ABSTRACT
Gefitinib is the first targeted drug approved for non-small cell lung cancer (NSCLC) treatment. Clinical trails showed that patients with certain clinical and histologic characteristics (such as women, patients of East Asian descent, no history of smoking, and adenocarcinoma) had higher rates of response and overall survival. Despite excellent clinical response to gefitinib in certain NSCLC patients, nearly all patients who respond initially to gefitinib later develop drug resistance. Isothiocyanates have been shown to possess antitumor activity, inhibiting several types of cancer cells growth. However, there are limited studies on their effects on chemoresistance of cancer cells. In this report, we found that benzyl isothiocyanate (BITC) inhibited gefitinib-resistant human NSCLC cells growth by inducing apoptosis in a dose-dependent manner, and activated caspase-3. There were no effects of BITC on epidermal growth factor receptor and multidrug resistant proteins expression. BITC caused cell cycle arrest at G2/M phase, reactive oxygen species generation, and glutathione depletion. Akt activity and NFκB transcriptional activation were suppressed; mitogen-activated protein kinase and activator protein 1 (AP-1) were activated. Our results demonstrated that BITC overcame gefitinib resistance in lung cancer cells. The further understanding of the anti-resistance mechanism of BITC would contribute to establish it as a potent lead compound for the synthesis of novel anticancer drugs.
Subject(s)
Apoptosis , Carcinoma, Non-Small-Cell Lung/pathology , Drug Resistance, Neoplasm , Isothiocyanates/pharmacology , MAP Kinase Signaling System , Quinazolines/pharmacology , Antineoplastic Agents/pharmacology , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Line, Tumor , Enzyme Activation , G2 Phase Cell Cycle Checkpoints , Gefitinib , Gene Expression Regulation, Neoplastic , Glutathione/metabolism , Humans , NF-kappa B/genetics , NF-kappa B/metabolism , Phosphorylation , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Reactive Oxygen Species/metabolism , Transcription Factor AP-1/genetics , Transcription Factor AP-1/metabolism , Transcriptional ActivationABSTRACT
AIM: To investigate the relationship between glutathione S-transferases gene polymorphism and susceptibility response to hypoxia. METHODS: In the case-control study, the gene polymorphisms of glutathione S-transferases were tested in Tibetan mountaineers and sea-level Han Chinese by multiple-PCR and PCR-RELP. RESULTS: The frequency of GSTT1 null genotype was significant different between Tibetan mountaineers and sea-level Han Chinese (P < 0.05), OR = 1.86 (95% CI = 1.01-3.39), and also for GSTP(1-105) mutant genotype in two groups (P < 0.01), OR = 2.19 (95% CI = 1.16-4.13). There was significant difference between A allele and G allele of GSTP(1-105) groups (P < 0.01). There was no difference for GSTM1 null genotype between two groups (P > 0.05), OR = 0.78 (95% CI = 0.43 - 1.42). CONCLUSION: GSTT1 and GSTP(1-105) genotype may be associated with susceptibility response to altitude hypoxia.
