Organic cation transporter 6 directly confers resistance to anticancer platinum drugs

Abstract

Abstract. Organic cation transporters (OCTs) of the solute carrier family 22 have a critical role in the cellular uptake of anticancer platinum drugs. Recently, we found that a decreased OCT6 expression is associated with a reduced intracellular uptake of cisplatin (CDDP), and concomitant resistance to CDDP. In the present study, we examined whether OCTs directly confer resistance to another platinum drug, oxaliplatin (L-OHP). To address this, we used parental lung cancer cell lines, PC-14 and SBC3; L-OHP-resistant sublines, PC-14/L-OHP and SBC3/L-OHP; and one CDDP-resistant subline PC-14/CDDP, to examine the relationships between the expression of OCTs and intracellular platinum drug concentration or platinum drug resistance. The two L-OHP-resistant sublines showed cross resistance to CDDP and L-OHP, and a decreased expression of OCT6. The intracellular accumulation of L-OHP in PC-14/L-OHP cells was reduced compared with the parental cells. The findings suggested that a reduced OCT6 expression confers platinum drug resistance in the sublines by decreasing the uptake of platinum drugs. Using the PC-14/CDDP cell line engineered to overexpress OCT6, we confirmed that the intracellular L-OHP concentration was increased concomitantly with OCT6 overexpression compared with the parental cell line. Additionally, OCT6 was expressed in a screening panel of lung and colon cancer tissues and matched normal control tissues. Taken together with the previous results, the present findings indicate that OCT6 is directly involved in platinum drug resistance by mediating platinum drug uptake in cancer cells.

Screening of molecular targets and construction of a ceRNA network for oxaliplatin resistance in colorectal cancer

“…12,13 Copper transporters are involved in the accumulation of oxaliplatin, 14 and the expression levels of organic cation transporters (OCT) positively correlate with oxaliplatin absorption and resistance. 15,16 ABC transporters, such as multidrug resistance proteins (MRPs) and sodium potassium ATPases, are also involved in oxaliplatin drug resistance. [17][18][19][20] (iii) Glutathione (GSH)-mediated oxaliplatin effusion reduces the amount of oxaliplatin in cancer cells.…”

Structural Factors Affecting Binding of Platinum Anticancer Agents with Phospholipids: Influence of Charge and Phosphate Clamp Formation

“…Distinct cellular accumulation pathways may possibly confer some tumor selectivity on these non‐specific cytotoxics. The influence of copper transporters (hCTR) and organic cation transporters (OCT) on platinum uptake even varies amongst the three clinically approved agents . Furthermore, hOCT transport is implicated in the kidney toxicity associated with cisplatin but not oxaliplatin or carboplatin .…”

Variants of SLC22A16 Predict the Efficacy of Platinum Combination Chemotherapy in Advanced Non-small-cell Lung Cancer

“…We previously reported that organic cation transporter 6 (OCT6) is a mediator of platinum influx into cancer cells, and down-regulation of OCT6 is one mechanism of acquired platinum resistance in lung cancer (6), as it is with other platinum derivatives (7). Single nucleotide polymorphisms (SNPs) are the most common type of genetic variation.…”