Characterization of molecular events in a series of bladder urothelial carcinoma cell lines with progressive resistance to arsenic trioxide.
Our previous studies have shown that arsenic trioxide (As2O3), a novel anti-cancer agent, may be active against urothelial carcinomas. A series of bladder urothelial carcinoma cells with progressive As2O3 resistance were established and studied to reveal molecular events in relation to the mechanisms of resistance to As2O3. A sensitive parental line (NTUB1) and three As2O3-resistant sublines (NTUB1/As) were used with their IC50s being 0.9, 1.2, 2.5 and 4.9 microM, respectively. Cellular resistance to As2O3 was associated with a lowered proliferation profile (increased p53 and p21Waf1/Cip1 and decreased c-Myc levels) and a greater resistance to apoptosis (elevated Bcl-2 levels). Cells with a stronger resistance had higher expressions of superoxide dismutase (Cu/Zn) and hMSH2 (but not hMLH1). GSH contents were up-regulated in resistant cells in a dose-dependent manner. The DNA-binding activities of NF-kappaB and AP-1 were down-regulated in resistant cells in a dose-dependent manner. Profound molecular alterations occur during the acquisition of secondary As2O3 resistance. Our in vitro cellular model may help to reveal resistance mechanisms to As2O3 in bladder urothelial carcinoma cells.
Hour
Tzyh-Chyuan
TC
Institute of Biochemistry, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC.
Huang
Chao-Yuan
CY
Lin
Chia-Chi
CC
Chen
Jun
J
Guan
Jing-Yi
JY
Lee
Jen-Mei
JM
Pu
Yeong-Shiau
YS
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000235:genetics; D004353:Drug Evaluation, Preclinical / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D005544:Forecasting; D005978:Glutathione / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D051718:MutS Homolog 2 Protein; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000473:pathology*; D019459:Urothelium / Q000473:pathology*
D001152:Arsenicals; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; C116115:MYCBP protein, human; D016328:NF-kappa B; D010087:Oxides; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D013482:Superoxide Dismutase; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein; D005978:Glutathione; D000077237:Arsenic Trioxide