|
1
|
Soeda I, Shibata M, Inaishi T, Ichikawa T, Sugino K, Kanaya E, Kanda M, Hayashi M, Masuda N. ATPase copper transporting beta attenuates malignant features with high expression as an indicator of favorable prognosis in breast cancer. Breast Cancer 2025; 32:803-815. [PMID: 40316883 DOI: 10.1007/s12282-025-01705-7] [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: 02/24/2025] [Accepted: 04/14/2025] [Indexed: 05/04/2025]
Abstract
BACKGROUND ATPase copper transporting beta (ATP7B) functions as a copper-transporting ATPase that ejects copper from cells. Although high expression of ATP7B has been reported to increase cisplatin resistance, its role in breast cancer (BC) remains unclear. This study aimed to elucidate the function of ATP7B in BC cells and its significance in patients with BC. METHODS The mRNA and protein expression levels of ATP7B were evaluated in BC and non-cancerous mammary cell lines. Polymerase chain reaction (PCR) array analysis was conducted to determine the correlation between ATP7B and 84 cancer-related genes. ATP7B knockdown was performed using small interfering RNA, and cell proliferation, invasiveness, and migration were analyzed. The associations between the mRNA and protein expression of ATP7B and clinicopathological factors were also investigated in 156 patients with BC. RESULTS ATP7B was found to be highly expressed in estrogen receptor-positive and human epidermal growth factor receptor 2-positive BC cell lines. PCR array analysis revealed a significant correlation between the expression level of ATP7B and those of cadherin 1, estrogen receptor 1, and MET proto-oncogene. ATP7B knockdown significantly increased the proliferation, invasiveness, and migration of MDA-MB-361 and MDA-MB-415 cells. Patients with high ATP7B expression at the mRNA and protein levels experienced favorable prognoses. In addition, ATP7B expression level was identified as an independent prognostic factor in multivariate analysis. CONCLUSIONS ATP7B is involved in promoting anti-cancer activities of tumor suppressors in BC cells across different subtypes and is considered a prognostic marker for BC.
Collapse
Affiliation(s)
- Ikumi Soeda
- Department of Breast and Endocrine Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Masahiro Shibata
- Department of Breast and Endocrine Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
- Department of Surgery, Nagoya Ekisaikai Hospital, 4-66, Shonen-cho, Nakagawa-ku, Nagoya, 454-8502, Japan.
| | - Takahiro Inaishi
- Department of Breast and Endocrine Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
- Department of Surgery, Komaki City Hospital, 1-20, Joubushi, Komaki, Aichi, 485-8520, Japan
| | - Takahiro Ichikawa
- Department of Breast and Endocrine Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Kayoko Sugino
- Department of Breast and Endocrine Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Emi Kanaya
- Department of Surgery and Science, Faculty of Medicine, Academic Assembly, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama, 930-0194, Japan
| | - Mitsuro Kanda
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Masamichi Hayashi
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Norikazu Masuda
- Department of Breast and Endocrine Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| |
Collapse
|
|
2
|
Roy J, Mouawad R, Kyani A, Hanafi M, Xu Y, Wen B, Sun D, Neamati N. Copper-KRAS-COX2 Axis: A Therapeutic Vulnerability in Pancreatic Cancer. J Med Chem 2025; 68:8400-8428. [PMID: 40135521 DOI: 10.1021/acs.jmedchem.4c03159] [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: 03/27/2025]
Abstract
KRAS mutations are a hallmark of pancreatic ductal adenocarcinoma (PDAC), occurring in over 90% of tumors. Tumors with these mutations are highly dependent on copper, making the targeting of copper homeostasis an attractive strategy for treating PDAC due to the higher copper requirement of cancer cells compared to normal cells. Herein, we present the discovery, lead optimization, and structure-activity relationship study of a series of novel quinolyl pyrazinamides for the treatment PDAC. These compounds induce cell death through copper-mediated apoptosis and necroptosis. Our optimized compounds, 39 and 52, are potent, water-soluble and metabolically stable. Compound 52 exhibits 55% oral bioavailability and demonstrates significant in vivo efficacy without obvious toxicity in syngeneic models of PDAC. Additionally, compound 52 showed significant synergy with celecoxib, a selective COX2 inhibitor, both in vitro and in vivo. Our data suggest that compound 52 is a promising candidate for further development in KRAS-mutated cancers.
Collapse
Affiliation(s)
- Joyeeta Roy
- Department of Medicinal Chemistry, College of Pharmacy, Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States
| | - Rima Mouawad
- Department of Medicinal Chemistry, College of Pharmacy, Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States
| | - Armita Kyani
- Department of Medicinal Chemistry, College of Pharmacy, Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States
| | - Maha Hanafi
- Department of Medicinal Chemistry, College of Pharmacy, Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
| | - Yibin Xu
- Department of Medicinal Chemistry, College of Pharmacy, Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States
| | - Bo Wen
- Department of Pharmaceutical Sciences, College of Pharmacy, Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States
| | - Duxin Sun
- Department of Pharmaceutical Sciences, College of Pharmacy, Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States
| | - Nouri Neamati
- Department of Medicinal Chemistry, College of Pharmacy, Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States
| |
Collapse
|
|
3
|
Kováčová M, Hlaváč V, Koževnikovová R, Rauš K, Gatěk J, Souček P. Artificial Intelligence-Driven Prediction Revealed CFTR Associated with Therapy Outcome of Breast Cancer: A Feasibility Study. Oncology 2024; 102:1029-1040. [PMID: 39025053 PMCID: PMC11614307 DOI: 10.1159/000540395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 07/09/2024] [Indexed: 07/20/2024]
Abstract
INTRODUCTION In silico tools capable of predicting the functional consequences of genomic differences between individuals, many of which are AI-driven, have been the most effective over the past two decades for non-synonymous single nucleotide variants (nsSNVs). When appropriately selected for the purpose of the study, a high predictive performance can be expected. In this feasibility study, we investigate the distribution of nsSNVs with an allele frequency below 5%. To classify the putative functional consequence, a tier-based filtration led by AI-driven predictors and scoring system was implemented to the overall decision-making process, resulting in a list of prioritised genes. METHODS The study has been conducted on breast cancer patients of homogeneous ethnicity. Germline rare variants have been sequenced in genes that influence pharmacokinetic parameters of anticancer drugs or molecular signalling pathways in cancer. After AI-driven functional pathogenicity classification and data mining in pharmacogenomic (PGx) databases, variants were collapsed to the gene level and ranked according to their putative deleterious role. RESULTS In breast cancer patients, seven of the twelve genes prioritised based on the predictions were found to be associated with response to oncotherapy, histological grade, and tumour subtype. Most importantly, we showed that the group of patients with at least one rare nsSNVs in cystic fibrosis transmembrane conductance regulator (CFTR) had significantly reduced disease-free (log rank, p = 0.002) and overall survival (log rank, p = 0.006). CONCLUSION AI-driven in silico analysis with PGx data mining provided an effective approach navigating for functional consequences across germline genetic background, which can be easily integrated into the overall decision-making process for future studies. The study revealed a statistically significant association with numerous clinicopathological parameters, including treatment response. Our study indicates that CFTR may be involved in the processes influencing the effectiveness of oncotherapy or in the malignant progression of the disease itself.
Collapse
Affiliation(s)
- Mária Kováčová
- Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Viktor Hlaváč
- Laboratory of Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
- Toxicogenomics Unit, National Institute of Public Health, Prague, Czech Republic
| | | | - Karel Rauš
- Institute for the Care for Mother and Child, Prague, Czech Republic
| | - Jiří Gatěk
- Department of Surgery, EUC Hospital and University of Tomas Bata in Zlin, Zlin, Czech Republic
| | - Pavel Souček
- Laboratory of Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
- Toxicogenomics Unit, National Institute of Public Health, Prague, Czech Republic
| |
Collapse
|
|
4
|
Shin VY, Liu MX, Siu JMT, Kwong A, Chu KM. Inhibition of EP2 receptor suppresses tumor growth and chemoresistance of gastric cancer. Am J Cancer Res 2022; 12:4680-4692. [PMID: 36381319 PMCID: PMC9641405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 07/20/2022] [Indexed: 06/16/2023] Open
Abstract
Gastric cancer is one of the leading causes of cancer death in the world. Early diagnosis and effective chemotherapy are vital to reduce the overall mortality. Prostaglandin E2 (PGE2) has been implicated as an important factor in gastric cancer carcinogenesis. ECF based regimen (epirubicin, cisplatin, 5-fluorouracil) is the first-line chemotherapy for advanced gastric cancer. However, patients develop resistance after chemotherapy. The aim of this study is sought to investigate the role of EP2 receptor, a PGE2 receptor, and the antagonism of EP2 receptor in response to ECF treatment. Expression of EP2 receptor was evaluated in gastric cancer tissue samples and cell lines. Cell proliferation and cell apoptosis assays were performed in vitro and in vivo, upon knockdown of EP2 receptor, antagonist of EP2 receptor and/or ECF treatment. Western Blot was applied for evaluation of proteins relating to cell cycle, apoptosis and drug transporter. Next generation sequencing and ingenuity pathway analysis were applied for screening for downstream targets of EP2 receptor. Expressions of the targets of EP2 receptor were further evaluated in gastric cancer cells and tissues. In this study, we found that expression of EP2 receptor was significantly upregulated in gastric cancer. Inhibition of EP2 receptor reduced gastric cancer cell proliferation, induced cell cycle arrest proteins, and enhanced cell apoptosis. Moreover, knockdown of EP2 receptor by siRNA or antagonist sensitized gastric cancer cells to ECF. Silence of EP2 receptor also significantly abrogated gastric cancer growth in a mice model. Analysis revealed that CAV1 was a downstream target of EP2 receptor in gastric cancer. Our findings illustrated that blocking EP2 receptor reduced tumor growth and induced apoptosis in gastric cancer. This novel study unraveled CAV1 was a downstream target of EP2 receptor. Antagonizing EP2 receptor could be a potential therapeutic target in gastric cancer, in particular those with high EP2 receptor expression.
Collapse
|
|
5
|
Lelièvre P, Sancey L, Coll JL, Deniaud A, Busser B. The Multifaceted Roles of Copper in Cancer: A Trace Metal Element with Dysregulated Metabolism, but Also a Target or a Bullet for Therapy. Cancers (Basel) 2020; 12:E3594. [PMID: 33271772 PMCID: PMC7760327 DOI: 10.3390/cancers12123594] [Citation(s) in RCA: 165] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 11/24/2020] [Accepted: 11/27/2020] [Indexed: 12/12/2022] Open
Abstract
In the human body, copper (Cu) is a major and essential player in a large number of cellular mechanisms and signaling pathways. The involvement of Cu in oxidation-reduction reactions requires close regulation of copper metabolism in order to avoid toxic effects. In many types of cancer, variations in copper protein levels have been demonstrated. These variations result in increased concentrations of intratumoral Cu and alterations in the systemic distribution of copper. Such alterations in Cu homeostasis may promote tumor growth or invasiveness or may even confer resistance to treatments. Once characterized, the dysregulated Cu metabolism is pinpointing several promising biomarkers for clinical use with prognostic or predictive capabilities. The altered Cu metabolism in cancer cells and the different responses of tumor cells to Cu are strongly supporting the development of treatments to disrupt, deplete, or increase Cu levels in tumors. The metallic nature of Cu as a chemical element is key for the development of anticancer agents via the synthesis of nanoparticles or copper-based complexes with antineoplastic properties for therapy. Finally, some of these new therapeutic strategies such as chelators or ionophores have shown promising results in a preclinical setting, and others are already in the clinic.
Collapse
Affiliation(s)
- Pierre Lelièvre
- Institute for Advanced Biosciences, UGA INSERM U1209 CNRS UMR5309, 38700 La Tronche, France; (P.L.); (L.S.); (J.-L.C.)
| | - Lucie Sancey
- Institute for Advanced Biosciences, UGA INSERM U1209 CNRS UMR5309, 38700 La Tronche, France; (P.L.); (L.S.); (J.-L.C.)
| | - Jean-Luc Coll
- Institute for Advanced Biosciences, UGA INSERM U1209 CNRS UMR5309, 38700 La Tronche, France; (P.L.); (L.S.); (J.-L.C.)
| | - Aurélien Deniaud
- Univ. Grenoble Alpes, CNRS, CEA, IRIG, Laboratoire de Chimie et Biologie des Métaux, 38000 Grenoble, France
| | - Benoit Busser
- Institute for Advanced Biosciences, UGA INSERM U1209 CNRS UMR5309, 38700 La Tronche, France; (P.L.); (L.S.); (J.-L.C.)
- Department of Clinical Biochemistry, Grenoble Alpes University Hospital, 38043 Grenoble, France
| |
Collapse
|
|
6
|
Lukanović D, Herzog M, Kobal B, Černe K. The contribution of copper efflux transporters ATP7A and ATP7B to chemoresistance and personalized medicine in ovarian cancer. Biomed Pharmacother 2020; 129:110401. [DOI: 10.1016/j.biopha.2020.110401] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 05/23/2020] [Accepted: 06/13/2020] [Indexed: 02/08/2023] Open
|
|
7
|
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
|
|
8
|
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
|
|
9
|
Abstract
RATIONALE Wilson disease (WD) is an autosomal recessive hereditary disease in which the patient usually has a reduced risk of developing cancer. In particular, with the exception of hepatocellular carcinoma and cholangiocarcinoma, the incidence of cancer is significantly lower in WD patients compared with the general population. This case study presents a rare case of WD complicated with primary breast cancer. PATIENT CONCERNS A 40-year-old woman who was diagnosed with WD at 25 years of age found a lump in her left breast. She has a family history of cancer. DIAGNOSES Ultrasound and mammography results were highly suggestive of a malignant lesion. After core needle biopsy, it was confirmed that she had invasive breast cancer. INTERVENTIONS A modified radical mastectomy was performed for the left breast. As the tumor was defined as a stage IIa triple negative breast cancer, the patient would have been recommended epirubicin/cyclophosphamide + docetaxel for 8 cycles if WD was not a comorbidity. As the patient had cirrhosis and abnormal liver function, she was given paclitaxel weekly for 6 cycles instead. OUTCOMES The patient showed good tolerance, and has not had a recurrence in 2 years. LESSONS We reviewed the literature for studies of patients with WD complicated with cancers, and to our knowledge, this is the first report on WD complicated with breast cancer. The patient received chemotherapy even with liver dysfunction, which suggests that patients with WD can be safely treated with paclitaxel chemotherapy under close surveillance.
Collapse
Affiliation(s)
- Dong Li
- Department of Breast Surgery, Shanxi Academy of Medical Scienses Shanxi Dayi Hospital
| | - Jun Wang
- Department of Anesthesia, Armed Police Corps Hospital in Shanxi Province, Xiaodian District, Taiyuan, Shanxi Province, P. R. China
| | - Jinnan Gao
- Department of Breast Surgery, Shanxi Academy of Medical Scienses Shanxi Dayi Hospital
| |
Collapse
|
|
10
|
Karginova O, Weekley CM, Raoul A, Alsayed A, Wu T, Lee SSY, He C, Olopade OI. Inhibition of Copper Transport Induces Apoptosis in Triple-Negative Breast Cancer Cells and Suppresses Tumor Angiogenesis. Mol Cancer Ther 2019; 18:873-885. [PMID: 30824611 DOI: 10.1158/1535-7163.mct-18-0667] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 12/18/2018] [Accepted: 02/22/2019] [Indexed: 11/16/2022]
Abstract
Treatment of advanced breast cancer remains challenging. Copper and some of the copper-dependent proteins are emerging therapeutic targets because they are essential for cell proliferation and survival, and have been shown to stimulate angiogenesis and metastasis. Here, we show that DCAC50, a recently developed small-molecule inhibitor of the intracellular copper chaperones, ATOX1 and CCS, reduces cell proliferation and elevates oxidative stress, triggering apoptosis in a panel of triple-negative breast cancer (TNBC) cells. Inhibition of ATOX1 activity with DCAC50 disrupts copper homeostasis, leading to increased copper levels, altered spatial copper redistribution, and accumulation of ATP7B to the cellular perinuclear region. The extent and impact of this disruption to copper homeostasis vary across cell lines and correlate with cellular baseline copper and glutathione levels. Ultimately, treatment with DCAC50 attenuates tumor growth and suppresses angiogenesis in a xenograft mouse model, and prevents endothelial cell network formation in vitro Co-treatment with paclitaxel and DCAC50 enhances cytotoxicity in TNBC and results in favorable dose reduction of both drugs. These data demonstrate that inhibition of intracellular copper transport targets tumor cells and the tumor microenvironment, and is a promising approach to treat breast cancer.
Collapse
Affiliation(s)
- Olga Karginova
- Department of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, Illinois
| | - Claire M Weekley
- Department of Chemistry, Institute for Biophysical Dynamics and Howard Hughes Medical Institute, The University of Chicago, Chicago, Illinois.,Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics and Howard Hughes Medical Institute, The University of Chicago, Chicago, Illinois
| | - Akila Raoul
- Department of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, Illinois
| | - Alhareth Alsayed
- Department of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, Illinois
| | - Tong Wu
- Department of Chemistry, Institute for Biophysical Dynamics and Howard Hughes Medical Institute, The University of Chicago, Chicago, Illinois.,Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics and Howard Hughes Medical Institute, The University of Chicago, Chicago, Illinois
| | - Steve Seung-Young Lee
- Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, Illinois
| | - Chuan He
- Department of Chemistry, Institute for Biophysical Dynamics and Howard Hughes Medical Institute, The University of Chicago, Chicago, Illinois.,Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics and Howard Hughes Medical Institute, The University of Chicago, Chicago, Illinois
| | - Olufunmilayo I Olopade
- Department of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, Illinois. .,Center for Clinical Cancer Genetics, The University of Chicago, Chicago, Illinois
| |
Collapse
|
|
11
|
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
|
|
12
|
Moinuddin FM, Hirano H, Shinsato Y, Higa N, Arita K, Furukawa T. ATP7B expression in human glioblastoma is related to temozolomide resistance. Oncol Lett 2017; 14:7777-7782. [PMID: 29250175 PMCID: PMC5727628 DOI: 10.3892/ol.2017.7249] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Accepted: 09/22/2017] [Indexed: 01/23/2023] Open
Abstract
Glioblastoma multiforme (GBM) is one of the most aggressive types of brain malignancy, with resistance to chemotherapy being a primary treatment obstacle. ATPase copper transporting β (ATP7B) is involved in multidrug resistance; however, its expression in GBM remains to be evaluated. In the present study, GBM specimens from 79 patients who underwent gross total tumor removal followed by concomitant temozolomide (TMZ) chemotherapy and radiotherapy were assessed immunohistochemically. The association between the overall survival times of patients and the expression of ATP7B in neoplastic cells was evaluated. In 12/79 tumors (15.2%) >10% of neoplastic cells were immunohistochemically-positive for ATP7B, and categorized as high-ATP7B GBM. In the remaining 67 tumors (84.8%) the rate of ATP7B-positive cells was <10% and recorded as low-ATP7B GBM. The median overall survival times of patients with high- and low-ATP7B GBM were 14.6, and 24.7 months, respectively. High expression of ATP7B was identified to be associated with shorter overall survival times (hazard ratio, 0.452; 95% confidence interval, 0.206–0.994; P=0.048). Of the 79 patients, 12 underwent a second operation due to recurrence. These tissue samples were also subjected to immunohistochemical study. The ATP7B positivity rate of tumor cells obtained during the second surgery was significantly higher compared with that in the first surgery (9.17±2.56 vs. 2.75±0.55%; P=0.008). In addition, two ATP7B-transfected GBM cell lines were identified to be significantly resistant (3.8- and 1.7-fold, respectively) to TMZ compared with the control cell line. The findings of the present study suggest that ATP7B influences GBM resistance to TMZ.
Collapse
Affiliation(s)
- F M Moinuddin
- Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan.,Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Hirofumi Hirano
- Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Yoshinari Shinsato
- Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan.,Center for The Research of Advanced Diagnosis and Therapy of Cancer, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Nayuta Higa
- Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan.,Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Kazunori Arita
- Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Tatsuhiko Furukawa
- Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan.,Center for The Research of Advanced Diagnosis and Therapy of Cancer, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| |
Collapse
|
|
13
|
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
|
|
14
|
Blockhuys S, Wittung-Stafshede P. Roles of Copper-Binding Proteins in Breast Cancer. Int J Mol Sci 2017; 18:ijms18040871. [PMID: 28425924 PMCID: PMC5412452 DOI: 10.3390/ijms18040871] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Revised: 04/11/2017] [Accepted: 04/18/2017] [Indexed: 12/17/2022] Open
Abstract
Copper ions are needed in several steps of cancer progression. However, the underlying mechanisms, and involved copper-binding proteins, are mainly elusive. Since most copper ions in the body (in and outside cells) are protein-bound, it is important to investigate what copper-binding proteins participate and, for these, how they are loaded with copper by copper transport proteins. Mechanistic information for how some copper-binding proteins, such as extracellular lysyl oxidase (LOX), play roles in cancer have been elucidated but there is still much to learn from a biophysical molecular viewpoint. Here we provide a summary of copper-binding proteins and discuss ones reported to have roles in cancer. We specifically focus on how copper-binding proteins such as mediator of cell motility 1 (MEMO1), LOX, LOX-like proteins, and secreted protein acidic and rich in cysteine (SPARC) modulate breast cancer from molecular and clinical aspects. Because of the importance of copper for invasion/migration processes, which are key components of cancer metastasis, further insights into the actions of copper-binding proteins may provide new targets to combat cancer.
