Contribution of Organic Cation Transporter 3 to Cisplatin Cytotoxicity in Human Cervical Cancer Cells

This study was conducted to investigate whether drug transporters play a role in determination of cisplatin resistance in cervical cancer cells. The transcript levels of the transporter genes previously associated with cisplatin transport and/or resistance were compared between the cisplatin-sensitive cervical adenocarcinoma KB-3-1 and its derivative cisplatin-resistant KB-CP20 cells. The expression of the efflux transporter gene multidrug resistance-associated protein 2 (MRP2) was significantly reduced in KB-CP20 cells, in support of previous studies indicating that MRP2 is unlikely responsible for cisplatin resistance in these cells. We observed that the expression of the uptake transporter organic cation transporter 3 (OCT3) was extremely downregulated in KB-CP20 compared with KB-3-1 cells. Consistently, the transport function for organic cations in the former was considerably low. OCT3 overexpression significantly increased cisplatin cellular accumulation and cytotoxicity in KB-3-1 cells, while its downregulation by short hairpin RNA or chemical inhibition increased the resistance. Interestingly, there was no effect of OCT3 overexpression on cisplatin accumulation and cytotoxicity in human embryonic kidney 293 cells. The present study indicates that OCT3 partially contributes to the sensitivity of cervical adenocarcinoma cells to cisplatin cytotoxicity. Further studies are required to determine OCT3 activity in cervical cancer tissues of different cisplatin chemoresponses and to elucidate the underlying mechanisms of different OCT3 function in different cell types. © 2011 Wiley Periodicals, Inc. and the American Pharmacists Association.