A Novel Monocarbonyl Analogue of Curcumin, (1E,4E)-1,5-Bis(2,3-dimethoxyphenyl)penta-1,4-dien-3-one, Induced Cancer Cell H460 Apoptosis via Activation of Endoplasmic Reticulum Stress Sig

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• 作者：Yi Wang ; Jian Xiao ; Huiping Zhou ; Shulin Yang ; Xiaoping Wu ; Chengxi Jiang ; Yunjie Zhao ; Donglou Liang ; Xiaokun Li ; Guang Liang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：June 9, 2011
• 年：2011
• 卷：54
• 期：11
• 页码：3768-3778
• 全文大小：1362K
• 年卷期：v.54,no.11(June 9, 2011)
• ISSN：1520-4804

文摘

Endoplasmic reticulum (ER) stress-induced cancer cell apoptosis has become a novel signaling target for development of cancer therapeutic drugs. Curcumin exhibits growth-suppressive activity against a variety of cancer cells. We previously synthesized a series of monocarbonyl analogues of curcumin with strong cytotoxicity against tumor cells. In this study, we found that only compound 19 [(1E,4E)-1,5-bis(2,3-dimethoxyphenyl)penta-1,4-dien-3-one] can induce C/EBP-homologous protein (CHOP) expression in human lung cancer H460 cells. Treatment with 19 induced H460 cell apoptosis in a dose-responsive manner, and this effect was associated with corresponding increases in a series of key components in ER stress-mediated apoptosis pathway, followed by caspase cleavage and activation. However, curcumin at the same concentrations does not display such properties. CHOP knockdown by specific siRNA attenuated 19-induced cell apoptosis, further indicating that the apoptotic pathway is ER stress-dependent. In vivo, 19 showed a dramatic 53.5% reduction in H460 xenograft tumor size after 22 days of treatment. Taken together, these mechanistic insights on the novel compound 19, with nontoxicity, may provide us with a novel anticancer candidate.