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2,3′,4,4′,5′-Pentamethoxy-trans-stilbene, the hybrid molecule of TMS and MR-4, induced colon cancer cells apoptosis via targeting microtubules.Resveratrol, a naturally occurring polyphenolic antioxidant, is a compound holding promise for cancer chemoprevention. Previous studies suggest that 2,3′,4,5′-tetramethoxy-trans-stilbene (TMS) and 3,4,4′,5,-tetramethoxy-trans-stilbene (MR-4), both of which are derivatives of resveratrol, are potent apoptosis-inducing agents with clinical potential. In this study, we chemically synthesized 2,3′,4,4′,5′-pentamethoxy-trans-stilbene (PMS), the hybrid molecule of TMS and MR-4, and determined its effects on colon cancer growth. When compared with its parent compounds, PMS displayed more potent in vitro anti-mitogenic effect on colon cancer cells (Caco-2, HT-29 and SW1116). Moreover, PMS inhibited tumor growth in vivo in a colon cancer xenograft model. In this connection, PMS strongly induced apoptosis in HT-29 cells as evidenced by increased PARP cleavage, DNA fragmentation, and accumulation of sub-G1 population. Further mechanistic analysis revealed that PMS enhanced the polymerization of microtubules, which was followed by G2/M mitotic arrest and caspase-dependent apoptosis. The activation of caspases-3, -7, -8, and -9 was involved in PMS-induced apoptosis with concomitant down-regulation of the pro-survival PI3K/Akt signaling. Collectively, these data suggest that PMS is a potent inducer of apoptosis via targeting microtubules and may merit investigation as a potential chemoprophylactic and therapeutic agent for colon cancer.