title: Apoptosis induced by benzyl isothiocyanate in gefitinib-resistant lung cancer cells is associated with Akt/MAPK pathways and generation of reactive oxygen species.
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.
authors.affiliation: Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China.
authors.forename: Bo-Ning
authors.initials: BN
authors.lastname: Liu
authors.forename: Hui-Qin
authors.initials: HQ
authors.lastname: Yan
authors.forename: Xiang
authors.initials: X
authors.lastname: Wu
authors.forename: Zhen-Hua
authors.initials: ZH
authors.lastname: Pan
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhu
authors.forename: Zhao-Wei
authors.initials: ZW
authors.lastname: Meng
authors.forename: Qing-Hua
authors.initials: QH
authors.lastname: Zhou
authors.forename: Ke
authors.initials: K
authors.lastname: Xu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D059565:G2 Phase Cell Cycle Checkpoints; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D000970:Antineoplastic Agents; D017879:Isothiocyanates; D016328:NF-kappa B; D011799:Quinazolines; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; C031403:benzyl isothiocyanate; D051057:Proto-Oncogene Proteins c-akt; D005978:Glutathione; D000077156:Gefitinib