ABCC11/MRP8 confers pemetrexed resistance in lung cancer

Abstract

We have previously shown that overexpression of thymidylate synthetase (TS) resulted in pemetrexed (MTA) resistance. To investigate another mechanism of MTA resistance, we investigated the expression of ATP-binding cassette (ABC)-transporters in MTAresistant lung cancer cell lines and found that the gene and protein expression of ABCC11 ⁄ MRP8 (ABCC11) was higher in MTA-resistant cells than in the parental cells. The MTA resistant cells showed cross-resistance to methotrexate (MTX), which is a substrate for ABCC11, and intracellular MTX accumulation in MTA-resistant cells was lower than in the parental cells. We then tested the effect of decreasing the expression of ABCC11 by siRNA and found that decreased expression of ABCC11 enhanced MTA cytotoxicity and increased intracellular MTX accumulation in MTA-resistant cells. These findings suggested that ABCC11 directly confers resistance to MTA by enhancing efflux of the intracellular anti-cancer drug. Next, we analyzed the relationship between ABCC11 gene expression and MTA sensitivity of 13 adenocarcinoma cells, but there was no correlation. The ABCC11 gene has been shown to have a functional single-nucleotide polymorphism (SNP), 538G>A. We then classified 13 lung adenocarcinoma cell lines into three groups based on the genotype of this ABCC11 SNP: G ⁄ G, G ⁄ A and A ⁄ A. The A ⁄ A group showed a significant reduction in the IC 50 of MTA compared with the combined G ⁄ G and G ⁄ A groups, indicating that the SNP (538G>A) in the ABCC11 gene is an important determinant of MTA sensitivity. These results showed that ABCC11 may be one of the biomarkers for MTA treatment in adenocarcinomas. (Cancer Sci 2010; 101: 2404-2410 C urrently, several folate-based antimetabolites are used for cancer treatment and have been studied intensively in clinical trials. Nearly 60 years ago, methotrexate (MTX) was the first antifolate used in oncology clinics that was shown to be active for the chemotherapeutic treatment of childhood acute lymphoblastic leukemia.(1) Methotrexate and its polyglutamate forms are potent inhibitors of the dihydrofolate reductase (DHFR) enzyme that plays a key role in intracellular metabolism and is essential for DNA synthesis and cell growth.(2) Recently, a new generation antifolate, pemetrexed (MTA) was approved for the treatment of malignant pleural mesothelioma and non-small-cell lung cancer (NSCLC). (3,4) Pemetrexed is transported into the cell, predominantly via the reduced folate carrier (RFC), and is metabolized to polyglutamated forms. Pemetrexed was found to be one of the best substrates for mammalian folylpoly-c-glutamate synthetase (FPGS), and it is believed that MTA polyglutamation and its polyglutamated metabolites play important roles in determining both the selectivity and antitumor activity of this agent. The polyglutamated metabolites of MTA are most active against thymidylate synthase (TS), followed by DHFR, glycinamide ribonucleotide formyltransferase (GARFT) and aminoimidazole carboxamide formyl transferase (AICARFT), and natural folate c...

Multidrug Resistance Proteins (MRPs) and Cancer Therapy

“…Although there is a report showing a decrease in MRP8 level in breast cancer (83), high level of MRP8 was reported in breast cancer and gastric cancer cell lines by other groups (84,85). Other substrates of MRP8 include MTX (79), 5-FU, and pemetrexed (86,87). Further studies are needed to eliminate the controversy of MRP8's role in clinical MDR.…”

Encapsulation in a rapid-release liposomal formulation enhances the anti-tumor efficacy of pemetrexed in a murine solid mesothelioma-xenograft model

“…These metabolites inhibit 3 folatedependent enzymes that are involved in de novo purine/pyridine synthesis: dihydrofolate reductase (DHFR), thymidylate synthase (TS), and glycinamide ribonucleotide formyltransferase (GARFT) (Chattopadhyay et al, 2007;Misset et al, 2004). Despite the fact that the combination of PMX and cisplatin has prolonged the survival of malignant mesothelioma patients for as long as 12 months, their response rates are still considered dismal (Uemura et al, 2010).…”

Prognostic Impact of the ABCC11/MRP8 Polymorphism in Adjuvant Oral Chemotherapy with S-1 for Non-Small Cell Lung Cancer

“…In a cell-based study, Uemura et al [36] showed that ABCC11/MRP8 directly confers resistance to pemetrexed by enhancing the efflux of the intracellular anticancer drug. They also reported that the A/A group showed a significant reduction in the IC 50 of pemetrexed compared to the G/G or G/A group, indicating that patients with the A/A type of SNP538 are sensitive to pemetrexed.…”