title: Potential antitumor agent from the endophytic fungus Pestalotiopsis photiniae induces apoptosis via the mitochondrial pathway in HeLa cells.
abstract: 4-(3',3'-Dimethylallyloxy)-5-methyl-6-methoxy-phthalide (DMMP) has previously been isolated from the endophytic fungus Pestalotiopsis photiniae. Although the cytotoxic activities of DMMP have been reported, little is known concerning the molecular mechanism of its cytotoxic effect. In the present study, we investigated the effect of DMMP on the growth of several types of cancer cell lines and investigated the mechanism of its antiproliferative effect. DMMP caused the growth inhibition of human cancer lines HeLa, MCF7 and MDA-MB-231, but had little antiproliferative effect on MRC5 normal lung cells. DMMP also significantly caused cell cycle arrest in the G1 phase and upregulated the cyclin-dependent kinase inhibitor p27KIPI protein in the HeLa cells. Moreover DMMP was able to induce marked nuclear apoptotic morphology in HeLa cells. DMMP induced apoptosis and loss of mitochondrial membrane potential (ΔΨm) in the HeLa cells. Although the activated forms of caspase-9 and -3 in HeLa cells were detected, pretreatment with caspase inhibitors (Ac-DEVD-CHO and Z-VAD-FMK) failed to attenuate DMMP-induced cell death. In addition, protein levels of the p53 family members, p53 and p73, were upregulated, and DMMP significantly increased the mRNA expression of pro-apoptotic Bcl-2 family genes (PUMA, NOXA, Bax, Bad and Bim). HPV E6-E7 mRNA levels were reduced. In conclusion, DMMP demonstrates potential for use in the treatment of cervical cancer.
authors.affiliation: College of Life Science, Hebei University, Baoding, Hebei 071002, P.R. China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Chen
authors.forename: Shu-Yuan
authors.initials: SY
authors.lastname: Hu
authors.forename: Du-Qiang
authors.initials: DQ
authors.lastname: Luo
authors.forename: Si-Yu
authors.initials: SY
authors.lastname: Zhu
authors.forename: Chuan-Qi
authors.initials: CQ
authors.lastname: Zhou
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D000072224:Bcl-2-Like Protein 11; D001572:Benzofurans / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008565:Membrane Proteins / Q000096:biosynthesis; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009687:Nuclear Proteins / Q000096:biosynthesis; D009842:Oligopeptides / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis; D015854:Up-Regulation; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy*; D013098:Xylariales / Q000166:cytology*; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis; D051025:bcl-Associated Death Protein / Q000096:biosynthesis
chemical_list: C588066:4-(3',3'-dimethylallyloxy)-5-methyl-6-methoxyphthalide; D000590:Amino Acid Chloromethyl Ketones; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C494819:BAD protein, human; C438378:BBC3 protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D001572:Benzofurans; C436291:CDKN1B protein, human; D061945:Caspase Inhibitors; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D009842:Oligopeptides; C498702:PMAIP1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D050760:Cyclin-Dependent Kinase Inhibitor p27; D053148:Caspase 3; D053453:Caspase 9