Enhanced tumor suppression by adenoviral PTEN gene therapy combined with cisplatin chemotherapy in small-cell lung cancer
Enhanced tumor suppression by adenoviral PTEN gene therapy combined with cisplatin chemotherapy in small-cell lung cancer
复制标题
腺病毒PTEN基因治疗联合顺铂化疗增强小细胞肺癌的抑瘤效果
DOI：
10.1038/cgt.2013.14
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发表时间：
2013-04-01
影响因子：
6.4
通讯作者：
Yang, J.
中科院分区：
文献类型：
--
作者：
Li, D.;Zhang, Y.;Yang, J.
破坏DNA的抗癌药物顺铂（顺式二氨二氯铂）（DDP）为基础的化疗是小细胞肺癌（SCLC）的主要和标准治疗方法。然而，SCLC的频繁复发和化疗耐药性仍然是一个重要的治疗障碍。10号染色体上缺失的肿瘤抑制性磷酸酶和张力蛋白同源物（PTEN）作为磷酸肌醇3-激酶/AKT生存通路的负调控因子，具有很强的肿瘤抑制活性。化学疗法和基因疗法的组合（化学基因疗法）在癌症治疗中是有前途的实践。在这份报告中，我们研究了腺病毒介导的PTEN（AdVPTEN）基因治疗和DDP化疗对无PTEN的NCI-H446人SCLC细胞的联合抗肿瘤作用在体外和在裸鼠体内。我们证明，AdVPTEN联合DDP增强体外NCI-H446肿瘤细胞和裸鼠皮下接种的NCI-H446异种移植瘤的生长抑制、细胞周期G1期阻滞和凋亡。在机制上，AdVPTEN联合DDP在体外和体内NCI-H446肿瘤细胞中对P53、P21、P27、Bax和Cleaved Caspase-3的上调以及Bcl-2和Survivin的下调产生重叠效应。此外，AdVPTEN联合DDP在体内可相加地降低肿瘤血管CD 34表达和微血管密度。AdVPTEN联合DDP的治疗效果增强与其通过显著调节细胞周期调控分子和激活内源性凋亡途径（P53恢复），叠加抑制肿瘤血管生成，诱导G1期阻滞和凋亡密切相关。因此，我们的研究结果表明，AdVPTEN联合DDP可能是一种新的和有效的化学基因治疗模式，对人类小细胞肺癌。
DNA-damaging anticancer drug cisplatin (cis-diamminedichloroplatinum)(DDP)-based chemotherapy is the mainstay and standard treatment for small-cell lung cancer (SCLC). However, frequent relapse and chemoresistance of SCLC remains a significant therapeutic hurdle. Tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) as a negative regulator of phosphoinositide 3-kinase/AKT survival pathway exhibits strong tumor-suppressive activities. A combination of chemotherapy and gene therapy (chemogene therapy) is a promising practice in cancer therapy. In this report, we examined the combined antitumor effect of adenovirus-mediated PTEN (AdVPTEN) gene therapy and DDP chemotherapy on PTEN-null NCI-H446 human SCLC cells in vitro and in vivo in athymic BALB/c nude mice. We demonstrated that AdVPTEN plus DDP enhanced growth suppression, cell-cycle G1 phase arrest and apoptosis in in vitro NCI-H446 tumor cells and in vivo NCI-H446 xenografted tumors subcutaneously inoculated in nude mice. Mechanistically, AdVPTEN plus DDP exerted an overlapping effect on upregulation of P53, P21, P27, Bax and Cleaved Caspase-3 as well as downregulation of Bcl-2 and survivin in in vitro and in vivo NCI-H446 tumor cells. Moreover, AdVPTEN plus DDP additively reduced tumor vessel CD34 expression and microvessel density in vivo. The enhanced therapeutic efficacy elicited by AdVPTEN plus DDP was closely associated with additive induction of G1 phase arrest and apoptosis via substantially modulating cell-cycle regulation molecules and activating intrinsic apoptotic pathway through P53 restoration, and overlapping inhibition of tumor angiogenesis. Thus, our results indicated that AdVPTEN combined with DDP may be a novel and effective chemogene therapy modality for human SCLC.