Collapse
Affiliation(s)
- Stéphanie Blockhuys
- Department Biology and Biological Engineering, Chalmers University of Technology, 412 96 Gothenburg, Sweden.
| | - Pernilla Wittung-Stafshede
- Department Biology and Biological Engineering, Chalmers University of Technology, 412 96 Gothenburg, Sweden.
| |
Collapse
|
|
15
|
Polishchuk EV, Polishchuk RS. The emerging role of lysosomes in copper homeostasis. Metallomics 2016; 8:853-62. [PMID: 27339113 DOI: 10.1039/c6mt00058d] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The lysosomal system operates as a focal point where a number of important physiological processes such as endocytosis, autophagy and nutrient sensing converge. One of the key functions of lysosomes consists of regulating the metabolism/homeostasis of metals. Metal-containing components are carried to the lysosome through incoming membrane flows, while numerous transporters allow metal ions to move across the lysosome membrane. These properties enable lysosomes to direct metal fluxes to the sites where metal ions are either used by cellular components or sequestered. Copper belongs to a group of metals that are essential for the activity of vitally important enzymes, although it is toxic when in excess. Thus, copper uptake, supply and intracellular compartmentalization have to be tightly regulated. An increasing number of publications have indicated that these processes involve lysosomes. Here we review studies that reveal the expanding role of the lysosomal system as a hub for the control of Cu homeostasis and for the regulation of key Cu-dependent processes in health and disease.
Collapse
Affiliation(s)
- Elena V Polishchuk
- Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, Pozzuoli (NA), 80078, Italy.
| | | |
Collapse
|
|
16
|
Dhar Dwivedi SK, Mustafi SB, Mangala LS, Jiang D, Pradeep S, Rodriguez-Aguayo C, Ling H, Ivan C, Mukherjee P, Calin GA, Lopez-Berestein G, Sood AK, Bhattacharya R. Therapeutic evaluation of microRNA-15a and microRNA-16 in ovarian cancer. Oncotarget 2016; 7:15093-104. [PMID: 26918603 PMCID: PMC4924772 DOI: 10.18632/oncotarget.7618] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Accepted: 01/23/2016] [Indexed: 12/23/2022] Open
Abstract
Treatment of chemo-resistant ovarian cancer (OvCa) remains clinically challenging and there is a pressing need to identify novel therapeutic strategies. Here we report that multiple mechanisms that promote OvCa progression and chemo-resistance could be inhibited by ectopic expression of miR-15a and miR-16. Significant correlations between low expression of miR-16, high expression of BMI1 and shortened overall survival (OS) were noted in high grade serous (HGS) OvCa patients upon analysis of The Cancer Genome Atlas (TCGA). Targeting BMI1, in vitro with either microRNA reduced clonal growth of OvCa cells. Additionally, epithelial to mesenchymal transition (EMT) as well as expression of the cisplatin transporter ATP7B were inhibited by miR-15a and miR-16 resulting in decreased degradation of the extra-cellular matrix and enhanced sensitization of OvCa cells to cisplatin. Nanoliposomal delivery of the miR-15a and miR-16 combination, in a pre-clinical chemo-resistant orthotopic mouse model of OvCa, demonstrated striking reduction in tumor burden compared to cisplatin alone. Thus, with the advent of miR replacement therapy some of which are in Phase 2 clinical trials, miR-15a and miR-16 represent novel ammunition in the anti-OvCa arsenal.
Collapse
Affiliation(s)
- Shailendra Kumar Dhar Dwivedi
- Department of Obstetrics and Gynecology, Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, OK, USA
| | - Soumyajit Banerjee Mustafi
- Department of Obstetrics and Gynecology, Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, OK, USA
| | - Lingegowda S. Mangala
- Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Dahai Jiang
- Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sunila Pradeep
- Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Cristian Rodriguez-Aguayo
- The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hui Ling
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Cristina Ivan
- Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Priyabrata Mukherjee
- Department of Pathology, Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, OK, USA
| | - George A. Calin
- The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Gabriel Lopez-Berestein
- The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anil K. Sood
- Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Resham Bhattacharya
- Department of Obstetrics and Gynecology, Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, OK, USA
- Department of Cell Biology, University of Oklahoma College of Medicine, Oklahoma City, OK, USA
| |
Collapse
|
|
17
|
Amable L. Cisplatin resistance and opportunities for precision medicine. Pharmacol Res 2016; 106:27-36. [PMID: 26804248 DOI: 10.1016/j.phrs.2016.01.001] [Citation(s) in RCA: 420] [Impact Index Per Article: 46.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2015] [Accepted: 01/01/2016] [Indexed: 01/11/2023]
Abstract
Cisplatin is one of the most commonly used chemotherapy drugs, treating a wide range of cancer types. Unfortunately, many cancers initially respond to platinum treatment but when the tumor returns, drug resistance frequently occurs. Resistance to cisplatin is attributed to three molecular mechanisms: increased DNA repair, altered cellular accumulation, and increased drug inactivation. The use of precision medicine to make informed decisions on a patient's cisplatin resistance status and predicting the tumor response would allow the clinician to tailor the chemotherapy program based on the biology of the disease. In this review, key biomarkers of each molecular mechanism will be discussed along with the current clinical research. Additionally, known polymorphisms for each biomarker will be discussed in relation to their influence on cisplatin resistance.
Collapse
Affiliation(s)
- Lauren Amable
- National Institute on Minority Health and Health Disparities, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, United States.
| |
Collapse
|
|
18
|
ZHENG RUIRUI, HU WEI, SUI CHENGGUANG, MA NAN, JIANG YOUHONG. Effects of doxorubicin and gemcitabine on the induction of apoptosis in breast cancer cells. Oncol Rep 2014; 32:2719-25. [DOI: 10.3892/or.2014.3513] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2014] [Accepted: 09/03/2014] [Indexed: 11/05/2022] Open
|
|
19
|
Sprowl JA, Ness RA, Sparreboom A. Polymorphic Transporters and Platinum Pharmacodynamics. Drug Metab Pharmacokinet 2013; 28:19-27. [DOI: 10.2133/dmpk.dmpk-12-rv-073] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
|
|
20
|
Katagiri H, Nakayama K, Rahman MT, Rahman M, Katagiri A, Ishibashi T, Ishikawa M, Iida K, Nakayama S, Otsuki Y, Miyazaki K. Is ATP7B a predictive marker in patients with ovarian carcinoma treated with platinum-taxane combination chemotherapy? Int J Gynecol Cancer 2013; 23:60-4. [PMID: 23221602 DOI: 10.1097/igc.0b013e318275afef] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE This study examined the prognostic significance of copper-transporting P-type adenosine triphosphatase (ATP7B) expression in patients with ovarian carcinoma treated with platinum-taxane combination chemotherapy. METHODS Expression of ATP7B in ovarian carcinoma was assessed by immunohistochemistry and clinical data collected by retrospective review of medical charts. RESULTS Overexpression of ATP7B was identified in 25 (29.1%) of 86 ovarian carcinomas. The frequency of ATP7B expression in clear cell carcinomas was significantly higher than that in serous high-grade carcinomas (P < 0.05). We observed no statistically significant correlations between high ATP7B protein expression and either disease-free survival (P = 0.722) or overall survival (P = 0.389). CONCLUSIONS Our study is the first to demonstrate a lack of statistically significant differences between ATP7B positive and negative cases with respect to prognosis of patients with ovarian carcinoma treated with a platinum-taxane combination regimen. However, that ATP7B expression in clear cell carcinomas was significantly higher than that in serous carcinomas may partially explain the difference in chemotherapeutic response and prognosis between patients with these 2 types of carcinomas.
