A Potent Derivative of Indolizino[6,7-b]Indole for Treatment of Human Non-Small Cell Lung Cancer Cells
A Potent Derivative of Indolizino[6,7-b]Indole for Treatment of Human Non-Small Cell Lung Cancer Cells
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DOI：
10.1016/j.neo.2016.02.005
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发表时间：
2016-04-01
期刊：
影响因子：
4.8
通讯作者：
Lee, Te-Chang
中科院分区：
文献类型：
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作者：
Chen, Chi-Wei;Wu, Ming-Hsi;Lee, Te-Chang
非小细胞肺癌（NSCLC）患者的治疗效果有限，因为内在和获得性耐药。因此，对于开发新药以改善NSCLC患者的治疗功效存在未满足的需求。本研究选择新型小分子中氮茚并[6，7-B]吲哚衍生物BO-1978，评价其对NSCLC的治疗作用及其在动物模型中的临床前毒性。体外细胞毒性试验显示，BO-1978显著抑制了表皮生长因子受体（EGFR）突变或未突变的各种NSCLC细胞系的生长。在机制上，我们证明BO-1978表现出多种作用模式，包括抑制拓扑异构酶I/II和诱导DNA交联。用BO-1978处理NSCLC细胞引起DNA损伤，扰乱细胞周期进程，并引发凋亡性细胞死亡。此外，BO-1978在异种移植肿瘤和原位肺肿瘤模型中显著抑制EGFR野生型和突变型NSCLC肿瘤的生长，体重减轻可忽略不计。BO-1978与吉非替尼的组合在异种移植肿瘤和原位肺肿瘤模型中进一步抑制EGFR突变体NSCLC细胞生长。临床前毒性研究表明，BO-1978给药在小鼠中未引起明显毒性。BO-1978具有显著的疗效和较低的药物毒性，是一种潜在的治疗NSCLC的药物。
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.