Overexpression of Human ABCB1 in Cancer Cells Leads to Reduced Activity of GSK461364, a Specific Inhibitor of Polo-like Kinase 1

Abstract

Polo-like kinase 1 (Plk1) is a serine/threonine kinase involved in the regulation of mitosis and is overexpressed in many tumor types. Inhibition of Plk1 leads to cell cycle arrest, onset of apoptosis, and cell death, thus Plk1 has emerged as an important target for cancer treatment. GSK461364 is a potent inhibitor of Plk1 that inhibits the proliferation of multiple human cancer cell lines by promoting G2/M cell cycle arrest at low concentrations. However, as is the case for many therapeutic drugs, the risk of developing drug resistance to GSK461364 can present a therapeutic challenge to clinicians. Since the overexpression of ATP-binding cassette (ABC) drug transporter ABCB1 is one of the most common mechanisms of drug resistance, we aimed to investigate the effect of ABCB1 on the cellular efficacy of GSK461364. In this study, we observed a significantly reduced activity of GSK461364 in cells overexpressing human ABCB1. We showed that GSK461364 stimulates the ABCB1 ATPase activity and competitively inhibits ABCB1-mediated efflux of calcein-AM in a concentration-dependent manner. Moreover, as a way to assess the impact of ABCB1 on the efficacy of GSK461364, we evaluated the G2/M cell cycle arrest and apoptosis induced by GSK461364. We discovered that, by inhibiting the function of ABCB1, the reduced G2/M cell cycle arrest, apoptosis, and sensitivity to GSK461364 treatment in ABCB1-overexpressing cells can be significantly restored. In conclusion, in order to achieve a better therapeutic outcome, combination therapy of GSK461364 with a modulator of ABCB1 should be further investigated as a potential treatment approach.

The GSK461364 PLK1 inhibitor exhibits strong antitumoral activity in preclinical neuroblastoma models

“…Cells in stasis might resume proliferation after treatment. Overexpression of the human multidrug resistance gene, ABCB1 , was also recently reported to reduce GSK461364 activity in cancer cells [60]. Future in-depth preclinical studies addressing whether neuroblastic tumors regrow after PLK1-inhibiting treatment ceases and identifying the resistance mechanisms involved should assist schedule refinement for incorporating PLK1 inhibitors into current protocols for high-risk or relapsed disease.…”

Drug Transporters and Na+/H+Exchange Regulatory Factor PSD-95/Drosophila Discs Large/ZO-1 Proteins

“…ABC transporters actively efflux a broad array of chemotherapeutic agents such as taxanes, camptothecins, and platinum agents, thus contributing to decreased intracellular drug accumulation in tumor cells and ultimately failure of chemotherapy (Gottesman et al, 2002). Pgp (MDR1), MRP1 (ABCC1), and BCRP (ABCG2), the ABC superfamily, play important roles in MDR (Doyle et al, 1998;Kunická and Sou cek, 2014;Wu et al, 2014). Overexpression of these transporters is well documented in many types of cancer and considered to be the underlying mechanism for chemoresistance attributable to ABC drug efflux in tumors (Szakacs et al, 2006;Teodori et al, 2006;Wu et al, 2014).…”

“…Pgp (MDR1), MRP1 (ABCC1), and BCRP (ABCG2), the ABC superfamily, play important roles in MDR (Doyle et al, 1998;Kunická and Sou cek, 2014;Wu et al, 2014). Overexpression of these transporters is well documented in many types of cancer and considered to be the underlying mechanism for chemoresistance attributable to ABC drug efflux in tumors (Szakacs et al, 2006;Teodori et al, 2006;Wu et al, 2014). Substrate-induced induction is one mechanism involved in the upregulation of ABC drug transporters, where chemotherapeutic drugs enhance chemoresistance through nuclear receptors involved in the transcriptional expression of efflux drug transporters (Chen, Drug Transporters and NHERF PDZ Proteins 673 2010; Herraez et al, 2012;Manceau et al, 2012;Oda et al, 2013).…”

Effect of AKT3 expression on MYC‐ and caspase‐8‐dependent apoptosis caused by polo‐like kinase inhibitors in HCT 116 cells

“…Various mechanisms, such as the increased expression of drug efflux transporters, the alteration of target molecules, the upregulation of survival signals, and the downregulation of cell death mechanisms, have been investigated . The overexpression of P‐glycoprotein (P‐GP) is one of the commonest resistance mechanisms to BI 2536, BI 6727, and GSK461364, which are investigated in this study . A PLK1 gene mutation has also been reported to confer resistance to BI 2536 …”

“…(15) The overexpression of P-glycoprotein (P-GP) is one of the commonest resistance mechanisms to BI 2536, BI 6727, and GSK461364, which are investigated in this study. (16)(17)(18) A PLK1 gene mutation has also been reported to confer resistance to BI 2536. (19) In this study, we established five BI 2536-resistant cell lines (BI 10-1-5, BI 10-1-10, BI 20-1, BI 40-1, and BI 40-2) from human colorectal cancer HCT 116 cells, to investigate the mechanisms responsible for the sensitivity to PLKis.…”