Copper transporter 2 regulates the cellular accumulation and cytotoxicity of Cisplatin and Carboplatin.

作者: Brian G. Blair , Christopher A. Larson , Roohangiz Safaei , Stephen B. Howell

DOI: 10.1158/1078-0432.CCR-09-0311

关键词:

摘要: Purpose: Copper transporter 2 (CTR2) is known to mediate the uptake of Cu +1 by mammalian cells. Several other transporters, including influx CTR1 and two efflux transporters ATP7A ATP7B, also regulate sensitivity platinum-containing drugs. We sought determine effect CTR2 on influx, intracellular trafficking, cisplatin carboplatin. Experimental Design: The role was examined knocking down expression in an isogenic pair mouse embryo fibroblasts consisting a +/+ line −/− which both alleles had been deleted. levels were determined quantitative reverse transcription-PCR Western blot analysis. Cisplatin (DDP) quantified inductively coupled plasma mass spectrometry 64 [ 14 C]carboplatin (CBDCA) accumulation γ scintillation counting. Results: Deletion reduced Cu, DDP, CBDCA increased resistance their cytotoxic effects 2- 3-fold. Knockdown only In contrast, knockdown whole-cell DDP DNA platination cells proportionately enhanced cytotoxicity while producing no vesicular or efflux. A significant correlation found between mRNA protein panel six ovarian carcinoma cell lines. Conclusions: major determinant CBDCA. functions limiting drug accumulation, its correlates with human lines DDP.

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