Collapse
Affiliation(s)
- Hiroshi Katagiri
- Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Japan
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
21
|
Mo W, Zhang JT. Human ABCG2: structure, function, and its role in multidrug resistance. INTERNATIONAL JOURNAL OF BIOCHEMISTRY AND MOLECULAR BIOLOGY 2011; 3:1-27. [PMID: 22509477 PMCID: PMC3325772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Received: 03/16/2012] [Accepted: 03/25/2011] [Indexed: 05/31/2023]
Abstract
Human ABCG2 is a member of the ATP-binding cassette (ABC) transporter superfamily and is known to contribute to multidrug resistance (MDR) in cancer chemotherapy. Among ABC transporters that are known to cause MDR, ABCG2 is particularly interesting for its potential role in protecting cancer stem cells and its complex oligomeric structure. Recent studies have also revealed that the biogenesis of ABCG2 could be modulated by small molecule compounds. These modulators, upon binding to ABCG2, accelerate the endocytosis and trafficking to lysosome for degradation and effectively reduce the half-life of ABCG2. Hence, targeting ABCG2 stability could be a new venue for therapeutic discovery to sensitize drug resistant human cancers. In this report, we review recent progress on understanding the structure, function, biogenesis, as well as physiological and pathophysiological functions of ABCG2.
Collapse
Affiliation(s)
- Wei Mo
- Department of Pharmacology and Toxicology and IU Simon Cancer Center, Indiana University School of Medicine Indianapolis, IN 46202, USA
| | | |
Collapse
|
|
22
|
Shahzad MMK, Lopez-Berestein G, Sood AK. Novel strategies for reversing platinum resistance. Drug Resist Updat 2009; 12:148-52. [PMID: 19805003 DOI: 10.1016/j.drup.2009.09.001] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2009] [Revised: 09/08/2009] [Accepted: 09/09/2009] [Indexed: 12/19/2022]
Abstract
Platinum-based drugs continue to be the mainstay of therapy for ovarian cancer. Along with adverse effects, chemoresistance (intrinsic or acquired) has become a major limitation in the management of recurrent disease. Even though much is known about the effects of platinum drugs on cancer cells, the mechanisms underlying resistance are poorly understood. In this review, we summarize the current data on chemoresistance and discuss novel strategies to reverse resistance to platinum-based drugs. The most important targets highlighted here include Aurora kinases, PARP, ATP7B, and ERCC1. Furthermore, we discuss the implications of these novel approaches for ovarian cancer treatment.
Collapse
Affiliation(s)
- Mian M K Shahzad
- Department of Gynecologic Oncology, U.T.M.D. Anderson Cancer Center, 1155 Herman Pressler, Unit 1362, Houston, TX 77030, USA
| | | | | |
Collapse
|
|
23
|
Mangala LS, Zuzel V, Schmandt R, Leshane ES, Halder JB, Armaiz-Pena GN, Spannuth WA, Tanaka T, Shahzad MM, Lin YG, Nick AM, Danes CG, Lee JW, Jennings NB, Vivas-Mejia PE, Wolf JK, Coleman RL, Siddik ZH, Lopez-Berestein G, Lutsenko S, Sood AK. Therapeutic Targeting of ATP7B in Ovarian Carcinoma. Clin Cancer Res 2009; 15:3770-80. [PMID: 19470734 PMCID: PMC2752981 DOI: 10.1158/1078-0432.ccr-08-2306] [Citation(s) in RCA: 112] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE Resistance to platinum chemotherapy remains a significant problem in ovarian carcinoma. Here, we examined the biological mechanisms and therapeutic potential of targeting a critical platinum resistance gene, ATP7B, using both in vitro and in vivo models. EXPERIMENTAL DESIGN Expression of ATP7A and ATP7B was examined in ovarian cancer cell lines by real-time reverse transcription-PCR and Western blot analysis. ATP7A and ATP7B gene silencing was achieved with targeted small interfering RNA (siRNA) and its effects on cell viability and DNA adduct formation were examined. For in vivo therapy experiments, siRNA was incorporated into the neutral nanoliposome 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC). RESULTS ATP7A and ATP7B genes were expressed at higher levels in platinum-resistant cells compared with sensitive cells; however, only differences in ATP7B reached statistical significance. ATP7A gene silencing had no significant effect on the sensitivity of resistant cells to cisplatin, but ATP7B silencing resulted in 2.5-fold reduction of cisplatin IC(50) levels and increased DNA adduct formation in cisplatin-resistant cells (A2780-CP20 and RMG2). Cisplatin was found to bind to the NH(2)-terminal copper-binding domain of ATP7B, which might be a contributing factor to cisplatin resistance. For in vivo therapy experiments, ATP7B siRNA was incorporated into DOPC and was highly effective in reducing tumor growth in combination with cisplatin (70-88% reduction in both models compared with controls). This reduction in tumor growth was accompanied by reduced proliferation, increased tumor cell apoptosis, and reduced angiogenesis. CONCLUSION These data provide a new understanding of cisplatin resistance in cancer cells and may have implications for therapeutic reversal of drug resistance.
