title: A synthetic compound, 1,5-bis(2-methoxyphenyl)penta-1,4-dien-3-one (B63), induces apoptosis and activates endoplasmic reticulum stress in non-small cell lung cancer cells.
abstract: Endoplasmic reticulum (ER) stress-induced cancer cell apoptosis has become a novel signaling target for the development of therapeutic drugs for cancer treatment. Curcumin, a dietary phytochemical, exhibits growth-suppressive activity against cancer cells via multitarget mechanisms. However, the low stability and poor pharmacokinetics significantly limit its clinical applications. Thus, we designed and synthesized a novel monocarbonyl analog of curcumin, 1,5-bis(2-methoxyphenyl) penta-1,4-dien-3-one (B63). This compound exhibited a higher chemical stability in cultural medium and a better intracellular profile than curcumin. Treatment with B63 potently induced apoptosis of human non-small cell lung cancer (NSCLC) cells in a dose-responsive manner, while exhibiting no cytotoxicity in normal lung fibroblast cells. Its antitumor effect was associated with the ER stress-mediated apoptotic pathway and, ultimately, the activation of the caspase cascades. However, curcumin at the same concentrations did not cause ER stress in H460 cells. Further, C/EBP homologous protein knockdown by siRNA attenuated B63-induced cell apoptosis, indicating that the apoptotic pathway is ER stress-dependent. In vivo, the volume and weight of the tumor were reduced significantly by pretreating the H460 tumor cells with B63 before implantation. Taken together, these insights on the novel compound B63, from both chemical and biological perspectives, may provide a novel anticancer candidate for the treatment of NSCLC.
authors.affiliation: Bioorganic & Medicinal Chemistry Research Center, Zhejiang Key Laboratory of Biotechnology Pharmaceutical Engineering, School of Pharmacy, Wenzhou Medical College, Wenzhou, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Xiao
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Peng
authors.forename: Lu
authors.initials: L
authors.lastname: Guo
authors.forename: Jie
authors.initials: J
authors.lastname: Hu
authors.forename: Menghua
authors.initials: M
authors.lastname: Cao
authors.forename: Xie
authors.initials: X
authors.lastname: Zhang
authors.forename: Hanqing
authors.initials: H
authors.lastname: Zhang
authors.forename: Zhouguang
authors.initials: Z
authors.lastname: Wang
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Li
authors.forename: Shulin
authors.initials: S
authors.lastname: Yang
authors.forename: Huiling
authors.initials: H
authors.lastname: Yang
authors.forename: Guang
authors.initials: G
authors.lastname: Liang
mesh_terms: D000818:Animals; D000840:Anisoles / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D003474:Curcumin / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D007659:Ketones / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C
chemical_list: C575448:1,5-bis(2-methoxyphenyl)penta-1,4-dien-3-one; D000840:Anisoles; D000970:Antineoplastic Agents; D007659:Ketones; D003474:Curcumin