2. State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou 510060, China.
Background: Multidrug resistance (MDR), most often mediated by overexpression of ABC efflux transporters, is severely limiting the usefulness of chemotherapy. Intense research effort has been made to search for inhibitors of these MDR transporters to circumvent resistance, yet with no success in the last decade. The recent discovery of potent and specific inhibition of various MDR transporters by the molecular targeted tyrosine kinase inhibitors has refueled the interest in developing drug transporter inhibitors for MDR circumvention. We investigated the circumvention of MDR by a novel Polo-like kinase (PLK) inhibitor (volasertib) and studied the underlying mechanisms.
Methods: The potential MDR reversal effect of volasertib was evaluated in resistant cancer cell lines with defined overexpression of the three major MDR transporters. Sulforhodamine dye-based cytotoxicity and annexin V apoptosis assay were used to evaluate the combination anticancer activity. Flow cytometric drug efflux assay was used to study the inhibition of transporter activity. ATPase assay was employed to investigate the drug-transporter interaction. Propidium iodide staining was used to study the cell cycle effect of drug combinations.
Results: Volasertib was found to reverse ABCB1- and ABCG2-mediated MDR by inhibiting transport activity of both transporters. The resulting synergistic cytotoxicity in combinations of volasertib with paclitaxel (ABCB1 substrate) or mitoxantrone (ABCG2 substrate) was remarkably higher in drug-resistant cells with transporter overexpression. Transporter inhibition was associated with inhibition of ATPase activity, but not a change in mRNA or protein expression. G2/M arrest mediated by PLK inhibition by volasertib also play an important role in the sensitization of resistant cells.
Conclusions: Our results demonstrated that volasertib reverse ABCB1- and ABCG2-mediated MDR by inhibiting both transporters and promoting more severe G2/M arrest in resistant cancer cells. Further mechanistic studies and animal work are warranted to fully understand and optimize the use of volasertib to sensitize resistant cancer cells to chemotherapy.
Keywords: ABCB1, ABCG2, efflux transporter, multidrug resistance, polo-like kinase inhibitor, volasertib