Collapse
Affiliation(s)
- Lingegowda S. Mangala
- Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center
| | - Vesna Zuzel
- Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon
| | - Rosemarie Schmandt
- Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center
| | - Erik S. Leshane
- Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon
| | - Jyotsna B. Halder
- Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center
| | - Guillermo N. Armaiz-Pena
- Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center
- Program in Cancer Biology, The University of Texas Graduate School of Biomedical Sciences at Houston
| | - Whitney A. Spannuth
- Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center
| | - Takemi Tanaka
- Brown Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas
| | - Mian M.K. Shahzad
- Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center
- Department of Obstetrics and Gynecology, Baylor College of Medicine
| | - Yvonne G. Lin
- Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center
| | - Alpa M. Nick
- Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center
| | - Christopher G. Danes
- Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center
| | - Jeong-Won Lee
- Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Nicholas B. Jennings
- Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center
| | - Pablo E. Vivas-Mejia
- Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center
| | - Judith K. Wolf
- Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center
| | - Robert L. Coleman
- Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center
| | - Zahid H. Siddik
- Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center
| | - Gabriel Lopez-Berestein
- Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center
| | - Svetlana Lutsenko
- Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon
| | - Anil K. Sood
- Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center
- Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center
| |
Collapse
|
|
24
|
Martinez-Balibrea E, Martínez-Cardús A, Musulén E, Ginés A, Manzano JL, Aranda E, Plasencia C, Neamati N, Abad A. Increased levels of copper efflux transporter ATP7B are associated with poor outcome in colorectal cancer patients receiving oxaliplatin-based chemotherapy. Int J Cancer 2009; 124:2905-10. [PMID: 19296535 DOI: 10.1002/ijc.24273] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Recently, the copper efflux transporters ATP7B and ATP7A have been implicated in the transport of and resistance to platinum drugs in breast and ovarian cancers. Because of the extensive use of oxaliplatin in colorectal cancer (CRC), we examined the expression of both transporters in tumors from CRC patients treated with oxaliplatin/5FU and sought to determine whether their expression can predict clinical outcome in these patients. ATP7B and ATP7A levels were determined by quantitative real-time PCR in 50 primary tumors of previously untreated patients with advanced colorectal adenocarcinoma who were subsequently treated with oxaliplatin/5FU. Additionally, ATP7B protein expression was assessed by immunohistochemical staining using a tissue microarray. Patients with the lowest mRNA expression levels of ATP7B had a significantly longer time to progression (TTP) (p = 0.0009) than patients with the highest levels (12.14 months vs. 6.43 months) who also had an increased risk of progression (HR = 3.56; 95% CI, 1.6-7.9; p = 0.002). Furthermore, patients with low levels of both protein and mRNA of ATP7B derived the maximum benefit from oxaliplatin/5FU with the longest TTP as compared with patients with high levels of ATP7B protein and mRNA (14.64 months vs. 4.63 months, respectively, p = 0.01) and showed a nonsignificant trend toward a lower response rate (37.5% and 75%, respectively). In conclusion, ATP7B mRNA and protein expression in colorectal tumors is associated with clinical outcome to oxaliplatin/5FU. Prospective studies are required to evaluate the role of this marker in tailoring chemotherapy.
Collapse
Affiliation(s)
- Eva Martinez-Balibrea
- Medical Oncology Service, Hospital Universitari Germans Trias i Pujol, Institut Català d'Oncologia, Badalona, Barcelona, Spain
| | | | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Leonhardt K, Gebhardt R, Mössner J, Lutsenko S, Huster D. Functional interactions of Cu-ATPase ATP7B with cisplatin and the role of ATP7B in the resistance of cells to the drug. J Biol Chem 2009; 284:7793-802. [PMID: 19141620 DOI: 10.1074/jbc.m805145200] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Cisplatin is a widely used chemotherapeutic agent for treatment of ovarian, testicular, lung, and stomach cancers. The initial response to the drug is robust; however, tumor cells commonly develop resistance to cisplatin, which complicates treatment. Recently, overexpression of the Cu-ATPase ATP7B in ovary cells was linked to the increased cellular resistance to cisplatin; and the role for Cu-ATPases in the export of cisplatin from cells was proposed. Our results support functional interactions between cisplatin and ATP7B but argue against the active transport through the copper translocation pathway as a mechanism of drug resistance. In hepatocytes, we observed no correlation between the levels of endogenous ATP7B and the resistance of cells to cisplatin. Unlike copper, cisplatin does not induce trafficking of ATP7B in hepatoma cells, neither does it compete with copper in a transport assay. However, cisplatin binds to ATP7B and stimulates catalytic phosphorylation with EC(50) similar to that of copper. Mutations of the first five N-terminal copper-binding sites of ATP7B do not inhibit the cisplatin-induced phosphorylation of ATP7B. In contrast, the deletion of the first four copper-binding sites abolishes the effect of cisplatin on the ATP7B activity. Thus, cisplatin binding to ATP7B and/or general changes in cellular copper homeostasis are likely contributors to the increased resistance to the drug. The link between changes in copper homeostasis and cisplatin resistance was confirmed by treating the Huh7 cells with copper chelator and increasing their resistance to cisplatin.cisplatin.
Collapse
Affiliation(s)
- Karoline Leonhardt
- Department of Medicine II and Department of Biochemistry, University of Leipzig, 04103 Leipzig, Germany
| | | | | | | | | |
Collapse
|
|
26
|
Mellor HR, Callaghan R. Resistance to chemotherapy in cancer: a complex and integrated cellular response. Pharmacology 2008; 81:275-300. [PMID: 18259091 DOI: 10.1159/000115967] [Citation(s) in RCA: 127] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2007] [Accepted: 09/10/2007] [Indexed: 12/30/2022]
Abstract
Inherent and acquired resistance pathways account for the high rate of failure in cancer chemotherapy. The mechanisms or pathways mediating resistance may be classified as pharmacokinetic (i.e. alter intratumour drug exposue) or pharmacodynamic (i.e. failure to elicit cytotoxicity). More often than not, the resistant phenotype is characterised by alterations in multiple pathways. Consequently, the pathways may act synergistically or generate a broad spectrum of resistance to anticancer drugs. There has been a great deal of systematic characterisation of drug resistance in vitro. However, translating this greater understanding into clinical efficacy has rarely been achieved. This review explores the phenomenon of drug resistance in cancer and highlights the gap between in vitro and in vivo observations. This gap presents a major obstacle in overcoming drug resistance and restoring sensitivity to chemotherapy.
Collapse
Affiliation(s)
- Howard R Mellor
- Growth Factor Group, Weatherall Institute of Molecular Medicine, Oxford, UK
| | | |
Collapse
|
|
27
|
Xu W, Cai B, Chen JL, Li LX, Zhang JR, Sun YY, Wan XP. ATP7B antisense oligodeoxynucleotides increase the cisplatin sensitivity of human ovarian cancer cell line SKOV3ipl. Int J Gynecol Cancer 2007; 18:718-22. [PMID: 17944925 DOI: 10.1111/j.1525-1438.2007.01085.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The objective of this study was to investigate the effect of ATP7B antisense oligodeoxynucleotides (ASODNs) on regulating the sensitivity to cisplatin in ovarian carcinoma cell line SKOV3ip1. The ATP7B ASODNs and the corresponding sense oligodeoxynucleotide (SODN) as control were transfected into SKOV3ip1 cells by lipofectamine-2000. The changes of ATP7B were detected by reverse transcription-polymerase chain reaction, flow cytometry, and Western blotting. The survival rate of the SKOV3ip1 cells was assessed by MTT assay. Compared with nontransfected cell, the transfer of ASODN/lipofectin (LF) into SKOV3ip1 cells resulted in (1) 73.70% and 48.30% reduction of ATP7B in messenger RNA and protein, respectively, (2) an obviously decreased intracellular fluorescence intensity from 79.42 to 50.87 (P < 0.01), and (3) a decreased IC(50) value for cisplatin from 126.63 to 80.90 micromol/L (P < 0.01), while no significant changes were detected for groups treated with SODN/LF and LF only. ASODN transfection can inhibit the expression of ATP7B and increase the cisplatin sensitivity in SKOV3ip1 cells.
