cancer tissues and cell lines (CAOV-3 and SNU119) was determined using real-time PCR assays; its effect on ovarian cancer cell chemoresistance to different concentrations of cisplatin was then assessed by measuring the cell viability using MTT assays. Next, miR-139 binding to the 3'UTR of ATP7A/B was confirmed using luciferase reporter gene assays. Finally, the combined effect of miR-139 and ATP7A/B on the chemoresistance of ovarian cancer cell was assessed. RESULTS miR-139 expression was down-regulated in cisplatin-resistant ovarian cancer tissues (**P < 0.01) and reduced by cisplatin treatment in ovarian cell lines (*P < 0.05, **P < 0.01); miR-139 could enhance cisplatin-induced suppression on ovarian cancer cell viability, shown as reduced lC50 values; ATP7A and ATP7B protein levesincreased approximately 2 ~ fold-changein cisplatin-resistant cell lines. MiR-139 directly bound to the 3'UTR of ATP7A/B, respectively; miR-139 inhibition increased lC50 values whereas ATP7A/B knockdown reduced lC50 values of CAOV-3 and SNU119 cell lines under cisplatin treatment; the effect of miR-139 inhibition could be partially attenuated by ATP7A/B knockdown. CONCLUSIONS MiR-139/ATP7A/B axis can be a reliable biomarker for ovarian cancer diagnosis, and may affect the chemoresistance of ovarian cancer to cisplatin-based chemotherapy; rescuing miR-139 expression thus to inhibit ATP7A/B might contribute to dealing with the chemoresistance of ovarian cancer.
Collapse
Affiliation(s)
- Fang Xiao
- Department of Gynecology and Obstetrics, The Third Xiangya Hospital of Central South University, No. 138, Tong zi po Rd, Yuelu District, Changsha, 410013, China
| | - Yueran Li
- Department of Gynecology and Obstetrics, The Third Xiangya Hospital of Central South University, No. 138, Tong zi po Rd, Yuelu District, Changsha, 410013, China
| | - Yajun Wan
- Department of Gynecology and Obstetrics, The Third Xiangya Hospital of Central South University, No. 138, Tong zi po Rd, Yuelu District, Changsha, 410013, China.
| | - Min Xue
- Department of Gynecology and Obstetrics, The Third Xiangya Hospital of Central South University, No. 138, Tong zi po Rd, Yuelu District, Changsha, 410013, China.
| |
Collapse
|
|
30
|
Desferal regulates hCtr1 and transferrin receptor expression through Sp1 and exhibits synergistic cytotoxicity with platinum drugs in oxaliplatin-resistant human cervical cancer cells in vitro and in vivo. Oncotarget 2018; 7:49310-49321. [PMID: 27384479 PMCID: PMC5226510 DOI: 10.18632/oncotarget.10336] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Accepted: 06/13/2016] [Indexed: 01/05/2023] Open
Abstract
The development of resistance to platinum drugs in cancer cells severely reduces the efficacy of these drugs. Thus, the discovery of novel drugs or combined strategies to overcome drug resistance is imperative. In addition to our previous finding that combined D-penicillamine with platinum drugs exerts synergistic cytotoxicity, we recently identified a novel therapeutic strategy by combining an iron chelating agent desferal with platinum drugs to overcome platinum resistance in an oxaliplatin-resistant human cervical cancer cell line, S3. Further study demonstrated that the level of platinum–DNA adduct formation positively correlated with cell death in combination of desferal with platinums than that of each drug alone in S3 cells. Decrement of human copper transporter 1 (hCtr1) and transferrin receptor 1 (TfR1) expression involved in the development of platinum resistance in S3 cells. Moreover, desferal promoted the expression of hCtr1 through the upregulation of Sp1. The overexpression of Sp1 increased the expression of NF-κB and translocated it into the nucleus to bind to the TfR1 promoter region, which subsequently increased the expression of TfR1. Importantly, the cotreatment of oxaliplatin with desferal significantly potentiated the oxaliplatin-elicited antitumoral effect in the oxaliplatin-resistant xenograft animal model without any toxic effect observed. Taken together, these results demonstrated that the combination of desferal with oxaliplatin can overcome oxaliplatin resistance through the regulation of hCtr1 and TfR1, and may have beneficial effect for treatment of patient with oxaliplatin-refractory tumors.
Collapse
|
|
31
|
Li YQ, Yin JY, Liu ZQ, Li XP. Copper efflux transporters ATP7A and ATP7B: Novel biomarkers for platinum drug resistance and targets for therapy. IUBMB Life 2018; 70:183-191. [PMID: 29394468 DOI: 10.1002/iub.1722] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Accepted: 01/12/2018] [Indexed: 12/22/2022]
Abstract
Platinum-based chemotherapy agents are widely used in the treatment of various solid malignancies. However, their efficacy is limited by drug resistance. Recent studies suggest that copper efflux transporters, which are encoded by ATP7A and ATP7B, play an important role in platinum drug resistance. Over-expressions of ATP7A and ATP7B are observed in multiple cancers. Moreover, their expressions are associated with cancer prognosis and treatment outcomes of platinum-based chemotherapy. In our review, we highlight the roles of ATP7A/7B in platinum drug resistance and cancer progression. We also discuss the possible mechanisms of platinum drug resistance mediated by ATP7A/7B and provide novel strategies for overcoming resistance. This review may be helpful for understanding the roles of ATP7A and ATP7B in platinum drug resistance. © 2018 IUBMB Life, 70(3):183-191, 2018.
Collapse
Affiliation(s)
- Yue-Qin Li
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, People's Republic of China.,Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, People's Republic of China
| | - Ji-Ye Yin
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, People's Republic of China
| | - Zhao-Qian Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, People's Republic of China
| | - Xiang-Ping Li
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, People's Republic of China.,Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, People's Republic of China
| |
Collapse
|
|
32
|
Guttmann S, Chandhok G, Groba SR, Niemietz C, Sauer V, Gomes A, Ciarimboli G, Karst U, Zibert A, Schmidt HH. Organic cation transporter 3 mediates cisplatin and copper cross-resistance in hepatoma cells. Oncotarget 2017; 9:743-754. [PMID: 29416650 PMCID: PMC5787505 DOI: 10.18632/oncotarget.23142] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Accepted: 11/15/2017] [Indexed: 12/12/2022] Open
Abstract
Platinum-based drugs are first-line compounds in the treatment of many solid cancers. Major obstacles are tumors that become resistant and toxic side effects, both largely due to the expression of transporters that mediate the cellular processing of platinum. In this study, we addressed the establishment of cisplatin resistance in the absence of copper transporter ATP7B that has been previously found to be overexpressed in various resistant cells. Cisplatin sensitivity, induction of apoptosis, drug accumulation, and transporter gene expression were determined in hepatoma cell lines. Knockout or overexpression of copper transporter ATP7B did not affect cisplatin sensitivity. Cisplatin resistant cells showed a stably reduced cisplatin accumulation and a downregulation of organic cation transporter 3 (OCT3). In contrast, OCT3 overexpression could reverse resistance. Reduced MT1 expression was detected in the resistant cell line, however transient and highly dependent on the presence of cisplatin. Cross-resistance to copper was also associated with OCT3 downregulation. Our results suggest that a decreased level of OCT3 expression results in resistance to cisplatin and copper. OCT3 may represent a novel target for improved prognosis and anticancer therapy, including HCC.
Collapse
Affiliation(s)
- Sarah Guttmann
- Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Germany
| | - Gursimran Chandhok
- Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Germany.,Present address: Monash Biomedicine Discovery Institute, and Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia
| | - Sara Reinartz Groba
- Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Germany
| | - Christoph Niemietz
- Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Germany
| | - Vanessa Sauer
- Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Germany
| | - Amanda Gomes
- Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Germany.,Present address: Wilson Disease Clinic, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Mumbai, India
| | - Giuliano Ciarimboli
- Universitätsklinikum Münster, Medizinische Klinik D, Experimentelle Nephrologie, Münster, Germany
| | - Uwe Karst
- Institute of Inorganic and Analytical Chemistry, University of Münster, Münster, Germany
| | - Andree Zibert
- Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Germany
| | - Hartmut H Schmidt
- Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Germany
| |
Collapse
|
|
33
|
Moinuddin FM, Shinsato Y, Komatsu M, Mitsuo R, Minami K, Yamamoto M, Kawahara K, Hirano H, Arita K, Furukawa T. ATP7B expression confers multidrug resistance through drug sequestration. Oncotarget 2017; 7:22779-90. [PMID: 26988911 PMCID: PMC5008400 DOI: 10.18632/oncotarget.8059] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Accepted: 02/23/2016] [Indexed: 11/30/2022] Open
Abstract
We previously reported that ATP7B is involved in cisplatin resistance and ATP7A confers multidrug resistance (MDR) in cancer cells. In this study, we show that ATP7B expressing cells also are resistant to doxorubicin, SN-38, etoposide, and paclitaxel as well as cisplatin. In ATP7B expressing cells, doxorubicin relocated from the nuclei to the late-endosome at 4 hours after doxorubicin exposure. EGFP-ATP7B mainly colocalized with doxorubicin. ATP7B has six metal binding sites (MBSs) in the N-terminal cytoplasmic region. To investigate the role of the MBSs of ATP7B in doxorubicin resistance, we used three mutant ATP7B (Cu0, Cu6 and M6C/S) expressing cells. Cu0 has no MBSs, Cu6 has only the sixth MBS and M6C/S carries CXXC to SXXS mutation in the sixth MBS. Cu6 expressing cells were less resistance to the anticancer agents than wild type ATP7B expressing cells, and had doxorubicin sequestration in the late-endosome. Cu0- and M6C/S-expressing cells were sensitive to doxorubicin. In these cells, doxorubicin did not relocalize to the late-endosome. EGFP-M6C/S mainly localized to the trans-Golgi network (TGN) even in the presence of copper. Thus the cysteine residues in the sixth MBS of ATP7B are essential for MDR phenotype. Finally, we found that ammonium chloride and tamoxifen suppressed late endosomal sequestration of doxorubicin, thereby attenuating drug resistance. These results suggest that the sequestration depends on the acidity of the vesicles partly. We here demonstrate that ATP7B confers MDR by facilitating nuclear drug efflux and late endosomal drug sequestration.
Collapse
Affiliation(s)
- F M Moinuddin
- Department of Neurosurgery, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.,Department of Molecular Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
| | - Yoshinari Shinsato
- Department of Molecular Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.,Center for the Research of Advanced Diagnosis and Therapy of Cancer, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
| | - Masaharu Komatsu
- Division of Food and Chemical Biology, Faculty of Fisheries, Kagoshima University, 4-50-20, Shimoarata, Kagoshima 890-0056, Japan
| | - Ryoichi Mitsuo
- Department of Molecular Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
| | - Kentaro Minami
- Department of Molecular Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.,Center for the Research of Advanced Diagnosis and Therapy of Cancer, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
| | - Masatatsu Yamamoto
- Department of Molecular Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.,Center for the Research of Advanced Diagnosis and Therapy of Cancer, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
| | - Kohich Kawahara
- Department of Molecular Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.,Center for the Research of Advanced Diagnosis and Therapy of Cancer, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
| | - Hirofumi Hirano
- Department of Neurosurgery, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
| | - Kazunori Arita
- Department of Neurosurgery, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
| | - Tatsuhiko Furukawa
- Department of Molecular Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.,Center for the Research of Advanced Diagnosis and Therapy of Cancer, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
| |
Collapse
|
|
34
|
Liu Y, Zheng X, Yu Q, Wang H, Tan F, Zhu Q, Yuan L, Jiang H, Yu L, Zeng S. Epigenetic activation of the drug transporter OCT2 sensitizes renal cell carcinoma to oxaliplatin. Sci Transl Med 2017; 8:348ra97. [PMID: 27440728 DOI: 10.1126/scitranslmed.aaf3124] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2016] [Accepted: 06/21/2016] [Indexed: 12/13/2022]
Abstract
Renal cell carcinoma (RCC) is known for its multidrug resistance. Using data obtained from the cancer transcriptome database Oncomine and the proteome database The Human Protein Atlas, we identified the repression of organic cation transporter OCT2 as a potential factor contributing to oxaliplatin resistance in RCC. By analyzing OCT2 expression in collected patient tissues and commercial tissue microarray specimens, we demonstrated OCT2 repression in RCC at both transcription and protein levels. Epigenetic analysis revealed that the repressed OCT2 promoter in RCC is characterized by hypermethylated CpG islands and the absence of H3K4 methylation. Further mechanistic studies showed that DNA hypermethylation blocked MYC activation of OCT2 by disrupting its interaction with the E-Box motif, which prevented MYC from recruiting MLL1 to catalyze H3K4me3 at the OCT2 promoter and resulted in repressed OCT2 transcription. Targeting this mechanism, we designed a sequential combination therapy and demonstrated that epigenetic activation of OCT2 by decitabine sensitizes RCC cells to oxaliplatin both in vitro and in xenografts. Our study highlights the potential of translating "omics" data into the development of targeted therapies.
Collapse
Affiliation(s)
- Yanqing Liu
- Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Xiaoli Zheng
- Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Qinqin Yu
- Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Hua Wang
- Department of Urology, Cancer Hospital of Zhejiang Province, Hangzhou 310022, China
| | - Fuqing Tan
- Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Qianying Zhu
- Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Lingmin Yuan
- Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Huidi Jiang
- Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Lushan Yu
- Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
| | - Su Zeng
- Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
| |
Collapse
|
|
35
|
Sun S, Cai J, Yang Q, Zhao S, Wang Z. The association between copper transporters and the prognosis of cancer patients undergoing chemotherapy: a meta-analysis of literatures and datasets. Oncotarget 2017; 8:16036-16051. [PMID: 27980217 PMCID: PMC5362544 DOI: 10.18632/oncotarget.13917] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 12/01/2016] [Indexed: 12/13/2022] Open
Abstract
Copper transporter 1 (CTR1), copper transporter 2 (CTR2), copper-transporting p-type adenosine triphosphatase 1 and 2 (ATP7A and ATP7B) are key mediators of cellular cisplatin, carboplatin and oxaliplatin accumulation. In this meta-analysis, we aimed to evaluate the relation of CTR1, CTR2, ATP7A and ATP7B to overall survival (OS), progression-free survival (PFS), disease-free survival (DFS) and treatment response (TR) of cancer patients who received chemotherapy based on published literatures, the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) datasets. Hazard ratios (HRs) and odds ratios (ORs) were pooled using random-effect models. Subgroup analysis and sensitivity analysis were conducted; heterogeneity and publication bias were assessed. Twelve literatures and eight datasets with 2149 patients were included. Our results suggested that high CTR1 expression was associated with favorable OS, PFS, DFS and TR in cancer patients who underwent chemotherapy with acceptable heterogeneity. The relationship of CTR1 to cancer prognosis remained significant in the subgroup of patients who underwent platinum-based chemotherapy, the patients with ovarian cancer and those with lung cancer. The significance of these relationships was not influenced by geological region of publication, data origin or detection method. However, there was no evidence for relation of CTR2, ATP7A or ATP7B to OS, PFS, DFS or TR. Test of publication bias and sensitivity analysis suggested a robustness of all the summary effect estimates. In conclusion, high CTR1 level predicts prolonged survival and enhanced response to chemotherapy in cancer patients who underwent chemotherapy and CTR1 might be a potential target to circumvent chemotherapy resistance.
Collapse
Affiliation(s)
- Si Sun
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Jing Cai
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Qiang Yang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Simei Zhao
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Zehua Wang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| |
Collapse
|
|
36
|
Emmerich P, Clipson L, Deming DA. Resistance Mechanisms to Colorectal Cancer Therapeutics and the Clinical Implications. CURRENT COLORECTAL CANCER REPORTS 2017. [DOI: 10.1007/s11888-017-0374-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
|
|
37
|
Quintanilha JCF, de Sousa VM, Visacri MB, Amaral LS, Santos RMM, Zambrano T, Salazar LA, Moriel P. Involvement of cytochrome P450 in cisplatin treatment: implications for toxicity. Cancer Chemother Pharmacol 2017; 80:223-233. [PMID: 28612092 DOI: 10.1007/s00280-017-3358-x] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Accepted: 06/07/2017] [Indexed: 12/23/2022]
Abstract
PURPOSE The aim of this study is to evaluate the relationship between the CYP450 enzyme family and cisplatin toxicity. METHODS This article examined a collection of studies suggesting that CYP450 enzymes may influence cisplatin toxicity. We performed a narrative mini-review. RESULTS The studies review showed that CYP450 enzymes have an important role in drug-induced hepatotoxicity and nephrotoxicity, mainly CYP2E1 and CYP4A11. The studies also suggested that the cisplatin and CYP2E1 interaction leads to the generation of reactive oxygen species (ROS) and other oxidants resulting in renal injury; and that ROS generated by both the use of cisplatin and by the CYP2E1 increases tissue damage, induces apoptosis, and causes liver failure. CONCLUSIONS We observed that there is an important relationship between CYP450 and cisplatin, involving increased toxicity. However, the possible mechanisms described for the involvement of CYP450 enzymes in nephrotoxicity and hepatotoxicity induced by cisplatin need to be confirmed by further studies. Therefore, there is a need for a deeper investigation focusing on cisplatin toxicity mediated by CYP450 enzymes, which would undoubtedly contribute to a better understanding of the mechanisms that have been implicated so far.
Collapse
Affiliation(s)
| | - Vanessa Marcilio de Sousa
- Faculty of Pharmaceutical Sciences, University of Campinas (UNICAMP), 200 Cândido Portinari, Campinas, 13083-871, SP, Brazil
| | | | - Laís Sampaio Amaral
- School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil
| | | | - Tomás Zambrano
- Center of Molecular Biology and Pharmacogenetics, Faculty of Medicine, University of La Frontera, Temuco, Chile
| | - Luis Antonio Salazar
- Center of Molecular Biology and Pharmacogenetics, Faculty of Medicine, University of La Frontera, Temuco, Chile
| | - Patricia Moriel
- School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil.
- Faculty of Pharmaceutical Sciences, University of Campinas (UNICAMP), 200 Cândido Portinari, Campinas, 13083-871, SP, Brazil.
| |
Collapse
|
|
38
|
Cerovska E, Elsnerova K, Vaclavikova R, Soucek P. The role of membrane transporters in ovarian cancer chemoresistance and prognosis. Expert Opin Drug Metab Toxicol 2017; 13:741-753. [PMID: 28511565 DOI: 10.1080/17425255.2017.1332179] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
INTRODUCTION Ovarian cancer has the highest mortality rate of all cancers in women. There is currently no effective method for early diagnosis, limiting the precision of clinical expectations. Predictions of therapeutic efficacy are currently not available either. Specifically, the development of chemoresistance against conventional chemotherapy poses a fundamental complication. Some membrane transporters have been reported to influence chemoresistance, which is often associated with a poor prognosis. Areas covered: The aim of this article is to review the existing information about membrane transporters and their role in both ovarian cancer chemoresistance and its outcomes. We then highlight limitations of current methodologies and suggest alternatives providing avenues for future research. Expert opinion: Membrane transporters play an important role in development of chemoresistance and affect prognosis of ovarian cancer patients; however, due to variations in methodology and in patient populations, their specific roles have yet to be clarified. For further evaluation of the clinical utility of membrane transporters, it is essential to validate results and improve methods for marker assessment across laboratories. A promising area for future research is to identify the genetic variability in potential markers in peripheral blood. These markers would then stratify patients into defined groups for optimal intervention.
