title: In vitro and in vivo anti-tumour effects of MPT0B014, a novel derivative aroylquinoline, and in combination with erlotinib in human non-small-cell lung cancer cells.
abstract: OBJECTIVE
  The purpose of the current study was to assess a novel anti-cancer drug, MPT0B014, which is not a substrate for the P-glycoprotein (P-gp) transporter, alone and in combination with erlotinib, against human non-small cell lung cancer (NSCLC).
  
  
  METHODS
  Cytotoxicity in human NSCLC cell lines was assessed by sulforhodamine B and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Cell cycle phase distributions were estimated with FACScan flow cytometry. Protein expression was detected by Western blotting analysis. Efflux of rhodamine 123 or calcein-acetoxymethylester was used to study the P-gp profile. The A549 xenograft model in mice was used to assess in vivo anti-tumour activity.
  
  
  RESULTS
  MPT0B014 showed potent anti-proliferative activity against A549, H1299 and H226 cells. It induced G2/M arrest with down-regulation of Cdc (Tyr15) and Cdc25C, and up-regulation of cyclin B1, phospho-Cdc2 (Thr161) and Aurora A/B. P-gp-overexpressing National Cancer Institute/Adriamycin-Resistant cells were also sensitive to B014. B014-induced loss of Mcl-1 was accompanied by activation of caspases-3, -7, -8 and -9, and initiation of apoptosis. B014 in combination with erlotinib caused significant tumour inhibition in vitro and in vivo.
  
  
  CONCLUSIONS
  MPT0B014 exerted cytotoxicity against human NSCLC cell lines with little susceptibility to P-gp. Combined with the EGF receptor inhibitor, erlotinib, MPT0B014 exerted significant growth inhibition of A549 cells both in vitro and in vivo. B014 could be useful as an anti-cancer agent.
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
authors.forename: An-Chi
authors.initials: AC
authors.lastname: Tsai
authors.forename: Hui-Chen
authors.initials: HC
authors.lastname: Pai
authors.forename: Chih-Ya
authors.initials: CY
authors.lastname: Wang
authors.forename: Jing-Ping
authors.initials: JP
authors.lastname: Liou
authors.forename: Che-Ming
authors.initials: CM
authors.lastname: Teng
authors.forename: Jing-Chi
authors.initials: JC
authors.lastname: Wang
authors.forename: Shiow-Lin
authors.initials: SL
authors.lastname: Pan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D064096:Aurora Kinase A / Q000378:metabolism; D064107:Aurora Kinase B / Q000378:metabolism; D016203:CDC2 Protein Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D000069347:Erlotinib Hydrochloride; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011799:Quinazolines / Q000008:administration & dosage; D011804:Quinolines / Q000008:administration & dosage; D034622:RNA Interference; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D020687:cdc25 Phosphatases / Q000378:metabolism
chemical_list: C000590772:6-(3',4',5'-trimethoxybenzoyl)quinoline; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C534699:CCNB1 protein, human; D019926:Cyclin B; D056744:Cyclin B1; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011799:Quinazolines; D011804:Quinolines; D000069347:Erlotinib Hydrochloride; C576917:AURKA protein, human; C576921:AURKB protein, human; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases; D020169:Caspases
keywords: MPT0B014; Mcl-1; NSCLC; P-gp; apoptosis; mitosis arrest