Volasertib (BI 6727), a novel polo-like kinase inhibitor, reverses ABCB1 and ABCG2-mediated multidrug resistance in cancer cells

Introduction Volasertib (BI 6727) is a highly potent molecular targeted anticancer agent that induces mitotic arrest and apoptosis by selectively targeting the Polo-like kinase (PLK) family of proteins [1]. It is currently in early clinical development against various human tumors. PLK1 is the best characterized member of the PLK family and is recognized to play essential roles in the regulation of mitotic progression [2]. Overexpression of PLK1 is common in various cancers and is associated with poor prognosis [3]. Therefore, PLK1 represents an attractive target for anticancer drug development, particularly related to the antimitotic approach [4,5]. Multidrug resistance (MDR) is a long-standing and unresolved problem hindering successful cancer chemo-therapy. Several cellular mechanisms are known to contribute to MDR, such as reduced apoptosis, enhanced DNA damage repair mechanisms or altered drug metabolism. However, the most common mechanism of resistance is the active efflux of drugs by ATP-binding cassette (ABC) transporters including P-glycoprotein (ABCB1/P-gp), ABCC1/ MRP1 and ABCG2 [6]. These transporters play a key role in the energy-dependent cellular efflux of toxic agents. They are capable of recognizing and extruding a broad range of functionally and structurally unrelated compounds, thereby causing the MDR phenotype in various cancer types. An obvious strategy to restore drug sensitivity in MDR cancer cells caused by ABC drug transporters is to block transporter-mediated drug efflux. Over the past decade, tremendous efforts have been made to discover and synthesize such inhibitors/modulators. Numerous clinical trials have been performed to evaluate the combination of ABCB1/P-gp modulators with standard chemotherapy regimens in enhancing anticancer efficacy [7]. However, none of them has been successfully put into clinical use, partly because of their low potency and lack of specificity Abstract 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 …