Received for publication June 30, 2008.
Revised August 14, 2008.
Accepted for publication August 14, 2008.

Significance of OCT3/SLC22A3, Organic Cation Transporter 3, Expression for the Cytotoxic Effect of Oxaliplatin in Colorectal Cancer

Abstract

The effect of oxaliplatin against colorectal cancer is superior to that of cisplatin, but the molecular mechanism(s) involved is not clear. We previously found that oxaliplatin, but not cisplatin, was transported by human (h) and rat OCT3/SLC22A3, organic cation transporter 3. In the present study, we examined whether hOCT3 was significantly involved in the oxaliplatin-induced cytotoxicity and accumulation of platinum in colorectal cancer. The level of hOCT3 mRNA in the colon was 9.7-fold higher in cancerous than normal tissues in six Japanese patients (P=0.0247). In human colorectal cancer-derived cell lines, the mRNA of hOCT3 was highly expressed compared to that of other organic cation transporters. The release of LDH and accumulation of platinum on oxaliplatin treatment were increased in SW480 cells transfected with hOCT3 cDNA compared to empty vector-transfected cells. T84 and SW837 cells, with high levels of hOCT3, released more LDH and accumulated more platinum after oxaliplatin treatment than low hOCT3-expressing cells such as SW480, HCT116, HT29 and Lovo. However, the amount of platinum accumulated following cisplatin treatment did not differ among these six cells. The levels of hOCT3 expression in colon and rectum were also higher in cancerous than normal tissues in Caucasian patients as determined by dot blotting. In conclusion, the hOCT3-mediated uptake of oxaliplatin into the cancers was suggested to be important for its cytotoxicity, and hOCT3 expression may be a marker for cancer chemotherapy including oxaliplatin.

Key words: anticancer agents, drug toxicity, membrane transport, organic cation transport, transporters