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A hybrid platinum drug dichloroacetate-platinum(II) overcomes cisplatin drug resistance through dual organelle targeting

Zhang, Yua,*; Guo, Guannanb,*; Ma, Bena; Du, Ronga; Xiao, Haihuac; Yang, Xiaoguangb; Li, Wenlianga; Gao, Yingd; Li, Yuxinb; Jing, Xiabinc

doi: 10.1097/CAD.0000000000000234
PRECLINICAL REPORTS
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A hybrid drug dichloroacetate-platinum(II) [DCA-Pt(II)] was found to overcome cisplatin drug resistance of ovarian cancer through a dual targeting mode, which is different from the mode of action of the present platinum (Pt) drugs used in clinics. DCA-Pt(II) exhibited remarkable cytotoxicity against both cisplatin-sensitive (A2780) and cisplatin-resistant (A2780DDP) ovarian cancer cells. The Pt and Pt-DNA adduct content test showed that there was less Pt cellular uptake and fewer Pt-DNA adducts were present after DCA-Pt(II) treatment compared with treatment with cisplatin, carboplatin, and some other drugs. In the study, the effects of DCA-Pt(II) on the cell cycle and apoptosis were also investigated, which showed that DCA-Pt(II) induced G2/M phase arrest and mitochondria-mediated apoptosis in both sensitive and resistant cells lines. Interestingly, DCA-Pt(II) had much greater effects on mitochondria in A2780DDP cell lines than in A2780 cell lines.

Supplemental Digital Content is available in the text.

aNational Engineering Laboratory for Druggable Gene and Protein Screening

bJilin Province Key Laboratory on Chemistry and Biology of Natural Drugs in Changbai Mountain, School of Life Sciences, Northeast Normal University

cState Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences

dSchool of Chemistry & Environmental Engineering, Changchun University of Science and Technology, Changchun, China

* Yu Zhang and Guannan Guo contributed equally to the writing of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (www.anti-cancerdrugs.com).

Correspondence to Wenliang Li, PhD, National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China Tel: +86 431 89165937; fax: +86 431 89165917; e-mail: liwl100@nenu.edu.cn and Yuxin Li, PhD, Jilin Province Key Laboratory on Chemistry and Biology of Natural Drugs in Changbai Mountain, School of Life Sciences, Northeast Normal University, Changchun 130024, China Tel/fax:+86 431 89165926; e-mail: yxli486@126.com

Received October 31, 2014

Accepted February 24, 2015

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