title: A novel derivative of quinazoline, WYK431 induces G2/M phase arrest and apoptosis in human gastric cancer BGC823 cells through the PI3K/Akt pathway.
abstract: WYK431, a novel synthetic quinazoline derivative, showing potent inhibition of proliferation activity against a broad spectrum of human cancer cell lines. We investigated the anticancer effects of WYK431 on BGC823 cells both in vitro and in vivo. The results showed that WYK431 inhibited proliferation, arrested the cell cycle at the G(2)/M phase, which was related to CDK1 and CDC25C, and induced apoptosis associated with activation of caspase-3 and caspase-9 rather than caspase-8 in BGC823 cells. Treatment of BGC823 cells with WYK431 resulted in upregulation of Bax, release of cytochrome c from the mitochondria to the cytosol and disruption of mitochondrial membrane potential. Western blot analysis showed that WYK431 downregulated the levels of the PI3K/Akt signaling pathway. Moreover, WYK431 effectively suppressed tumor growth in xenograft models in BALB/c athymic nude mice without major side action. TUNEL analysis showed that WYK431 induced BGC823 cell apoptosis in vivo. Collectively, WYK431 is a novel small molecule agent which inhibits BGC823 cell proliferation inducing G(2)/M phase arrest and apoptosis via the mitochondrial apoptotic pathway. To assess its potential as a promising anticancer agent requires further investigation.
authors.affiliation: Department of Pharmacology, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China.
authors.forename: Tian-En
authors.initials: TE
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China.
authors.forename: Yong-Kang
authors.initials: YK
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department of Pharmacology, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China.
authors.forename: Bai-Ling
authors.initials: BL
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China.
authors.forename: Xiao-Guang
authors.initials: XG
authors.lastname: Chen
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D020287:In Situ Nick-End Labeling; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; C000594718:WYK431; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt