title: Mechanistic basis of a combination D-penicillamine and platinum drugs synergistically inhibits tumor growth in oxaliplatin-resistant human cervical cancer cells in vitro and in vivo.
abstract: The platinum-based regimen is the front-line treatment of chemotherapy. However, development of platinum resistance often causes therapeutic failure in this disease. We previously have generated an oxaliplatin-resistant subline, named S3, from human cervical carcinoma SiHa cells, and its resistant phenotype was well-characterized. In the present study, we aimed to identify the novel therapeutic strategy by combining copper chelator D-penicillamine with oxaliplatin, and to elucidate the underlying mechanisms for overcoming oxaliplatin resistance. As the result, D-penicillamine exerted synergistic killing effects only in S3 cells when combined with oxaliplatin and cisplatin by using Chou-Talalay method. Further study showed that the amounts of platinum DNA adduct formed were positively correlated to the percentage of cell death in S3 cells when co-treated D-penicillamine with oxaliplatin and cisplatin. D-penicillamine promoted copper influx transporter hCtr1 expression through upregulation of Sp1. Sp1 overexpression induced p53 translocation from nucleus to cytosol and caused p53 degradation through ubiquitination, which subsequently suppressed the expression of the copper efflux transporter ATP7A. Importantly, co-treatment of cisplatin with D-penicillamine enhanced oxaliplatin-elicited antitumor effect in the oxalipatin-resistant S3 xenograft tumors, but not found in SiHa xenograft model. Notably, Mice received D-penicillamine alone or in combination of D-penicillamine ad oxalipatin, increased hCtrl protein level in S3 xenograft tumor, however, the protein level of ATP7A was decreased. Taken together, this study provides insight into that the co-manipulation of hCtrl and ATP7A by D-penicillamine could increase the therapeutic efficacy of platinum drugs in oxaliplatin resistant tumors, especially in resistant phenotype with downexpression of hCtrl and overexpression of ATP7A.
authors: Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC; National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan, ROC.
authors: Szu-Jung
authors: SJ
authors: Chen
authors: Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan 350, Taiwan, ROC.
authors: Ching-Chuan
authors: CC
authors: Kuo
authors: National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan, ROC.
authors: Hsin-Yi
authors: HY
authors: Pan
authors: Division of Environmental Health and Occupational Medicine National Health Research Institutes, Zhunan 350, Taiwan, ROC.
authors: Tsui-Chun
authors: TC
authors: Tsou
authors: Division of Environmental Health and Occupational Medicine National Health Research Institutes, Zhunan 350, Taiwan, ROC.
authors: Szu-Ching
authors: SC
authors: Yeh
authors: Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC; National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan, ROC; Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC. Electronic address: jychang@nhri.org.tw.
authors: Jang-Yang
authors: JY
authors: Chang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002614:Chelating Agents / Q000008:administration & dosage; D002945:Cisplatin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009944:Organoplatinum Compounds / Q000008:administration & dosage*; D000077150:Oxaliplatin; D010396:Penicillamine / Q000008:administration & dosage*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D002614:Chelating Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010396:Penicillamine; D002945:Cisplatin
keywords: Copper transporter ATP7A; Oxaliplatin resistance; Specificity protein 1 Sp1; d-penicillamine; p53