https://scholars.lib.ntu.edu.tw/handle/123456789/383594
標題: | 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 | 作者: | CHE-MING TENG | 關鍵字: | apoptosis; Mcl-1; mitosis arrest; MPT0B014; NSCLC; P-gp | 公開日期: | 2014 | 卷: | 171 | 期: | 1 | 起(迄)頁: | 122-133 | 來源出版物: | British Journal of Pharmacology | 摘要: | Background and Purpose 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). Experimental Approach 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. Key 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 and Implications 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. ? 2013 The British Pharmacological Society. |
URI: | http://www.scopus.com/inward/record.url?eid=2-s2.0-84890288898&partnerID=MN8TOARS http://scholars.lib.ntu.edu.tw/handle/123456789/383594 |
DOI: | 10.1111/bph.12427 | SDG/關鍵字: | 3 (4,5 dimethyl 2 thiazolyl) 2,5 diphenyltetrazolium bromide; aurora A kinase; aurora B kinase; calcein; caspase 3; caspase 7; caspase 8; caspase 9; cell cycle protein; cyclin B1; doxorubicin; erlotinib; mpt0b014; multidrug resistance protein; paclitaxel; protein mcl 1; protein tyrosine phosphatase; quinoline derivative; rhodamine 123; sulforhodamine B; threonine; tyrosine; unclassified drug; vincristine; animal experiment; animal model; antineoplastic activity; apoptosis; article; cancer cell culture; cancer inhibition; cell cycle phase; cell proliferation; chemosensitivity; controlled study; down regulation; drug cytotoxicity; drug potency; drug potentiation; drug structure; flow cytometry; fluorescence activated cell sorting; G2 phase cell cycle checkpoint; gene overexpression; human; human cell; in vitro study; in vivo study; inhibition kinetics; lung non small cell cancer; mouse; nonhuman; priority journal; protein expression; tumor xenograft; upregulation; Western blotting; apoptosis; Mcl-1; mitosis arrest; MPT0B014; NSCLC; P-gp; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Aurora Kinase A; Aurora Kinase B; Carcinoma, Non-Small-Cell Lung; Caspases; cdc25 Phosphatases; Cell Line, Tumor; Cell Proliferation; Cyclin B; Cyclin B1; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; G2 Phase Cell Cycle Checkpoints; Humans; Lung Neoplasms; Male; Mice; Mice, Nude; Microtubules; Myeloid Cell Leukemia Sequence 1 Protein; P-Glycoprotein; Phosphorylation; Quinazolines; Quinolines; RNA Interference; Time Factors; Transfection; Tumor Burden; Xenograft Model Antitumor Assays |
顯示於: | 醫學系 |
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