Huang Jian, Wang Haibo, Song Zhuqin, Lin Xueping, Zhang Chengwen
Department of Biochemistry and Molecular Cell Biology, Institute of Medical Science, Shanghai Jiaotong University School of Medicine, Shanghai, China.
J Chemother. 2011 Aug;23(4):221-6. doi: 10.1179/joc.2011.23.4.221.
Dexamethasone (DEX) has been frequently used as a co-medication in cytotoxic cancer therapy, mostly for supportive care in alleviating the acute toxic effects on healthy tissues. Although recent studies have demonstrated DeXinduced resistance to cytotoxic treatment in several solid tumors, no specific molecular mechanism of action has been reported. Here, we assessed the effect of DEX on the cisplatin-induced cytotoxicity in fresh surgically resected specimens from Chinese patients with lung cancer. We also examined the effects of DEX and cisplatin on the apoptotic signaling pathway in the well-established human lung adenocarcinoma cell line A549. Our results show that DEX treatment inhibits cisplatin-induced cell apoptosis by up-regulation of cellular mitogen-activated protein kinase phosphatase-1 (MKP-1) and subsequent deactivation of p38 protein kinase. Knock down of MKP-1 by RNA interference reversed the DEX-induced inhibition of cisplatininduced cell apoptosis. These data suggest that administration of DEX during the clinical therapy of Chinese lung cancer patients must be carefully considered, and indicate that MKP-1 and p38 protein kinase are potential targets for DEX-induced drug resistance.
地塞米松（DEX）经常在细胞毒性癌症治疗中作为辅助用药，主要用于支持性治疗，以减轻对健康组织的急性毒性作用。尽管最近的研究表明DEX在几种实体瘤中会诱导对细胞毒性治疗产生耐药性，但尚未报道具体的分子作用机制。在此，我们评估了DEX对中国肺癌患者手术切除新鲜标本中顺铂诱导的细胞毒性的影响。我们还研究了DEX和顺铂对成熟的人肺腺癌细胞系A549凋亡信号通路的影响。我们的结果表明，DEX处理通过上调细胞丝裂原活化蛋白激酶磷酸酶-1（MKP-1）并随后使p38蛋白激酶失活来抑制顺铂诱导的细胞凋亡。通过RNA干扰敲低MKP-1可逆转DEX诱导的对顺铂诱导的细胞凋亡的抑制作用。这些数据表明，在中国肺癌患者的临床治疗期间，必须谨慎考虑使用DEX，并表明MKP-1和p38蛋白激酶是DEX诱导耐药性的潜在靶点。
