2,3',4,4',5'-Pentamethoxy-trans-stilbene, a resveratrol derivative, is a potent inducer of apoptosis in colon cancer cells 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-G(1) population. Further mechanistic analysis revealed that PMS enhanced the polymerization of microtubules, which was followed by G(2)/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.
Li
Haitao
H
School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong, China.
Wu
William Ka Kei
WK
Zheng
Zongping
Z
Che
Chun Tao
CT
Yu
Le
L
Li
Zhi Jie
ZJ
Wu
Ya Chun
YC
Cheng
Ka-Wing
KW
Yu
Jun
J
Cho
Chi Hin
CH
Wang
Mingfu
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002455:Cell Division; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology*; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D016195:G2 Phase; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*
C544677:2,3',4,4',5'-pentamethoxystilbene; D013267:Stilbenes; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases