A Potent Derivative of Indolizino[6,7-b]Indole for Treatment of Human Non-Small Cell Lung Cancer Cells

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• 作者：Chi-Wei Chen^* ; ^&dagger ; ; Ming-Hsi Wu^&dagger ; ; Yi-Fan Chen^* ; ^&dagger ; ; Tsai-Yi Yen^&Dagger ; ; Yi-Wen Lin^&dagger ; ; Shu-Hsin Chao^&dagger ; ; Satishkumar Tala^&dagger ; ; ³ ; Tung-Hu Tsai^c ; Tsann-Long Su^&dagger ; ; Te-Chang Lee^* ; ^&dagger ; ; ^§ ; ; ^{bmtcl@ibms.sinica.edu.tw" class="auth_mail" title="E-mail the corresponding author}
• 关键词：EGFR ; epidermal growth factor receptor ; ICLs ; interstrand DNA cross-links ; MDR ; multiple drug resistance ; NSCLC ; Non-small cell lung cancer ; TKIs ; tyrosine kinase inhibitors ; Topo ; topoisomerase
• 刊名：Neoplasia
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：18
• 期：4
• 页码：199-212
• 全文大小：2562 K

文摘

The therapeutic effect in non–small cell lung cancer (NSCLC) patients is limited because of intrinsic and acquired resistance. Thus, an unmet need exists for the development of new drugs to improve the therapeutic efficacy in NSCLC patients. In this study, the novel small molecule indolizino[6,7-b]indole derivative BO-1978 was selected to evaluate its therapeutic effects on NSCLC and its preclinical toxicity in animal models. An in vitro cytotoxicity assay revealed that BO-1978 significantly suppressed the growth of various NSCLC cell lines with or without mutations in epidermal growth factor receptor (EGFR). Mechanistically, we demonstrated that BO-1978 exhibited multiple modes of action, including inhibition of topoisomerase I/II and induction of DNA cross-linking. Treatment of NSCLC cells with BO-1978 caused DNA damage, disturbed cell cycle progression, and triggered apoptotic cell death. Furthermore, BO-1978 significantly suppressed the growth of EGFR wild-type and mutant NSCLC tumors in xenograft tumor and orthotopic lung tumor models with negligible body weight loss. The combination of BO-1978 with gefitinib further suppressed EGFR mutant NSCLC cell growth in xenograft tumor and orthotopic lung tumor models. Preclinical toxicity studies showed that BO-1978 administration did not cause apparent toxicity in mice. Based on its significant therapeutic efficacy and low drug toxicity, BO-1978 is a potential therapeutic agent for treatment of NSCLC.