期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 54, 期 11, 页码 3768-3778出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm200017g
关键词
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资金
- National Natural Science Foundation of China [20802054, 30872308, 30901819]
- Zhejiang Department of Health [2009QN020]
- Wenzhou Science and Technology Bureau [Y20090009, Y20100006]
- Zhejiang Natural Science Fund [Y2090358, Y2090680, Y2090668, Y4090261]
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.
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