title: SKLB-M8 induces apoptosis through the AKT/mTOR signaling pathway in melanoma models and inhibits angiogenesis with decrease of ERK1/2 phosphorylation.
abstract: SKLB-M8, a derivative of millepachine, showed significant anti-proliferative effects in melanoma cell lines. In this study, we investigated the anti-melanoma and anti-angiogenic activity of SKLB-M8 on three melanoma cell lines (A2058, CHL-1, and B16F10) and human umbilical vein endothelial cells (HUVECs). In vitro, SKLB-M8 showed anti-proliferative activity with IC50 values of 0.07, 0.25, and 0.88 μM in A2058, CHL-1, and B16F10 cell lines, respectively. Flow cytometory analysis showed that SKLB-M8 induced G2/M arrest in three melanoma cell lines, and western blotting demonstrated that SKLB-M8 down-regulated the expression of cdc2, up-regulated p53 in A2058 and CHL-1 cells, and triggered cell apoptosis through down-regulating AKT and phosphorylated mTOR (p-mTOR). SKLB-M8 also inhibited HUVEC proliferation, migration, invasion, and tube formation in vitro with the inhibition of phosphorylated ERK1/2 (p-ERK1/2). In vivo, alginate-encapsulated tumor cell assay revealed that SKLB-M8 suppressed B16F10 tumor angiogenesis. In CHL-1- and B16F10-tumor-bearing mouse models, SKLB-M8 inhibited tumor growth by oral treatment with less toxicity. CD31 immunofluoresence staining and caspase-3 immunohistochemistry indicated that SKLB-M8 inhibited melanoma tumor growth by targeting angiogenesis and inducing caspase3-dependent apoptosis. SKLB-M8 might be a potential anti-melanoma drug candidate.
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wang
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Yang
authors.forename: Jiaolin
authors.initials: J
authors.lastname: Wen
authors.forename: Feng
authors.initials: F
authors.lastname: Ma
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Kun
authors.initials: K
authors.lastname: Yu
authors.forename: Minghai
authors.initials: M
authors.lastname: Tang
authors.forename: Wenshuang
authors.initials: W
authors.lastname: Wu
authors.forename: Yinfeng
authors.initials: Y
authors.lastname: Dong
authors.forename: Xia
authors.initials: X
authors.lastname: Cheng
authors.forename: Chunlai
authors.initials: C
authors.lastname: Nie
authors.forename: Lijuan
authors.initials: L
authors.lastname: Chen
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047188:Chalcones / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C000602091:3-(3-amino-4-methoxyphenyl)-1-(5-methoxy-2,2-dimethyl-2H-chromen- 8-yl)prop-2-en-1-one; D020533:Angiogenesis Inhibitors; D047188:Chalcones; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3