Collapse
Affiliation(s)
- Ela Cerovska
- a Toxicogenomics Unit , National Institute of Public Health , Prague , Czech Republic
| | - Katerina Elsnerova
- a Toxicogenomics Unit , National Institute of Public Health , Prague , Czech Republic.,b 3rd Faculty of Medicine , Charles University , Prague , Czech Republic.,c Biomedical Center, Faculty of Medicine in Pilsen , Charles University , Pilsen , Czech Republic
| | - Radka Vaclavikova
- a Toxicogenomics Unit , National Institute of Public Health , Prague , Czech Republic.,c Biomedical Center, Faculty of Medicine in Pilsen , Charles University , Pilsen , Czech Republic
| | - Pavel Soucek
- a Toxicogenomics Unit , National Institute of Public Health , Prague , Czech Republic.,c Biomedical Center, Faculty of Medicine in Pilsen , Charles University , Pilsen , Czech Republic
| |
Collapse
|
|
39
|
Copper transporter 1 in human colorectal cancer cell lines: Effects of endogenous and modified expression on oxaliplatin cytotoxicity. J Inorg Biochem 2017; 177:249-258. [PMID: 28551160 DOI: 10.1016/j.jinorgbio.2017.04.022] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Revised: 04/13/2017] [Accepted: 04/23/2017] [Indexed: 11/23/2022]
Abstract
Oxaliplatin-based chemotherapy is the mainstay for the treatment of advanced colorectal cancer. Copper transporter proteins have been implicated in the transport of platinum-based anticancer drugs, but their expression in human colorectal cancer cell lines and roles in controlling their sensitivity to oxaliplatin are not well studied or understood. The endogenous and modified expression of copper uptake transporter 1 (hCTR1) was studied in a panel of human colorectal cancer cell lines (DLD-1, SW620, HCT-15 and COLO205) with ~20-fold variation in oxaliplatin sensitivity. hCTR1 protein was expressed more abundantly than ATP7A and ATP7B proteins, but with broadly similar levels and patterns of expression across four colorectal cancer cell lines. In a colorectal cancer cell-line background (DLD-1), stable transfection of the hCtr1 gene enhanced hCTR1 protein expression and increased the sensitivity of the cells to the cytotoxicity of copper and oxaliplatin. Treatment with copper chelators (ammonium tetrathiomolybdate, bathocuproinedisulfonic acid and D-penicillamine) increased expression of hCTR1 protein in DLD-1 and SW620 cells, and potentiated the cytotoxicity of oxaliplatin in DLD-1 but not SW620 cells. Treatment with copper chloride altered neither the expression of copper transporters nor cytotoxicity of oxaliplatin in colorectal cancer lines. In conclusion, human colorectal cancer cell lines consistently express hCTR1 protein despite their variable sensitivity to oxaliplatin. Genetic or pharmacological modification of hCTR1 protein expression may potentiate oxaliplatin sensitivity in some but not all colorectal cancer cell lines.
Collapse
|
|
40
|
English DP, Menderes G, Black J, Schwab CL, Santin AD. Molecular diagnosis and molecular profiling to detect treatment-resistant ovarian cancer. Expert Rev Mol Diagn 2016; 16:769-82. [PMID: 27169329 DOI: 10.1080/14737159.2016.1188692] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Epithelial ovarian cancer remains the gynecologic tumor with the highest rate of recurrence after initial optimal cytoreductive surgery followed by adjuvant chemotherapy. Unfortunately, with the development of recurrent ovarian cancer often comes the discovery of chemo-resistant disease. The absence of improvement in long term survival, notwithstanding the use of newer agents as is seen in other cancers, emphasizes the need for improved understanding of the processes that lead to chemo-resistant disease. AREAS COVERED This review will cover the following topics: 1. Molecular and cellular mechanisms in platinum and paclitaxel resistance 2. Other molecular mediators of chemo-resistance 3. Expression of stem cell markers in ovarian cancer and relationship to chemo-resistance 4. MicroRNA and long non-coding RNA expression in chemo-resistant ovarian cancer 5. Determination of chromosomal aberrations as markers of chemo-resistance 6. Molecular profiling in chemo-resistant disease. A standard MEDLINE search was performed using the key words; ovarian cancer, chemo-resistant disease, molecular profiling, cancer stem cells and chemotherapy. Expert Commentary: Over the next few years the challenge remains to precisely determine the mechanisms responsible for the onset and maintenance of chemo-resistance and to effectively target these mechanisms.
