Tubulin is a validated target for
antitumor drugs. However, the effectiveness of these microtubule-interacting agents is limited by the fact that they are substrates for
drug efflux pumps (
P-glycoprotein) and/or by the acquisition of point mutations in
tubulin residues important for
drug-
tubulin binding. To bypass these resistance systems, we have identified and characterized a novel synthetic
imidazole derivative
IRC-083927, which inhibits the
tubulin polymerization by a binding to the
colchicine site.
IRC-083927 inhibits in vitro cell growth of human
cancer cell lines in the low nanomolar range. More interesting, it remains highly active against cell lines resistant to microtubule-interacting agents (
taxanes,
Vinca alkaloids, or
epothilones). Such resistances are due to the presence of efflux pumps (NCI-H69/LX4 resistant to
navelbine and
paclitaxel) and/or the presence of mutations on
beta-tubulin and on
alpha-tubulin and
beta-tubulin (A549.EpoB40/A549.EpoB480 resistant to
epothilone B or
paclitaxel).
IRC-083927 displayed cell cycle arrest in G(2)-M phase in
tumor cells, including in the
drug-resistant cells. In addition,
IRC-083927 inhibited endothelial cell proliferation in vitro and vessel formation in the low nanomolar range supporting an antiangiogenic behavior. Finally, chronic oral treatment with
IRC-083927 (5 mg/kg) inhibits the growth of two human
tumor xenografts in nude mice (C33-A, human
cervical cancer and MDA-MB-231, human
hormone-independent
breast cancer). Together, the antitumor effects induced by
IRC-083927 on
tumor models resistant to
tubulin agents support further investigations to fully evaluate its potential for the treatment of advanced
cancers, particularly those resistant to current clinically available drugs.