Abstract
BackgroundOver-expression of Aurora kinases promotes the tumorigenesis of cells. The aim of this study was to determine the preclinical profile of a novel pan-Aurora kinase inhibitor, BPR1K653, as a candidate for anti-cancer therapy. Since expression of the drug efflux pump, MDR1, reduces the effectiveness of various chemotherapeutic compounds in human cancers, this study also aimed to determine whether the potency of BPR1K653 could be affected by the expression of MDR1 in cancer cells.Principal FindingsBPR1K653 specifically inhibited the activity of Aurora-A and Aurora-B kinase at low nano-molar concentrations in vitro. Anti-proliferative activity of BPR1K653 was evaluated in various human cancer cell lines. Results of the clonogenic assay showed that BPR1K653 was potent in targeting a variety of cancer cell lines regardless of the tissue origin, p53 status, or expression of MDR1. At the cellular level, BPR1K653 induced endo-replication and subsequent apoptosis in both MDR1-negative and MDR1-positive cancer cells. Importantly, it showed potent activity against the growth of xenograft tumors of the human cervical carcinoma KB and KB-derived MDR1-positive KB-VIN10 cells in nude mice. Finally, BPR1K653 also exhibited favorable pharmacokinetic properties in rats.Conclusions and SignificanceBPR1K653 is a novel potent anti-cancer compound, and its potency is not affected by the expression of the multiple drug resistant protein, MDR1, in cancer cells. Therefore, BPR1K653 is a promising anti-cancer compound that has potential for the management of various malignancies, particularly for patients with MDR1-related drug resistance after prolonged chemotherapeutic treatments.
Highlights
Mitosis is a key step in cell cycle that is tightly regulated by many proteins
BPR1K653 is a novel potent anti-cancer compound, and its potency is not affected by the expression of the multiple drug resistant protein, MDR1, in cancer cells
Western blot analysis revealed that the amount of phosphor-Aurora-A, -B and -C kinase present in HCT116 cancer cells treated with a pan-Aurora kinase inhibitor, VX680, was reduced in a concentrationdependent manner (Figure 1C)
Summary
Mitosis is a key step in cell cycle that is tightly regulated by many proteins. Abnormal expression or activation of these regulatory proteins could result in aberrant mitosis, leading to the development of cancers [1,2]. The first proof-of-concept pan-Aurora kinase inhibitor, VX-680 (MK0457, Tozasertib), was developed in 2004 by Vertex Pharmaceuticals (in collaboration with Merck) with an aim to target cancer cells. This specific inhibitor has been shown effective in targeting cancer cells both in vitro and in vivo, and has received approval from the US Food and Drug Administration (FDA) to enter clinical trials [12,13,14]. The aim of this study was to determine the preclinical profile of a novel pan-Aurora kinase inhibitor, BPR1K653, as a candidate for anti-cancer therapy. Since expression of the drug efflux pump, MDR1, reduces the effectiveness of various chemotherapeutic compounds in human cancers, this study aimed to determine whether the potency of BPR1K653 could be affected by the expression of MDR1 in cancer cells
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