Collapse
Affiliation(s)
- W Xu
- Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated First People's Hospital, Shanghai, People's Republic of China
| | | | | | | | | | | | | |
Collapse
|
|
28
|
Wu DL, Yi HX, Sui FY, Jiang XH, Jiang XM, Zhao YY. Expression of ATP7B in human gastric cardiac carcinomas in comparison with distal gastric carcinomas. World J Gastroenterol 2006; 12:7695-8. [PMID: 17171802 PMCID: PMC4088055 DOI: 10.3748/wjg.v12.i47.7695] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyze expression of ATP7B in gastric cardiac adenocarcinomas, its clinicopathologic significance, in comparison with distal gastric adenocarcinomas.
METHODS: Immunohistochemical avidin-biotin peroxidase complex method was applied to detect the expression of ATP7B in 49 cases of cardiac carcinomas, the corresponding adjacent non-neoplastic epithelium and 55 cases of distal gastric carcinomas.
RESULTS: The proportion of ATP7B positive samples in gastric cardiac carcinomas (51.0%, 25 of 49) was significantly higher than that in the corresponding adjacent non-neoplastic epithelium (22.4%, 11 of 49) (P = 0.003). ATP7B expression in poorly differentiated gastric cardiac carcinomas was significantly higher than that in well/moderately differentiated gastric cardiac carcinomas (P = 0.030). ATP7B expression in gastric cardiac carcinomas was independent of age, tumor size, nodal stage and metastasis status. ATP7B protein was detected in 30.9% (17/55 cases) of distal gastric carcinomas, markedly lower than that in gastric cardiac carcinomas (P = 0.037).
CONCLUSION: ATP7B protein is frequently overexpressed in gastric cardiac carcinomas, and correlated with the differentiation of cardiac carcinoma. ATP7B expression in gastric cardiac carcinomas is significantly higher than that in distal gastric carcinomas, which might partially explain the difference of chemotherapy response and prognosis between these two gastric carcinomas.
Collapse
Affiliation(s)
- Da-Long Wu
- Department of Pharmacology, School of Medicine, College of Jiaxing, Jiaxing 314001, Zhejiang Province, China.
| | | | | | | | | | | |
Collapse
|
|
29
|
Abstract
Cisplatin, a platinum coordinated complex, is a widely used antineoplastic agent for the treatment of metastatic tumors of the testis, metastatic ovarian tumors, lung cancer, advanced bladder cancer and many other solid tumors. The cytotoxic action of the drug is often thought to be associated with its ability to bind DNA to form cisplatin-DNA adducts. The development of resistance to cisplatin during treatment is common and constitutes a major obstacle to the cure of sensitive tumors. Although to understand the clinically relevant mechanisms of resistance, many studies have been aimed at clarifying the biochemical/molecular alterations of cisplatin-resistance cells, these studies did not conclusively identify the basis of cellular resistance to cisplatin. In this review, cisplatin resistance was discussed in terms of the relevant transporters, such as copper transporters (CTRs), organic cation transporters (OCTs) and multi-drug resistance related transporters (MDRs). These transporters seem to be contributed to cisplatin resistance through the reduction of drug accumulation in the cell. Better understanding the mechanism of cisplatin resistance associated with transporters will provide the useful informations for overcoming the cisplatin resistance.
Collapse
Affiliation(s)
- Min-Koo Choi
- Department of Pharmaceutics, College of Pharmacy, Seoul National University, Seoul 151-742, Korea
| | | |
Collapse
|
|
30
|
Safaei R, Howell SB. Copper transporters regulate the cellular pharmacology and sensitivity to Pt drugs. Crit Rev Oncol Hematol 2005; 53:13-23. [PMID: 15607932 DOI: 10.1016/j.critrevonc.2004.09.007] [Citation(s) in RCA: 191] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/23/2004] [Indexed: 11/19/2022] Open
Abstract
Recent studies have demonstrated that the major Cu influx transporter CTR1 regulates tumor cell uptake of cisplatin (DDP), carboplatin (CBDCA) and oxaliplatin (L-OHP), and that the two Cu efflux transporters ATP7A and ATP7B regulate the efflux of these drugs. Evidence for the concept that these platinum (Pt) drugs enter cells and are distributed to various subcellular compartments via transporters that have evolved to manage Cu homeostasis includes the demonstration of: (1) bidirectional cross-resistance between cells selected for resistance to either the Pt drugs or Cu; (2) parallel changes in the transport of Pt and Cu drugs in resistant cells; (3) altered cytotoxic sensitivity and Pt drug accumulation in cells transfected with Cu transporters; and (4) altered expression of Cu transporters in Pt drug-resistant tumors. Appreciation of the role of the Cu transporters in the development of resistance to DDP, CBDCA, and L-OHP offers novel insights into strategies for preventing or reversing resistance to this very important family of anticancer drugs.
Collapse
Affiliation(s)
- Roohangiz Safaei
- Department of Medicine and the Rebecca and John Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093-0058, USA.
| | | |
Collapse
|
|
31
|
Xu H, Choi SM, An CS, Min YD, Kim KC, Kim KJ, Choi CH. Concentration-dependent collateral sensitivity of cisplatin-resistant gastric cancer cell sublines. Biochem Biophys Res Commun 2005; 328:618-22. [PMID: 15694393 DOI: 10.1016/j.bbrc.2005.01.015] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2004] [Indexed: 11/20/2022]
Abstract
The cisplatin-resistant gastric cancer cell sublines, SNU-601/Cis2 and /Cis10, were 49 and >530 times more resistant to cisplatin, respectively, compared with the drug-sensitive cells, SNU-601/WT. The SNU-601/Cis2 showed cross-resistance to carboplatin, heptaplatin, doxorubicin, mitomycin C, and 5-fluorouracil compared with the SNU-601/WT whereas the SNU-601/Cis10 displayed collateral sensitivity to these drugs with the exception of cisplatin compared with the SNU-601/Cis2, suggesting that the cross-resistance and collateral sensitivity of cisplatin-resistant gastric cancer cells are dependent upon cisplatin concentrations. Altered expression of the antioxidant and transporter genes (metallothionein, catalase, superoxide dismutases, P-glycoprotein, and the breast cancer resistance protein) was involved in these phenotypes of the cisplatin-resistant gastric cancer cell lines.
