Human drug efflux transporter ABCC5 confers acquired resistance to pemetrexed in breast cancer

Abstract

Aim Pemetrexed, a new generation antifolate drug, has been approved for the treatment of locally advanced or metastatic breast cancer. However, factors affecting its efficacy and resistance have not been fully elucidated yet. ATP-binding cassette (ABC) transporters are predictors of prognosis as well as of adverse effects of several xenobiotics. This study was designed to explore whether ABC transporters affect pemetrexed resistance and can contribute to the optimization of breast cancer treatment regimen. Methods First, we measured the expression levels of ABC transporter family members in cell lines. Subsequently, we assessed the potential role of ABC transporters in conferring resistance to pemetrexed in primary breast cancer cells isolated from 34 breast cancer patients and the role of ABCC5 in mediating pemetrexed transport and apoptotic pathways in MCF-7 cells. Finally, the influence of ABCC5 expression on the therapeutic effect of pemetrexed was evaluated in an in vivo xenograft mouse model of breast cancer. Results The expression levels of ABCC2, ABCC4, ABCC5, and ABCG2 significantly increased in the pan-resistant cell line, and the ABCC5 level in the MCF-7-ADR cell line was 5.21 times higher than that in the control group. ABCC5 expression was inversely correlated with pemetrexed sensitivity (IC50, r = 0.741; p < 0.001) in breast cancer cells derived from 34 patients. Furthermore, we found that the expression level of ABCC5 influenced the efflux and cytotoxicity of pemetrexed in MCF-7 cells, with IC50 values of 0.06 and 0.20 μg/mL in ABCC5 knockout and over-expression cells, respectively. In the in vivo study, we observed that ABCC5 affected the sensitivity of pemetrexed in breast tumor-bearing mice, and the tumor volume was much larger in the ABCC5-overexpressing group than in the control group when compared with their own initial volumes (2.7-fold vs. 1.3-fold). Conclusions Our results indicated that ABCC5 expression was associated with pemetrexed resistance in vitro and in vivo, and it may serve as a target or biomarker for the optimization of pemetrexed regimen in breast cancer treatment.

The Potential Mechanism of HDAC1-Catalyzed Histone Crotonylation of Caspase-1 in Nonsmall Cell Lung Cancer

“…Alimta (also known as pemetrexed) is a multitargeted antifolate agent that has been proved to exhibit e ective single-agent activity in patients with NSCLC [6][7][8][9] and is widely studied as the synergetic agent for NSCLC therapy in various clinical studies [10][11][12][13]. However, the resistance to pemetrexed is frequently occurred in multiple cancers and severely a ects the NSCLC therapy [14][15][16].…”

FOXM1 Promotes Drug Resistance in Cervical Cancer Cells by Regulating ABCC5 Gene Transcription

“…Proteins in the ABCC subfamily are closely involved in mediating drug transport [ 6 ]. Amongst the nine primary transporters (ABCC1-6, ABCC10-12, or MRP 1-9) in the ABCC family, ABCC5 was found to transport nucleoside monophosphate analogues and produce cancer drug resistance [ 21 – 23 ].…”

Impact of ABC Transporters in Osteosarcoma and Ewing’s Sarcoma: Which Are Involved in Chemoresistance and Which Are Not?

“…This association was confirmed in a germline study including 132 OS patients [ 19 ]. Furthermore, in a subset of 52 patients, higher ABCC5 RNA expression levels were revealed in tumor tissues of patients carrying the germline risk allele (GG/GA) compared to those with AA genotypes, showing that the elevated ABCC5 expression might be associated with resistance to cisplatin and doxorubicin in OS patients [ 123 ].…”