Significance of Organic Cation Transporter 3 (SLC22A3) Expression for the Cytotoxic Effect of Oxaliplatin in Colorectal Cancer
Significance of Organic Cation Transporter 3 (SLC22A3) Expression for the Cytotoxic Effect of Oxaliplatin in Colorectal Cancer
复制标题
DOI：
10.1124/dmd.108.023168
复制
发表时间：
2008-11-01
影响因子：
3.9
通讯作者：
Inui, Ken-ichi
中科院分区：
文献类型：
--
作者：
Yokoo, Sachiko;Masuda, Satohiro;Inui, Ken-ichi
奥沙利铂治疗结直肠癌的疗效上级顺铂，但其分子机制尚不清楚。我们之前发现奥沙利铂（而非顺铂）通过人（h）和大鼠有机阳离子转运蛋白3（OCT 3）/SLC 22 A3转运。在本研究中，我们研究了hOCT 3是否显著参与奥沙利铂诱导的细胞毒性和铂在结直肠癌中的蓄积。6例日本患者结肠癌组织中hOCT 3 mRNA水平是正常组织的9.7倍（P = 0.0247）。在人结直肠癌细胞系中，与其他有机阳离子转运蛋白相比，hOCT 3的mRNA高表达。与空载体转染的细胞相比，在奥沙利铂处理下，转染hOCT 3 cDNA的SW 480细胞中乳酸脱氢酶（LDH）的释放和铂的积累增加。奥沙利铂处理后，具有高水平hOCT 3的T84和SW 837细胞比低hOCT 3表达细胞（如SW 480、HCT 116、HT 29和Lovo）释放更多LDH并积累更多铂。然而，顺铂治疗后积累的铂量在这六种细胞系中没有差异。通过斑点印迹法测定，高加索患者结肠和直肠中的hOCT 3表达水平在癌组织中也高于正常组织。总之，hOCT 3介导的奥沙利铂在癌症中的摄取对其细胞毒性很重要，hOCT 3表达可能是包括奥沙利铂在内的癌症化疗的标志物。
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.