Imidazopyridine CCT129202 is an inhibitor of
Aurora kinase activity and displays a favorable
antineoplastic effect in preclinical studies. Here, we investigated the enhanced effect of
CCT129202 on the cytotoxicity of chemotherapeutic drugs in multidrug resistant (MDR) cells with overexpression of
ATP-binding cassette (
ABC) transporters and
cancer stem-like cells.
CCT129202 of more than 90% cell survival concentration significantly enhanced the cytotoxicity of substrate drugs and increased the intracellular accumulations of
doxorubicin and
rhodamine 123 in ABCB1 and ABCG2 overexpressing cells, while no effect was found on parental sensitive cells. Interestingly,
CCT129202 also potentiated the sensitivity of
cancer stem-like cells to
doxorubicin. Importantly,
CCT129202 increased the inhibitory effect of
vincristine and
paclitaxel on ABCB1 overexpressing KBv200 cell xenografts in nude mice and human
esophageal cancer tissue overexpressing ABCB1 ex vivo, respectively. Furthermore, the
ATPase activity of ABCB1 was inhibited by
CCT129202. Homology modeling predicted the binding conformation of
CCT129202 within the large hydrophobic cavity of ABCB1. On the other hand,
CCT129202 neither apparently altered the expression levels of ABCB1 and ABCG2 nor inhibited the activity of
Aurora kinases in MDR cells under the concentration of reversal MDR. In conclusion,
CCT129202 significantly reversed ABCB1- and ABCG2-mediated MDR in vitro, in vivo and ex vivo by inhibiting the function of their transporters and enhanced the eradication of
cancer stem-like cells by chemotherapeutic agents.
CCT129202 may be a candidate as MDR reversal agent for
antineoplastic combination
therapy and merits further clinical investigation.