2,3′,4,4′,5′-Pentamethoxy-trans-stilbene, a resveratrol derivative, is a potent inducer of apoptosis in colon cancer cells via targeting microtubules |
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Authors: | Haitao Li Zongping Zheng Le Yu Ya Chun Wu Jun Yu Chi Hin Cho Mingfu Wang |
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Institution: | a School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong, China b School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China c Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China d School of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong, China e Institute of Digestive Diseases, The Chinese University of Hong Kong, Hong Kong, China |
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Abstract: | 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. |
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Keywords: | PI3K phosphatidylinositol 3-kinase Akt protein kinase B MAPK mitogen-activated protein kinase Erk extracellular signal-regulated kinase p38 p38 mitogen-activated protein kinases JNK c-Jun amino-terminal kinase U0126 1 4-diamino-2 3-dicyano-1 4-bis(o-aminophenylmercapto)butadiene ethanolate SB203580 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole SP600125 1 9-pyrazoloanthrone anthrapyrazolone |
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