Department of Physiology, Medical School, Research Institute for Endocrine Sciences, Chonbuk National University, JeonJu, 561-180, Republic of Korea.
Mol Biol Rep. 2012 Apr;39(4):4311-8. doi: 10.1007/s11033-011-1218-z. Epub 2011 Jul 22.
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.
三氧化二砷（ATO；As(2)O(3)）可诱导多种癌细胞包括肺癌细胞发生凋亡性细胞死亡。然而，ATO 对正常原代肺细胞的毒理学作用知之甚少。在这项研究中，我们研究了 ATO 对人肺成纤维细胞（HPF）的细胞效应，涉及细胞生长抑制和死亡。ATO 在 24 小时时以约 30-40μM 的 IC50 抑制 HPF 细胞生长，并诱导伴有线粒体膜电位（MMP；ΔΨ(m)）丧失的细胞死亡。因此，HPF 细胞被认为对 ATO 刺激非常有抗性。ATO 增加了 p53 蛋白的表达并降低了 Bcl-2 蛋白的表达。该试剂在 HPF 细胞中激活了 caspase-8，但没有激活 caspase-3。Z-VAD（一种广谱半胱天冬酶抑制剂；15μM）对 ATO 引起的细胞生长抑制、死亡和 MMP（ΔΨ(m)）丧失没有显著影响。此外，Bax 或 caspase-8 siRNA 的给药减轻了 ATO 诱导的 HPF 细胞死亡，而 p53 或 caspase-3 siRNA 则不影响细胞死亡。总之，HPF 细胞对 ATO 有抗性，较高剂量的 ATO 通过调节 Bcl-2 家族和 caspase-8 诱导 HPF 细胞的生长抑制和死亡。
