A novel resveratrol derivative induces mitotic arrest, centrosome fragmentation and cancer cell death by inhibiting gamma-tubulin

Background: Resveratrol and its natural stilbene-containing derivatives have been extensively investigated as potential chemotherapeutic agents. The synthetic manipulation of the stilbene scaffold has led to the generation of new analogues with improved anticancer activity and better bioavailability. In the present study we investigated the anticancer activity of a novel trimethoxystilbene derivative (3,4,4'-trimethoxylstilbene), where two methoxyl groups are adjacent on the benzene ring (ortho configuration), and compared its activity to 3,5,4'-trimethoxylstilbene, whose methoxyl groups are in meta configuration. Results: We provide evidence that the presence of the two methoxyl groups in ortho configuration renders 3,4,4'-trimethoxystilbene more efficient than the meta isomer in inhibiting cell proliferation and producing apoptotic death in colorectal cancer cells. Confocal microscopy of alpha- and gamma-tubulin staining shows that the novel compound strongly depolymerizes the mitotic spindle and produces fragmentation of the pericentrosomal material. Computer assisted docking studies indicate that both molecules potentially interact with gamma-tubulin, and that 3,4,4'-trimethoxystilbene is likely to establish stronger interactions with the protein.