Significance of Organic Cation Transporter 3 (SLC22A3) Expression for the Cytotoxic Effect of Oxaliplatin in Colorectal Cancer

Abstract

ABSTRACT:The effect of oxaliplatin against colorectal cancer is superior to that of cisplatin, but the molecular mechanism(s) involved is not clear. We found previously that oxaliplatin, but not cisplatin, was transported by human (h) and rat organic cation transporter 3 (OCT3)/SLC22A3. 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 in normal tissues in six Japanese patients (P ‫؍‬ 0.0247). In human colorectal cancer-derived cell lines, the mRNA of hOCT3 was highly expressed compared with that of other organic cation transporters. The release of lactate dehydrogenase (LDH) and accumulation of platinum with oxaliplatin treatment were increased in SW480 cells transfected with hOCT3 cDNA compared with 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 after cisplatin treatment did not differ among these six cell lines. The levels of hOCT3 expression in colon and rectum were also higher in cancerous than in 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.

Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver

“…The rs3088442 variant is in complete linkage to the intronic OCT3 variant rs2048327 and, of note, in a genome-wide association study investigating susceptibility for coronary artery disease, 54 this variant was recently identified. Thus, in addition to a potential clinical relevance of OCT3 for drug response (such as efficacy of oxaliplatin chemotherapy, 55 lamivudine as drug substrate 19,20 ) OCT3 (SLC22A3) may contribute also as a susceptibility factor for development of certain diseases such as coronary artery disease 54 but also other diseases (such as obsessive-compulsive disorder 37 ).…”

Interaction of Ethambutol with Human Organic Cation Transporters of the SLC22 Family Indicates Potential for Drug-Drug Interactions during Antituberculosis Therapy

“…hOCTs are also involved in the pharmacological action of platinum antineoplastics (e.g., cisplatin and oxaliplatin), raising the possibility for significant DDIs during chemotherapy in TB patients (43)(44)(45)(46). Patients receiving cisplatin therapy frequently experience cumulative dose-dependent nephrotoxicity involving the proximal tubule (47)(48)(49).…”

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

“…Overexpression of rat and human OCT2 and OCT3 enhances oxaliplatin accumulation and cytotoxicity Yokoo et al, 2007). In fact, expression of OCT3 in a human colorectal cancer-derived cell line correlates with sensitivity to oxaliplatin cytotoxicity (Yokoo et al, 2008).…”