Mechanistic basis for overcoming platinum resistance using copper chelating agents

Zheng D. Liang, Yan Long, Wen Bin Tsai, Siqing Fu, Razelle Kurzrock, Mihai Gagea-Iurascu, Fan Zhang, Helen H.W. Chen, Bryan T. Hennessy, Gordon B. Mills, Niramol Savaraj, Macus Tien Kuo

Research output: Contribution to journalArticle

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Abstract

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, hadmore 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.

Original languageEnglish
Pages (from-to)2483-2494
Number of pages12
JournalMolecular Cancer Therapeutics
Volume11
Issue number11
DOIs
Publication statusPublished - 2012 Nov 1

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Chelating Agents
Platinum
Copper
Drug Resistance
Ovarian Neoplasms
Drug Therapy
Cell Line
Heterografts
Pharmaceutical Preparations
Antineoplastic Agents
Cisplatin
Neoplasms
Homeostasis
Clinical Trials
Gene Expression
Therapeutics

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Liang, Z. D., Long, Y., Tsai, W. B., Fu, S., Kurzrock, R., Gagea-Iurascu, M., ... Kuo, M. T. (2012). Mechanistic basis for overcoming platinum resistance using copper chelating agents. Molecular Cancer Therapeutics, 11(11), 2483-2494. https://doi.org/10.1158/1535-7163.MCT-12-0580
Liang, Zheng D. ; Long, Yan ; Tsai, Wen Bin ; Fu, Siqing ; Kurzrock, Razelle ; Gagea-Iurascu, Mihai ; Zhang, Fan ; Chen, Helen H.W. ; Hennessy, Bryan T. ; Mills, Gordon B. ; Savaraj, Niramol ; Kuo, Macus Tien. / Mechanistic basis for overcoming platinum resistance using copper chelating agents. In: Molecular Cancer Therapeutics. 2012 ; Vol. 11, No. 11. pp. 2483-2494.
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Liang, ZD, Long, Y, Tsai, WB, Fu, S, Kurzrock, R, Gagea-Iurascu, M, Zhang, F, Chen, HHW, Hennessy, BT, Mills, GB, Savaraj, N & Kuo, MT 2012, 'Mechanistic basis for overcoming platinum resistance using copper chelating agents', Molecular Cancer Therapeutics, vol. 11, no. 11, pp. 2483-2494. https://doi.org/10.1158/1535-7163.MCT-12-0580

Mechanistic basis for overcoming platinum resistance using copper chelating agents. / Liang, Zheng D.; Long, Yan; Tsai, Wen Bin; Fu, Siqing; Kurzrock, Razelle; Gagea-Iurascu, Mihai; Zhang, Fan; Chen, Helen H.W.; Hennessy, Bryan T.; Mills, Gordon B.; Savaraj, Niramol; Kuo, Macus Tien.

In: Molecular Cancer Therapeutics, Vol. 11, No. 11, 01.11.2012, p. 2483-2494.

Research output: Contribution to journalArticle

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T1 - Mechanistic basis for overcoming platinum resistance using copper chelating agents

AU - Liang, Zheng D.

AU - Long, Yan

AU - Tsai, Wen Bin

AU - Fu, Siqing

AU - Kurzrock, Razelle

AU - Gagea-Iurascu, Mihai

AU - Zhang, Fan

AU - Chen, Helen H.W.

AU - Hennessy, Bryan T.

AU - Mills, Gordon B.

AU - Savaraj, Niramol

AU - Kuo, Macus Tien

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N2 - 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, hadmore 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.

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