Collapse
Affiliation(s)
- Haidong Xu
- Research Center for Resistant Cells, Chosun University, Gwangju 501-759, Republic of Korea
| | | | | | | | | | | | | |
Collapse
|
|
32
|
Samimi G, Safaei R, Katano K, Holzer AK, Rochdi M, Tomioka M, Goodman M, Howell SB. Increased expression of the copper efflux transporter ATP7A mediates resistance to cisplatin, carboplatin, and oxaliplatin in ovarian cancer cells. Clin Cancer Res 2005; 10:4661-9. [PMID: 15269138 DOI: 10.1158/1078-0432.ccr-04-0137] [Citation(s) in RCA: 251] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
PURPOSE The goal of this study was to determine the effect of small changes in ATP7A expression on the pharmacodynamics of cisplatin, carboplatin, and oxaliplatin in human ovarian carcinoma cells. EXPERIMENTAL DESIGN Drug sensitivity and cellular pharmacology parameters were determined in human 2008 ovarian carcinoma cells and a subline transfected with an ATP7A-expression vector ATP7A (2008/MNK). Drug sensitivity was determined by clonogenic assay, platinum (Pt) levels were measured by inductively coupled plasma mass spectroscopy, copper (Cu) accumulation was quantified with (64)Cu, and the subcellular distribution of ATP7A was assessed by confocal digital microscopy. RESULTS The 1.5-fold higher expression of ATP7A in the 2008/MNK cells was sufficient to alter Cu cellular pharmacokinetics but not confer Cu resistance. In contrast, it was sufficient to render the 2008/MNK cells resistant to cisplatin, carboplatin, and oxaliplatin. Resistance was associated with increased rather than decreased whole-cell Pt drug accumulation and increased sequestration of Pt into the vesicular fraction. Cu triggered relocalization of ATP7A away from the perinuclear region, whereas at equitoxic concentrations the Pt drugs did not. CONCLUSIONS A small increase in ATP7A expression produced resistance to all three of the clinically available Pt drugs. Whereas increased expression of ATP7A reduced Cu accumulation, it did not reduce accumulation of the Pt drugs. Under conditions where Cu triggered ATP7A relocalization, the Pt drugs did not. Thus, although ATP7A is an important determinant of sensitivity to the Pt drugs, there are substantial differences between Cu and the Pt drugs with respect to how they interact with ATP7A and the mechanism by which ATP7A protects the cell.
Collapse
Affiliation(s)
- Goli Samimi
- Department of Medicine, University of California San Diego, La Jolla, California, 92093-0058, USA
| | | | | | | | | | | | | | | |
Collapse
|
|
33
|
Safaei R, Holzer AK, Katano K, Samimi G, Howell SB. The role of copper transporters in the development of resistance to Pt drugs. J Inorg Biochem 2004; 98:1607-13. [PMID: 15458823 DOI: 10.1016/j.jinorgbio.2004.05.006] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2004] [Revised: 05/12/2004] [Accepted: 05/12/2004] [Indexed: 12/30/2022]
Abstract
Recent studies in yeast, mouse and human cells suggest that the conserved metal binding transporters of the Cu homeostasis pathway can mediate resistance to Pt drugs in cancer cells. This review summarizes the data available from these studies. The observation that cells selected for resistance to Cu or the Pt drugs display bidirectional cross-resistance, parallel defects in the transport of Cu and the Pt drugs and altered expression of Cu transporters is consistent with the concept that the Cu homeostasis proteins regulate sensitivity to the Pt drugs by influencing their uptake, efflux and intracellular distribution. This model is supported by the finding that when mammalian and yeast cells are genetically engineered to express altered levels of the Cu transporters they exhibit altered sensitivity to Pt drugs and are defective in intracellular Pt accumulation due to altered uptake and/or efflux rates. Negative associations between the expression of ATP7A and ATP7B and the outcome of Pt therapy further support the significance of the Cu homeostasis proteins as both markers of and contributors to Pt resistance.
Collapse
Affiliation(s)
- Roohangiz Safaei
- Department of Medicine and the Rebecca and John Moores Cancer Center, University of California, 9500 Gilman Drive, San Diego, La Jolla, CA 92093-0058, USA.
| | | | | | | | | |
Collapse
|
|
34
|
Samimi G, Katano K, Holzer AK, Safaei R, Howell SB. Modulation of the cellular pharmacology of cisplatin and its analogs by the copper exporters ATP7A and ATP7B. Mol Pharmacol 2004; 66:25-32. [PMID: 15213293 DOI: 10.1124/mol.66.1.25] [Citation(s) in RCA: 119] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
The copper efflux transporters ATP7A and ATP7B sequester intracellular copper into the vesicular secretory pathway for export from the cell. The influence of these transporters on the pharmacodynamics of cisplatin, carboplatin, and oxaliplatin was investigated using human Menkes' disease fibroblasts (Me32a) that do not express either transporter and sublines molecularly engineered to express either ATP7A (MeMNK) or ATP7B (MeWND). Cellular copper levels were significantly higher in the Me32a cells than in the MeMNK and MeWND sublines. These transporter-proficient sublines were resistant to the cytotoxic effect of copper, cisplatin, and carboplatin but were hypersensitive to oxaliplatin. Whole-cell accumulation of platinum after a 24-h exposure was significantly increased in the MeMNK and MeWND cells for all three platinum drugs, but this was accompanied by an increase in the amount of platinum reaching the DNA only for oxaliplatin. Vesicles isolated from MeMNK cells contained more platinum after exposure to cisplatin and carboplatin, whereas the platinum content of vesicles from MeWND cells was increased after exposure to all three drugs. Although copper triggered relocalization of ATP7A from the perinuclear region to more peripheral locations, the platinum drugs did not. These results demonstrate that both ATP7A and ATP7B modulate the pharmacodynamics of all three clinically used platinum drugs. The data are consistent with the hypothesis that these copper exporters sequester the platinum drugs into subcellular compartments, limiting their cytotoxicity, similar to their effect on copper. However, in this model system, although copper is readily exported after vesicular sequestration, the platinum drugs are not.
Collapse
Affiliation(s)
- Goli Samimi
- Department of Medicine, the Rebecca and John Moores University of California San Diego Cancer Center, Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, USA
| | | | | | | | | |
Collapse
|
|
35
|
Katano K, Safaei R, Samimi G, Holzer A, Rochdi M, Howell SB. The copper export pump ATP7B modulates the cellular pharmacology of carboplatin in ovarian carcinoma cells. Mol Pharmacol 2003; 64:466-73. [PMID: 12869652 DOI: 10.1124/mol.64.2.466] [Citation(s) in RCA: 92] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Human tumor cells lines with acquired resistance to cisplatin (DDP) and carboplatin (CBDCA) are often cross-resistant to copper and vice versa, and some DDP-resistant cells overexpress the copper export pump ATP7B. We sought to demonstrate that ATP7B directly mediates resistance to DDP and CBDCA by stably transfecting human carcinoma cells with a vector designed to express ATP7B. Increased expression of ATP7B rendered all three cell lines tested more resistant to a 1-h exposure to DDP (1.6-2.6-fold), CBDCA (1.5-1.6-fold), and copper (1.2-1.4-fold). The effect of ATP7B on the cellular pharmacology of 64Cu and [14C]CBDCA was investigated in more detail using one cell pair (2008 cells transfected with an empty vector or an ATP7B-expressing vector). In the 2008/ATP7B subline, steady-state copper levels were decreased under both basal and copper-supplemented conditions, as was steady-state CBDCA content upon exposure to 50 microM [14C]CBDCA. Over the first 5 min, the average rate of accumulation of copper and CBCDA in the 2008/ATP7B cells was reduced by 37 and 61%, respectively. Efflux was more rapid from 2008/ATP7B cells for both copper and CBDCA. Two-compartment modeling indicated that the second phase of efflux was increased by a factor of 3.9-fold for CBCDA and to an even greater extent for copper. We conclude that expression of ATP7B regulates sensitivity to CBDCA as well as to DDP and copper and that a transporter that normally mediates copper homeostasis modulates the cellular pharmacology of CBDCA.
Collapse
Affiliation(s)
- Kuniyuki Katano
- Department of Medicine, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0058, USA
| | | | | | | | | | | |
Collapse
|
|
36
|
|