Collapse
Affiliation(s)
- Diana P English
- a Department of Obstetrics and Gynecology, Division of Gynecologic Oncology , Stanford University , Stanford , CA , USA
| | - Gulden Menderes
- b Department of Obstetrics, Gynecology & Reproductive Sciences, Division of Gynecologic Oncology , Yale University School of Medicine , New Haven , CT , USA
| | - Jonathan Black
- a Department of Obstetrics and Gynecology, Division of Gynecologic Oncology , Stanford University , Stanford , CA , USA
| | - Carlton L Schwab
- b Department of Obstetrics, Gynecology & Reproductive Sciences, Division of Gynecologic Oncology , Yale University School of Medicine , New Haven , CT , USA
| | - Alessandro D Santin
- b Department of Obstetrics, Gynecology & Reproductive Sciences, Division of Gynecologic Oncology , Yale University School of Medicine , New Haven , CT , USA
| |
Collapse
|
|
41
|
Guancial EA, Kilari D, Xiao GQ, Abu-Farsakh SH, Baran A, Messing EM, Kim ES. Platinum Concentration and Pathologic Response to Cisplatin-Based Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer. PLoS One 2016; 11:e0155503. [PMID: 27187160 PMCID: PMC4871463 DOI: 10.1371/journal.pone.0155503] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Accepted: 04/30/2016] [Indexed: 01/09/2023] Open
Abstract
Background Platinum (Pt)-based chemotherapy is the standard of care for muscle-invasive bladder cancer (MIBC). However, resistance is a major limitation. Reduced intratumoral drug accumulation is an important mechanism of platinum resistance. Our group previously demonstrated a significant correlation between tissue Pt concentration and tumor response to Pt-based neoadjuvant chemotherapy (NAC) in lung cancer. We hypothesized that increased Pt concentration in radical cystectomy (RC) specimens would correlate with improved pathologic response to Pt-based NAC in MIBC. Methods A cohort of 19 clinically annotated, archived, fresh frozen RC specimens from patients with MIBC treated with Pt-based NAC was identified [ypT0 (pathologic complete response, pCR), N = 4; ≤ypT1N0M0 (pathologic partial response, pPR), N = 6; ≥ypT2 (minimal pathologic response/progression), N = 9)]. RC specimens from 2 patients with MIBC who did not receive NAC and 1 treated with a non-Pt containing NAC regimen were used as negative controls. Total Pt concentration in normal adjacent urothelial tissue and bladder tumors from RC specimens was measured by flameless atomic absorption spectrophotometry. Results Total Pt concentration in normal urothelium differed by tumor pathologic response (P = 0.011). Specimens with pCR had the highest Pt concentrations compared to those with pPR (P = 0.0095) or no response/progression (P = 0.020). There was no significant difference in Pt levels in normal urothelium and tumor between pPR and no response/progression groups (P = 0.37; P = 0.25, respectively). Conclusions: Our finding of increased intracellular Pt in RC specimens with pCR following NAC for MIBC compared to those with residual disease suggests that enhanced Pt accumulation may be an important determinant of Pt sensitivity. Factors that modulate intracellular Pt concentration, such as expression of Pt transporters, warrant further investigation as predictive biomarkers of response to Pt-based NAC in MIBC.
Collapse
Affiliation(s)
- Elizabeth A. Guancial
- Department of Medicine/James P. Wilmot Cancer Institute, University of Rochester, Rochester, New York, United States of America
- * E-mail:
| | - Deepak Kilari
- Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
| | - Guang-Qian Xiao
- Department of Pathology, University of Rochester, Rochester, New York, United States of America
| | - Sohaib H. Abu-Farsakh
- Department of Pathology, University of Rochester, Rochester, New York, United States of America
| | - Andrea Baran
- Department of Biostatistics and Computational Biology, University of Rochester, Rochester, New York, United States of America
| | - Edward M. Messing
- Department of Urology, University of Rochester, Rochester, New York, United States of America
| | - Eric S. Kim
- Department of Medicine/James P. Wilmot Cancer Institute, University of Rochester, Rochester, New York, United States of America
| |
Collapse
|
|
42
|
KATAOKA JUNRO, SHIRAHA HIDENORI, HORIGUCHI SHIGERU, SAWAHARA HIROAKI, UCHIDA DAISUKE, NAGAHARA TERUYA, IWAMURO MASAYA, MORIMOTO HIROKI, TAKEUCHI YASUTO, KUWAKI KENJI, ONISHI HIDEKI, NAKAMURA SHINICHIRO, TAKAKI AKINOBU, NOUSO KAZUHIRO, YAGI TAKAHITO, YAMAMOTO KAZUHIDE, OKADA HIROYUKI. Loss of Runt-related transcription factor 3 induces resistance to 5-fluorouracil and cisplatin in hepatocellular carcinoma. Oncol Rep 2016; 35:2576-2582. [PMID: 26985715 PMCID: PMC4811400 DOI: 10.3892/or.2016.4681] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 12/18/2015] [Indexed: 12/17/2022] Open
Abstract
Runt-related transcription factor 3 (RUNX3) is known to function as a tumor suppressor in gastric cancer and other types of cancers, including hepatocellular carcinoma (HCC). However, its role has not been fully elucidated. In the present study, we aimed to evaluate the role of RUNX3 in HCC. We used the human HCC cell lines Hep3B, Huh7 and HLF; RUNX3 cDNA was introduced into Hep3B and Huh7 cells, which were negative for endogenous RUNX3 expression, and RUNX3 siRNA was transfected into HLF cells, which were positive for endogenous RUNX3. We analyzed the expression of RUNX3 and multidrug resistance-associated protein (MRP) by immunoblotting. MTT assays were used to determine the effects of RUNX3 expression on 5-fluorouracil (5-FU) and cisplatin (CDDP) sensitivity. Finally, 23 HCC specimens resected from patients with HCC at Okayama University Hospital were analyzed, and correlations among immunohistochemical expression of RUNX3 protein and MRP protein were evaluated in these specimens. Exogenous RUNX3 expression reduced the expression of MRP1, MRP2, MRP3 and MRP5 in the RUNX3-negative cells, whereas knockdown of RUNX3 in the HLF cells stimulated the expression of these MRPs. An inverse correlation between RUNX3 and MRP expression was observed in the HCC tissues. Importantly, loss of RUNX3 expression contributed to 5-FU and CDDP resistance by inducing MRP expression. These data have important implications in the study of chemotherapy resistance in HCC.
Collapse
Affiliation(s)
- JUNRO KATAOKA
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - HIDENORI SHIRAHA
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - SHIGERU HORIGUCHI
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - HIROAKI SAWAHARA
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - DAISUKE UCHIDA
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - TERUYA NAGAHARA
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - MASAYA IWAMURO
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - HIROKI MORIMOTO
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - YASUTO TAKEUCHI
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - KENJI KUWAKI
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - HIDEKI ONISHI
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - SHINICHIRO NAKAMURA
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - AKINOBU TAKAKI
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - KAZUHIRO NOUSO
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - TAKAHITO YAGI
- Department of Gastroenterological Surgery, Transplant and Surgical Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - KAZUHIDE YAMAMOTO
- Department of Gastroenterology, Okayama Saiseikai General Hospital, Okayama 700-8511, Japan
| | - HIROYUKI OKADA
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| |
Collapse
|
|
43
|
Galgamuwa R, Hardy K, Dahlstrom JE, Blackburn AC, Wium E, Rooke M, Cappello JY, Tummala P, Patel HR, Chuah A, Tian L, McMorrow L, Board PG, Theodoratos A. Dichloroacetate Prevents Cisplatin-Induced Nephrotoxicity without Compromising Cisplatin Anticancer Properties. J Am Soc Nephrol 2016; 27:3331-3344. [PMID: 26961349 DOI: 10.1681/asn.2015070827] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Accepted: 01/27/2016] [Indexed: 01/01/2023] Open
Abstract
Cisplatin is an effective anticancer drug; however, cisplatin use often leads to nephrotoxicity, which limits its clinical effectiveness. In this study, we determined the effect of dichloroacetate, a novel anticancer agent, in a mouse model of cisplatin-induced AKI. Pretreatment with dichloroacetate significantly attenuated the cisplatin-induced increase in BUN and serum creatinine levels, renal tubular apoptosis, and oxidative stress. Additionally, pretreatment with dichloroacetate accelerated tubular regeneration after cisplatin-induced renal damage. Whole transcriptome sequencing revealed that dichloroacetate prevented mitochondrial dysfunction and preserved the energy-generating capacity of the kidneys by preventing the cisplatin-induced downregulation of fatty acid and glucose oxidation, and of genes involved in the Krebs cycle and oxidative phosphorylation. Notably, dichloroacetate did not interfere with the anticancer activity of cisplatin in vivo. These data provide strong evidence that dichloroacetate preserves renal function when used in conjunction with cisplatin.
Collapse
Affiliation(s)
| | - Kristine Hardy
- Faculty of Education, Science, Technology and Mathematics, University of Canberra, Australian Capital Territory, Australia
| | - Jane E Dahlstrom
- ACT Pathology and ANU Medical School, The Canberra Hospital, Australian Capital Territory, Australia
| | | | - Elize Wium
- Departments of Cancer Biology and Therapeutics and
| | | | | | | | | | - Aaron Chuah
- Genome Discovery Unit, John Curtin School of Medical Research, Australian National University, Australian Capital Territory, Australia
| | - Luyang Tian
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; and
| | - Linda McMorrow
- Archaeogeochemistry and Marine Biogeochemistry Groups, Research School of Earth Sciences, Australian National University, Australian Capital Territory, Australia
| | | | | |
Collapse
|
|
44
|
Kilari D, Guancial E, Kim ES. Role of copper transporters in platinum resistance. World J Clin Oncol 2016; 7:106-113. [PMID: 26862494 PMCID: PMC4734932 DOI: 10.5306/wjco.v7.i1.106] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 09/04/2015] [Accepted: 11/25/2015] [Indexed: 02/06/2023] Open
Abstract
Platinum (Pt)-based antitumor agents are effective in the treatment of many solid malignancies. However, their efficacy is limited by toxicity and drug resistance. Reduced intracellular Pt accumulation has been consistently shown to correlate with resistance in tumors. Proteins involved in copper homeostasis have been identified as Pt transporters. In particular, copper transporter receptor 1 (CTR1), the major copper influx transporter, has been shown to play a significant role in Pt resistance. Clinical studies demonstrated that expression of CTR1 correlated with intratumoral Pt concentration and outcomes following Pt-based therapy. Other CTRs such as CTR2, ATP7A and ATP7B, may also play a role in Pt resistance. Recent clinical studies attempting to modulate CTR1 to overcome Pt resistance may provide novel strategies. This review discusses the role of CTR1 as a potential predictive biomarker of Pt sensitivity and a therapeutic target for overcoming Pt resistance.
Collapse
|
|
45
|
Wang S, Zhang H, Scharadin TM, Zimmermann M, Hu B, Pan AW, Vinall R, Lin TY, Cimino G, Chain P, Vuyisich M, Gleasner C, Mcmurry K, Malfatti M, Turteltaub K, de Vere White R, Pan CX, Henderson PT. Molecular Dissection of Induced Platinum Resistance through Functional and Gene Expression Analysis in a Cell Culture Model of Bladder Cancer. PLoS One 2016; 11:e0146256. [PMID: 26799320 PMCID: PMC4723083 DOI: 10.1371/journal.pone.0146256] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Accepted: 12/15/2015] [Indexed: 01/24/2023] Open
Abstract
We report herein the development, functional and molecular characterization of an isogenic, paired bladder cancer cell culture model system for studying platinum drug resistance. The 5637 human bladder cancer cell line was cultured over ten months with stepwise increases in oxaliplatin concentration to generate a drug resistant 5637R sub cell line. The MTT assay was used to measure the cytotoxicity of several bladder cancer drugs. Liquid scintillation counting allowed quantification of cellular drug uptake and efflux of radiolabeled oxaliplatin and carboplatin. The impact of intracellular drug inactivation was assessed by chemical modulation of glutathione levels. Oxaliplatin- and carboplatin-DNA adduct formation and repair was measured using accelerator mass spectrometry. Resistance factors including apoptosis, growth factor signaling and others were assessed with RNAseq of both cell lines and included confirmation of selected transcripts by RT-PCR. Oxaliplatin, carboplatin, cisplatin and gemcitabine were significantly less cytotoxic to 5637R cells compared to the 5637 cells. In contrast, doxorubicin, methotrexate and vinblastine had no cell line dependent difference in cytotoxicity. Upon exposure to therapeutically relevant doses of oxaliplatin, 5637R cells had lower drug-DNA adduct levels than 5637 cells. This difference was partially accounted for by pre-DNA damage mechanisms such as drug uptake and intracellular inactivation by glutathione, as well as faster oxaliplatin-DNA adduct repair. In contrast, both cell lines had no significant differences in carboplatin cell uptake, efflux and drug-DNA adduct formation and repair, suggesting distinct resistance mechanisms for these two closely related drugs. The functional studies were augmented by RNAseq analysis, which demonstrated a significant change in expression of 83 transcripts, including 50 known genes and 22 novel transcripts. Most of the transcripts were not previously associated with bladder cancer chemoresistance. This model system and the associated phenotypic and genotypic data has the potential to identify some novel details of resistance mechanisms of clinical importance to bladder cancer.
