Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, Iowa 52242, USA.
Cancer Res. 2011 Jun 1;71(11):3932-40. doi: 10.1158/0008-5472.CAN-10-3425. Epub 2011 Apr 11.
Redox regulation of epidermal growth factor receptor (EGFR) signaling helps protect cells against oxidative stress. In this study, we investigated whether the cytotoxicity of an EGFR tyrosine kinase inhibitor, erlotinib (ERL), was mediated by induction of oxidative stress in human head and neck cancer (HNSCC) cells. ERL elicited cytotoxicity in vitro and in vivo while increasing a panel of oxidative stress parameters which were all reversible by the antioxidant N-acetyl cysteine. Knockdown of EGFR by using siRNA similarly increased these oxidative stress parameters. Overexpression of mitochondrial targeted catalase but not superoxide dismutase reversed ERL-induced cytotoxicity. Consistent with a general role for NADPH oxidase (NOX) enzymes in ERL-induced oxidative stress, ERL-induced cytotoxicity was reversed by diphenylene iodonium, a NOX complex inhibitor. ERL reduced the expression of NOX1, NOX2, and NOX5 but induced the expression of NOX4. Knockdown of NOX4 by using siRNA protected HNSCC cells from ERL-induced cytotoxicity and oxidative stress. Our findings support the concept that ERL-induced cytotoxicity is based on a specific mechanism of oxidative stress mediated by hydrogen peroxide production through NOX4 signaling.
氧化还原调节表皮生长因子受体（EGFR）信号有助于保护细胞免受氧化应激。在这项研究中，我们研究了 EGFR 酪氨酸激酶抑制剂厄洛替尼（ERL）的细胞毒性是否通过诱导人头颈癌（HNSCC）细胞中的氧化应激来介导。ERL 在体外和体内均表现出细胞毒性，同时增加了一系列氧化应激参数，这些参数均可通过抗氧化剂 N-乙酰半胱氨酸逆转。使用 siRNA 敲低 EGFR 同样增加了这些氧化应激参数。过表达靶向线粒体的过氧化氢酶而不是超氧化物歧化酶可逆转 ERL 诱导的细胞毒性。与 NADPH 氧化酶（NOX）酶在 ERL 诱导的氧化应激中的一般作用一致，NOX 复合物抑制剂二苯碘鎓可逆转 ERL 诱导的细胞毒性。ERL 降低了 NOX1、NOX2 和 NOX5 的表达，但诱导了 NOX4 的表达。使用 siRNA 敲低 NOX4 可保护 HNSCC 细胞免受 ERL 诱导的细胞毒性和氧化应激。我们的发现支持这样一种观点，即 ERL 诱导的细胞毒性是基于通过 NOX4 信号产生过氧化氢介导的特定氧化应激机制。
