title: Induction of G2/M phase arrest and apoptosis by a new tetrahydroingenol diterpenoid from Euphorbia erythradenia Bioss. in melanoma cancer cells.
abstract: In the current study, a new tetrahydroingenol diterpene isolated from Euphorbia erythradenia, 7,13-diacetyl-5-angeloyl-20-nicotinyl-3-propionyl-1,2,6,7-tetrahydroingenol (DANPT), were tested for the molecular mechanism of its anti-cancer activity in two human melanoma cancer cell lines, A375 and HMCB. DANPT was found cytotoxic against A375 and HMCB cells with IC50 value of 15.37±2.6μM and 15.62±1.89μM, respectively. Flow cytometric analysis showed that DANPT halted the A375 and HMCB cells in G2/M phase and induced apoptosis in a dose-dependent manner. Cell cycle arrest was associated with down-regulation of cyclin B and Cdk-1 and subsequent up-regulation of p53 and p21. Moreover, DANPT induced Bax and inhibited Bcl-2 expression, which results in increasing Bax/Bcl-2 ratio and activation of caspase-3. Furthermore, the apoptotic effect of DANPT was also related to ROS production and loss of mitochondrial membrane potential (ΔYm). Overall, our results suggest that DANPT can inhibit proliferation of human melanoma cancer cells by promoting apoptosis and inducing cell cycle arrest and therefore, it can be a promising natural agent for the treatment of melanoma cancer.
authors.affiliation: Department of Clinical Biochemistry, Faculty of Medicine, Qom University of Medical Sciences, Qom, Iran; Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran.
authors.forename: Faranak
authors.initials: F
authors.lastname: Fallahian
authors.affiliation: Isfahan Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Ghanadian
authors.affiliation: Department of Clinical Biochemistry, School of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran. Electronic address: maghaei@pharm.mui.ac.ir.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Aghaei
authors.affiliation: Faculty of Pharmacy, Baqiyatollah University of Medical Sciences, Tehran, Iran.
authors.forename: Seyed Mohammad
authors.initials: SM
authors.lastname: Zarei
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004224:Diterpenes / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D028481:Euphorbia / Q000737:chemistry*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D004224:Diterpenes; D010936:Plant Extracts; D017382:Reactive Oxygen Species
keywords: Apoptosis; Cancer; Euphorbia erythradenia; Melanoma; Tetrahydroingenol