Collapse
Affiliation(s)
- Sisi Wang
- Department of Internal Medicine, Division of Hematology and Oncology, University of California Davis, Sacramento, California, United States of America
| | - Hongyong Zhang
- Department of Internal Medicine, Division of Hematology and Oncology, University of California Davis, Sacramento, California, United States of America
| | - Tiffany M. Scharadin
- Department of Internal Medicine, Division of Hematology and Oncology, University of California Davis, Sacramento, California, United States of America
| | - Maike Zimmermann
- Department of Internal Medicine, Division of Hematology and Oncology, University of California Davis, Sacramento, California, United States of America
- Accelerated Medical Diagnostics Incorporated, Dublin, California, United States of America
| | - Bin Hu
- Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
| | - Amy Wang Pan
- Department of Internal Medicine, Division of Hematology and Oncology, University of California Davis, Sacramento, California, United States of America
| | - Ruth Vinall
- Department of Urology, University of California Davis, Sacramento, California, United States of America
| | - Tzu-yin Lin
- Department of Internal Medicine, Division of Hematology and Oncology, University of California Davis, Sacramento, California, United States of America
| | - George Cimino
- Accelerated Medical Diagnostics Incorporated, Dublin, California, United States of America
| | - Patrick Chain
- Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
| | - Momchilo Vuyisich
- Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
| | - Cheryl Gleasner
- Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
| | - Kim Mcmurry
- Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
| | - Michael Malfatti
- Lawrence Livermore National Laboratory, Livermore, California, United States of America
| | - Kenneth Turteltaub
- Lawrence Livermore National Laboratory, Livermore, California, United States of America
| | - Ralph de Vere White
- Department of Urology, University of California Davis, Sacramento, California, United States of America
| | - Chong-xian Pan
- Department of Internal Medicine, Division of Hematology and Oncology, University of California Davis, Sacramento, California, United States of America
- Department of Urology, University of California Davis, Sacramento, California, United States of America
- VA Northern California Health Care System, Mather, California, United States of America
- * E-mail: (PTH); (CXP)
| | - Paul T. Henderson
- Department of Internal Medicine, Division of Hematology and Oncology, University of California Davis, Sacramento, California, United States of America
- Accelerated Medical Diagnostics Incorporated, Dublin, California, United States of America
- * E-mail: (PTH); (CXP)
| |
Collapse
|
|
46
|
Wirth R, White JD, Moghaddam AD, Ginzburg AL, Zakharov LN, Haley MM, DeRose VJ. Azide vs Alkyne Functionalization in Pt(II) Complexes for Post-treatment Click Modification: Solid-State Structure, Fluorescent Labeling, and Cellular Fate. J Am Chem Soc 2015; 137:15169-75. [PMID: 26512733 DOI: 10.1021/jacs.5b09108] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Tracking of Pt(II) complexes is of crucial importance toward understanding Pt interactions with cellular biomolecules. Post-treatment fluorescent labeling of functionalized Pt(II)-based agents using the bioorthogonal Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction has recently been reported as a promising approach. Here we describe an azide-functionalized Pt(II) complex, cis-[Pt(2-azidobutyl)amido-1,3-propanediamine)Cl2] (1), containing the cis geometry and difunctional reactivity of cisplatin, and present a comparative study with its previously described alkyne-functionalized congener. Single-crystal X-ray diffraction reveals a dramatic change in the solid-state arrangement with exchange of the alkyne for an azide moiety wherein 1 is dominated by a pseudo-chain of Pt-Pt dimers and antiparallel alignment of the azide substituents, in comparison with a circular arrangement supported by CH/π(C≡C) interactions in the alkyne version. In vitro studies indicate similar DNA binding and click reactivity of both congeners observed by fluorescent labeling. Interestingly, complex 1 shows in vitro enhanced click reactivity in comparison to a previously reported azide-appended Pt(II) complex. Despite their similar behavior in vitro, preliminary in cellulo HeLa studies indicate a superior imaging potential of azide-functionalized 1. Post-treatment fluorescent labeling of 1 observed by confocal fluorescence microscopy shows nuclear and intense nucleolar localization. These results demonstrate the potential of 1 in different cell line localization studies and for future isolation and purification of Pt-bound targets.
Collapse
Affiliation(s)
- Regina Wirth
- Department of Chemistry & Biochemistry and Institute of Molecular Biology, University of Oregon , Eugene, Oregon 97403-1253, United States
| | - Jonathan D White
- Department of Chemistry & Biochemistry and Institute of Molecular Biology, University of Oregon , Eugene, Oregon 97403-1253, United States
| | - Alan D Moghaddam
- Department of Chemistry & Biochemistry and Institute of Molecular Biology, University of Oregon , Eugene, Oregon 97403-1253, United States
| | - Aurora L Ginzburg
- Department of Chemistry & Biochemistry and Institute of Molecular Biology, University of Oregon , Eugene, Oregon 97403-1253, United States
| | - Lev N Zakharov
- CAMCOR, University of Oregon , 1443 East 13th Avenue, Eugene, Oregon 97403, United States
| | - Michael M Haley
- Department of Chemistry & Biochemistry and Institute of Molecular Biology, University of Oregon , Eugene, Oregon 97403-1253, United States
| | - Victoria J DeRose
- Department of Chemistry & Biochemistry and Institute of Molecular Biology, University of Oregon , Eugene, Oregon 97403-1253, United States
| |
Collapse
|
|
47
|
Perego P, Robert J. Oxaliplatin in the era of personalized medicine: from mechanistic studies to clinical efficacy. Cancer Chemother Pharmacol 2015; 77:5-18. [PMID: 26589793 DOI: 10.1007/s00280-015-2901-x] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 10/30/2015] [Indexed: 12/22/2022]
Abstract
Oxaliplatin is a third-generation platinum compound approved for clinical use relatively recently as compared to other drugs of the same class. Its main cellular target is DNA, where similarly to cisplatin and carboplatin it forms cross-links. However, due to a unique indication for colorectal cancer, synergistic interaction with fluoropyrimidines and peculiar toxicity profile, oxaliplatin is different from those compounds. Multiple lines of evidence indicate differences in transport and metabolism, consequences of DNA platination, as well as DNA repair and transduction of DNA damage. Here, we explore the preclinical features that may explain the unique properties of oxaliplatin in the clinics. Among them, the capability to accumulate in tumor cells via organic cation transporters, to kill KRAS mutant cells and to activate immunogenic cell death appears helpful to explain in part its clinical behavior. The continuous investigation of the molecular pharmacology of oxaliplatin is expected to provide clues to the definitions of predictors of drug activity and toxicity to translate to the clinical setting.
Collapse
Affiliation(s)
- Paola Perego
- Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133, Milan, Italy.
| | - Jacques Robert
- INSERM U916, Institut Bergonié, University of Bordeaux, 229 Cours de l'Argonne, 33000, Bordeaux, France
| |
Collapse
|
|
48
|
Gokhale A, Vrailas-Mortimer A, Larimore J, Comstra HS, Zlatic SA, Werner E, Manvich DF, Iuvone PM, Weinshenker D, Faundez V. Neuronal copper homeostasis susceptibility by genetic defects in dysbindin, a schizophrenia susceptibility factor. Hum Mol Genet 2015. [PMID: 26199316 DOI: 10.1093/hmg/ddv282] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Environmental factors and susceptible genomes interact to determine the risk of neurodevelopmental disorders. Although few genes and environmental factors have been linked, the intervening cellular and molecular mechanisms connecting a disorder susceptibility gene with environmental factors remain mostly unexplored. Here we focus on the schizophrenia susceptibility gene DTNBP1 and its product dysbindin, a subunit of the BLOC-1 complex, and describe a neuronal pathway modulating copper metabolism via ATP7A. Mutations in ATP7A result in Menkes disease, a disorder of copper metabolism. Dysbindin/BLOC-1 and ATP7A genetically and biochemically interact. Furthermore, disruption of this pathway causes alteration in the transcriptional profile of copper-regulatory and dependent factors in the hippocampus of dysbindin/BLOC-1-null mice. Dysbindin/BLOC-1 loss-of-function alleles do not affect cell and tissue copper content, yet they alter the susceptibility to toxic copper challenges in both mammalian cells and Drosophila. Our results demonstrate that perturbations downstream of the schizophrenia susceptibility gene DTNBP1 confer susceptibility to copper, a metal that in excess is a neurotoxin and whose depletion constitutes a micronutrient deficiency.
Collapse
Affiliation(s)
- Avanti Gokhale
- Department of Cell Biology, Emory University, Atlanta, GA 30322, USA
| | | | | | - Heather S Comstra
- Department of Cell Biology, Emory University, Atlanta, GA 30322, USA
| | | | - Erica Werner
- Department of Biochemistry, Emory University, Atlanta, GA 30322, USA
| | - Daniel F Manvich
- Department of Human Genetics, Emory University, Atlanta, GA 30322, USA
| | - P Michael Iuvone
- Department of Ophthalmology, Emory University, Atlanta, GA 30322, USA
| | - David Weinshenker
- Department of Human Genetics, Emory University, Atlanta, GA 30322, USA
| | - Victor Faundez
- Department of Cell Biology, Emory University, Atlanta, GA 30322, USA, Center for Social Translational Neuroscience, Emory University, Atlanta, GA 30322, USA,
| |
Collapse
|
|
49
|
Martinez-Balibrea E, Martínez-Cardús A, Ginés A, Ruiz de Porras V, Moutinho C, Layos L, Manzano JL, Bugés C, Bystrup S, Esteller M, Abad A. Tumor-Related Molecular Mechanisms of Oxaliplatin Resistance. Mol Cancer Ther 2015; 14:1767-76. [PMID: 26184483 DOI: 10.1158/1535-7163.mct-14-0636] [Citation(s) in RCA: 219] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2014] [Accepted: 05/16/2015] [Indexed: 01/04/2023]
Abstract
Oxaliplatin was the first platinum drug with proven activity against colorectal tumors, becoming a standard in the management of this malignancy. It is also considered for the treatment of pancreatic and gastric cancers. However, a major reason for treatment failure still is the existence of tumor intrinsic or acquired resistance. Consequently, it is important to understand the molecular mechanisms underlying the appearance of this phenomenon to find ways of circumventing it and to improve and optimize treatments. This review will be focused on recent discoveries about oxaliplatin tumor-related resistance mechanisms, including alterations in transport, detoxification, DNA damage response and repair, cell death (apoptotic and nonapoptotic), and epigenetic mechanisms.
Collapse
Affiliation(s)
- Eva Martinez-Balibrea
- Medical Oncology Service, Catalan Institute of Oncology (ICO), Hospital Germans Trias i Pujol, Badalona, Barcelona, Catalonia, Spain. Health Sciences Research Institute of the Germans Trias i Pujol Foundation (IGTP). Badalona, Catalonia, Spain.
| | - Anna Martínez-Cardús
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain
| | - Alba Ginés
- Health Sciences Research Institute of the Germans Trias i Pujol Foundation (IGTP). Badalona, Catalonia, Spain
| | - Vicenç Ruiz de Porras
- Health Sciences Research Institute of the Germans Trias i Pujol Foundation (IGTP). Badalona, Catalonia, Spain
| | - Catia Moutinho
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain
| | - Laura Layos
- Medical Oncology Service, Catalan Institute of Oncology (ICO), Hospital Germans Trias i Pujol, Badalona, Barcelona, Catalonia, Spain
| | - José Luis Manzano
- Medical Oncology Service, Catalan Institute of Oncology (ICO), Hospital Germans Trias i Pujol, Badalona, Barcelona, Catalonia, Spain
| | - Cristina Bugés
- Medical Oncology Service, Catalan Institute of Oncology (ICO), Hospital Germans Trias i Pujol, Badalona, Barcelona, Catalonia, Spain. Health Sciences Research Institute of the Germans Trias i Pujol Foundation (IGTP). Badalona, Catalonia, Spain. Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain. Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain. Oncology Unit, Hospital CIMA Sanitas, Barcelona, Catalonia, Spain
| | - Sara Bystrup
- Health Sciences Research Institute of the Germans Trias i Pujol Foundation (IGTP). Badalona, Catalonia, Spain
| | - Manel Esteller
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain. Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain
| | - Albert Abad
- Medical Oncology Service, Catalan Institute of Oncology (ICO), Hospital Germans Trias i Pujol, Badalona, Barcelona, Catalonia, Spain. Health Sciences Research Institute of the Germans Trias i Pujol Foundation (IGTP). Badalona, Catalonia, Spain. Oncology Unit, Hospital CIMA Sanitas, Barcelona, Catalonia, Spain
| |
Collapse
|
|
50
|
Trudu F, Amato F, Vaňhara P, Pivetta T, Peña-Méndez E, Havel J. Coordination compounds in cancer: Past, present and perspectives. J Appl Biomed 2015. [DOI: 10.1016/j.jab.2015.03.003] [Citation(s) in RCA: 95] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
|