Mechanistic basis for overcoming platinum resistance using copper chelating agents.
Platinum-based antitumor agents are widely used in cancer chemotherapy. Drug resistance is a major obstacle to the successful use of these agents because once drug resistance develops, other effective treatment options are limited. Recently, we conducted a clinical trial using a copper-lowering agent to overcome platinum drug resistance in ovarian cancer patients and the preliminary results are encouraging. In supporting this clinical study, using three pairs of cisplatin (cDDP)-resistant cell lines and two ovarian cancer cell lines derived from patients who had failed in platinum-based chemotherapy, we showed that cDDP resistance associated with reduced expression of the high-affinity copper transporter (hCtr1), which is also a cDDP transporter, can be preferentially resensitized by copper-lowering agents because of enhanced hCtr1 expression, as compared with their drug-sensitive counterparts. Such a preferential induction of hCtr1 expression in cDDP-resistant variants by copper chelation can be explained by the mammalian copper homeostasis regulatory mechanism. Enhanced cell-killing efficacy by a copper-lowering agent was also observed in animal xenografts bearing cDDP-resistant cells. Finally, by analyzing a public gene expression dataset, we found that ovarian cancer patients with elevated levels of hCtr1 in their tumors, but not ATP7A and ATP7B, had more favorable outcomes after platinum drug treatment than those expressing low hCtr1 levels. This study reveals the mechanistic basis for using copper chelation to overcome cDDP resistance in clinical investigations.
Department of Molecular Pathology, Unit 951, Room 2SCR4.3025, The University of Texas MD Anderson Cancer Center, 7435 Fannin Blvd, Houston, TX 77054, USA.
Zheng D
ZD
Liang
Yan
Y
Long
Wen-Bin
WB
Tsai
Siqing
S
Fu
Razelle
R
Kurzrock
Mihai
M
Gagea-Iurascu
Fan
F
Zhang
Helen H W
HH
Chen
Bryan T
BT
Hennessy
Gordon B
GB
Mills
Niramol
N
Savaraj
Macus Tien
MT
Kuo
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D003300:Copper / Q000494:pharmacology* / Q000627:therapeutic use; D000079923:Copper Transporter 1; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D010984:Platinum / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D027682:Cation Transport Proteins; D002614:Chelating Agents; D000079923:Copper Transporter 1; D012333:RNA, Messenger; C490079:SLC31A1 protein, human; D010984:Platinum; D003300:Copper; D002945:Cisplatin