title: MT-4 suppresses resistant ovarian cancer growth through targeting tubulin and HSP27.
abstract: OBJECTIVE
  In this study, the anticancer mechanisms of MT-4 were examined in A2780 and multidrug-resistant NCI-ADR/res human ovarian cancer cell lines.
  
  
  METHODS
  To evaluate the activity of MT-4, we performed in vitro cell viability and cell cycle assays and in vivo xenograft assays. Immunoblotting analysis was carried out to evaluate the effect of MT-4 on ovarian cancer. Tubulin polymerization was determined using a tubulin binding assay.
  
  
  RESULTS
  MT-4 (2-Methoxy-5-[2-(3,4,5-trimethoxy-phenyl)-ethyl]-phenol), a derivative of moscatilin, can inhibit both sensitive A2780 and multidrug-resistant NCI-ADR/res cell growth and viability. MT-4 inhibited tubulin polymerization to induce G2/M arrest followed by caspase-mediated apoptosis. Further studies indicated that MT-4 is not a substrate of P-glycoprotein (p-gp). MT-4 also caused G2/M cell cycle arrest, accompanied by the upregulation of cyclin B, p-Thr161 Cdc2/p34, polo-like kinase 1 (PLK1), Aurora kinase B, and phospho-Ser10-histone H3 protein levels. In addition, we found that p38 MAPK pathway activation was involved in MT-4-induced apoptosis. Most importantly, MT-4 also decreased heat shock protein 27 expression and reduced its interaction with caspase-3, which inured cancer cells to chemotherapy resistance. Treatment of cells with SB203580 or overexpression of dominant negative (DN)-p38 or wild-type HSP27 reduced PARP cleavage caused by MT-4. MT-4 induced apoptosis through regulation of p38 and HSP27. Our xenograft models also show the in vivo efficacy of MT-4. MT-4 inhibited both A2780 and NCI-ADR/res cell growth in vitro and in vivo.
  
  
  CONCLUSIONS
  These findings indicate that MT-4 could be a potential lead compound for the treatment of multidrug-resistant ovarian cancer.
authors: Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Hui Chen
authors: HC
authors: Pai
authors: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
authors: Sunil
authors: S
authors: Kumar
authors: National Research Institute of Chinese Medicine, Taipei, Taiwan.
authors: Chien-Chang
authors: CC
authors: Shen
authors: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
authors: Jing Ping
authors: JP
authors: Liou
authors: Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei, Taiwan.
authors: Shiow Lin
authors: SL
authors: Pan
authors: Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Che Ming
authors: CM
authors: Teng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D064107:Aurora Kinase B / Q000235:genetics / Q000378:metabolism; D001593:Benzyl Compounds / Q000494:pharmacology*; D016203:CDC2 Protein Kinase; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D055551:HSP27 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D018832:Molecular Chaperones; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D014404:Tubulin / Q000235:genetics* / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D064107:Aurora Kinase B; D001593:Benzyl Compounds; D016203:CDC2 Protein Kinase; D053148:Caspase 3; D018797:Cell Cycle Proteins; D019926:Cyclin B; D018844:Cyclin-Dependent Kinases; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D006657:Histones; D007093:Imidazoles; D018832:Molecular Chaperones; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D014404:Tubulin; D050257:Tubulin Modulators; D048051:p38 Mitogen-Activated Protein Kinases; D000097869:Polo-Like Kinase 1; C057725:HSPB1 protein, human; C071845:dendrophenol; C576921:AURKB protein, human; C528899:CDK1 protein, human; C093642:SB 203580