title: 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 signaling pathway.
abstract: 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.
authors.affiliation: Wenzhou Medical College, Wenzhou 325035, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Jian
authors.initials: J
authors.lastname: Xiao
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhou
authors.forename: Shulin
authors.initials: S
authors.lastname: Yang
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wu
authors.forename: Chengxi
authors.initials: C
authors.lastname: Jiang
authors.forename: Yunjie
authors.initials: Y
authors.lastname: Zhao
authors.forename: Donglou
authors.initials: D
authors.lastname: Liang
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Li
authors.forename: Guang
authors.initials: G
authors.lastname: Liang
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy; D000077192:Adenocarcinoma of Lung; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003474:Curcumin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D018384:Oxidative Stress; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C560296:1,5-bis(2,3-dimethoxyphenyl)penta-1,4-dien-3-one; D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D051742:Transcription Factor CHOP; D020169:Caspases; D003474:Curcumin