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Apoptosis Induced by Benzyl Isothiocyanate in Gefitinib-Resistant Lung Cancer Cells is Associated with Akt/MAPK Pathways and Generation of Reactive Oxygen Species

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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 gefinitib 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.

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Authors and Affiliations

  1. Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China

    Bo-Ning Liu, Hui-Qin Yan, Zhen-Hua Pan, Yu Zhu, Qing-Hua Zhou & Ke Xu

  2. Core Facility Center, Tianjin Medical University General Hospital, Tianjin, 300052, China

    Xiang Wu

  3. Department of Nuclear Medicine, Tianjin Medical University General Hospital, Tianjin, 300052, China

    Zhao-Wei Meng

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  1. Bo-Ning Liu
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  2. Hui-Qin Yan
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  4. Zhen-Hua Pan
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Correspondence to Ke Xu.

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Liu, BN., Yan, HQ., Wu, X. et al. Apoptosis Induced by Benzyl Isothiocyanate in Gefitinib-Resistant Lung Cancer Cells is Associated with Akt/MAPK Pathways and Generation of Reactive Oxygen Species. Cell Biochem Biophys 66, 81–92 (2013). https://doi.org/10.1007/s12013-012-9456-9

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