title: Arsenic trioxide induces human pulmonary fibroblast cell death via the regulation of Bcl-2 family and caspase-8.
abstract: Arsenic trioxide (ATO; As(2)O(3)) can induce apoptotic cell death in various cancer cells including lung cancer cells. However, little is known about the toxicological effects of ATO on normal primary lung cells. In this study, we investigated the cellular effects of ATO on human pulmonary fibroblast (HPF) cells in relation to cell growth inhibition and death. ATO inhibited HPF cell growth with an IC(50) of approximately 30-40 μM at 24 h and induced cell death accompanied by the loss of mitochondrial membrane potential (MMP; ΔΨ(m)). Thus, HPF cells were considered to be very resistant to ATO insults. ATO increased the expression of p53 protein and decreased that of Bcl-2 protein. This agent activated caspase-8 but not caspase-3 in HPF cells. Z-VAD (a pan-caspase inhibitor; 15 μM) did not significantly decrease cell growth inhibition, death and MMP (ΔΨ(m)) loss by ATO. Moreover, administration of Bax or casase-8 siRNA attenuated HPF cell death by ATO whereas p53 or caspase-3 siRNAs did not affect cell death. In conclusion, HPF cells were resistant to ATO and higher doses of ATO induced the growth inhibition and death in HPF cells via the regulation of Bcl-2 family and caspase-8.
authors.affiliation: Department of Physiology, Medical School, Research Institute for Endocrine Sciences, Chonbuk National University, JeonJu, 561-180, Republic of Korea. parkwh71@chonbuk.ac.kr
authors.forename: Woo Hyun
authors.initials: WH
authors.lastname: Park
authors.forename: Suhn Hee
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D053181:Caspase 8 / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D006801:Humans; D008168:Lung / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology; D010087:Oxides / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D001152:Arsenicals; D009842:Oligopeptides; D010087:Oxides; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; C517629:benzyloxycarbonyl-valyl-alanyl-aspartic acid; C505530:CASP8 protein, human; D053181:Caspase 8; D000077237:Arsenic Trioxide