5-(N-methylmaleimid-3-yl)-chromone, a novel microtubule inhibitor,
exerts anti-proliferative effects in MDR cancer cells and cancer stem
cells
Abstract
Background and Purpose: The success of cancer chemotherapy is limited by
multidrug resistance (MDR), which is mainly caused by P-glycoprotein
(P-gp) overexpression. In the present study, we describe a novel
microtubule inhibitor, 5-(N-methylmaleimid-3-yl)-chromone (SPC-160002),
that can be used to overcome MDR. Experimental Approach: Key Results: A
synthetic chromone derivative, SPC-160002, showed a broad spectrum of
anti-proliferative effects on various human cancer cells without
affecting P-gp expression and its drug efflux function. Treatment with
SPC-160002 arrested the cell cycle at the M phase, as evidenced using
fluorescence-activated cell sorting analysis, and increased the levels
of mitotic marker proteins, including cyclin B, pS10-H3, and chromosomal
passenger complex. This mitotic arrest by SPC-160002 was mediated by
promoting and stabilizing microtubule polymerization, similar to the
mechanism observed in case of taxane-based drugs. Furthermore,
SPC-160002 suppressed the growth and sphere-forming activity of cancer
stem cells. Conclusion and Implications: Our data herein strongly
suggest that SPC-160002, a novel microtubule inhibitor, can be used to
overcome MDR and can serve as an attractive candidate for anticancer
drugs.