Overcoming platinum drug resistance with copper-lowering agents

Helen H.W Chen, Macus Tien Kuo

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Platinum (Pt)-based antitumor agents have been the mainstay of cancer chemotherapy for the last three decades. While multiple mechanisms are responsible for treatment failure, deficiency in drug transport is an important contributor. The human high-affinity copper (Cu) transporter-1 (hCtr1) can also transport Pt-based drugs including cisplatin (cDDP) and carboplatin. Reduced hCtr1 expression frequently occurs in cDDP-resistant cell lines and in cancer in patients who failed chemotherapy with these drugs. We previously demonstrated that Cu chelation induces the expression of transcription factor Sp1 which binds the promoters of Sp1 and hCtr1, thereby, upregulating their expression, whereas Cu overload shuts down hCtr1 and Sp1 expression by dissociating Sp1 from their promoter promoters. Thus, mammalian Cu homeostasis is transcriptionally regulated within a loop consisting of Sp1, hCtr1, and Cu in a three-way mutually regulated manner. These findings suggest that it is feasible to module cDDP transport capacity through intervention of mammalian Cu homeostasis. Indeed, we found that cDDP resistance can be overcome by Culowering agents through enhanced hCtr1 expression by upregulation of Sp1 in cultured cells. This discovery provided a mechanistic basis for the ongoing clinical study using Cu chelator to overcome cDDP resistance in ovarian cancer chemotherapy. Preliminary study using copper chelator (trientine) for enhancing the treatment efficacy of carboplatin in 5 ovarian cancer patients showed encouraging results. This short review describes the perspectives of using Cu-lowering agents in overcoming Pt resistance in cancer chemotherapy.

Original languageEnglish
Pages (from-to)4157-4162
Number of pages6
JournalAnticancer Research
Volume33
Issue number10
Publication statusPublished - 2013 Oct 1

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Platinum
Drug Resistance
Copper
Drug Therapy
Carboplatin
Chelating Agents
Ovarian Neoplasms
Homeostasis
Pharmaceutical Preparations
Trientine
Sp1 Transcription Factor
Neoplasms
Treatment Failure
Antineoplastic Agents
Cisplatin
Cultured Cells
Up-Regulation
Cell Line

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Chen, Helen H.W ; Kuo, Macus Tien. / Overcoming platinum drug resistance with copper-lowering agents. In: Anticancer Research. 2013 ; Vol. 33, No. 10. pp. 4157-4162.
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Overcoming platinum drug resistance with copper-lowering agents. / Chen, Helen H.W; Kuo, Macus Tien.

In: Anticancer Research, Vol. 33, No. 10, 01.10.2013, p. 4157-4162.

Research output: Contribution to journalArticle

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