Dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 has a therapeutic potential and sensitizes cisplatin in nasopharyngeal carcinoma.
Dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 has a therapeutic potential and sensitizes cisplatin in nasopharyngeal carcinoma.
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雷帕霉素抑制剂 NVP-BEZ235 的双重磷酸肌醇 3-激酶/哺乳动物靶标具有治疗潜力，并使顺铂在鼻咽癌中增敏
DOI：
10.1371/journal.pone.0059879
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Zhu XF
中科院分区：
文献类型：
--
作者：
Yang F;Qian XJ;Qin W;Deng R;Wu XQ;Qin J;Feng GK;Zhu XF
磷脂酰肌醇3-激酶(PI3K)/AKT/雷帕霉素抑制物(MTOR)通路的哺乳动物靶点在人类肿瘤细胞中经常被结构性激活，因此被认为是一种很有前途的药物靶点。为了确定鼻咽癌的治疗途径，我们假设NVP-BEZ235在鼻咽癌中具有抗肿瘤活性。NVP-BEZ235是一种新的、有效的咪唑并[4，5-c]喹诺酮衍生物，它同时抑制PI3K和mTOR激酶活性。不出所料，我们发现NVP-BEZ235选择性地抑制鼻咽癌细胞的增殖，而不是正常的鼻咽癌细胞。在鼻咽癌细胞系中，与野生型PIK3CA细胞相比，NVP-BEZ235能选择性地抑制携带PIK3CA突变的鼻咽癌细胞的增殖。此外，NVP-BEZ235作用于鼻咽癌细胞后，碘化丙啶摄取实验结果显示鼻咽癌细胞生长停滞于G1期，Western blotting结果显示细胞周期蛋白D1和CDK4表达下降，P27和P21表达水平升高，但未见明显的细胞凋亡。此外，我们还发现顺铂(CDDP)激活了PI3K/AKT和mTORC1通路，而NVP-BEZ235通过双重靶向PI3K和mTOR激酶而减轻了CDDP的激活作用。NVP-BEZ235联合顺铂对鼻咽癌细胞具有协同抑制增殖和诱导凋亡的作用。在CNE2和HONE1裸鼠移植瘤模型中，口服NVP-BEZ235可有效抑制肿瘤生长，且无明显毒性。NVP-BEZ235联合顺铂通过增加Noxa、Bax、降低Mcl-1、Bcl2，在缩小肿瘤体积和诱导细胞凋亡方面具有显著的协同作用。基于上述结果，NVP-BEZ235已进入I/II期临床试验，用于晚期实体瘤患者，具有作为单一疗法或与顺铂联合治疗鼻咽癌的潜力。
Phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin inhibitor (mTOR) pathway is often constitutively activated in human tumor cells and thus has been considered as a promising drug target. To ascertain a therapeutical approach of nasopharyngeal carcinoma (NPC), we hypothesized NVP-BEZ235, a novel and potent imidazo[4,5-c] quinolone derivative, that dually inhibits both PI3K and mTOR kinases activities, had antitumor activity in NPC. Expectedly, we found that NVP-BEZ235 selectively inhibited proliferation of NPC cells rather than normal nasopharyngeal cells using MTT assay. In NPC cell lines, with the extended exposure, NVP-BEZ235 selectively inhibited proliferation of NPC cells harboring PIK3CA mutation, compared to cells with wild-type PIK3CA. Furthermore, exposure of NPC cells to NVP-BEZ235 resulted in G1 growth arrest by Propidium iodide uptake assay, reduction of cyclin D1and CDK4, and increased levels of P27 and P21 by Western blotting, but negligible apoptosis. Moreover, we found that cisplatin (CDDP) activated PI3K/AKT and mTORC1 pathways and NVP-BEZ235 alleviated the activation by CDDP through dually targeting PI3K and mTOR kinases. Also, NVP-BEZ235 combining with CDDP synergistically inhibited proliferation and induced apoptosis in NPC cells. In CNE2 and HONE1 nude mice xenograft models, orally NVP-BEZ235 efficiently attenuated tumor growth with no obvious toxicity. In combination with NVP-BEZ235 and CDDP, there was dramatic synergy in shrinking tumor volumes and inducing apoptosis through increasing Noxa, Bax and decreasing Mcl-1, Bcl-2. Based on the above results, NVP-BEZ235, which has entered phase I/II clinical trials in patients with advanced solid tumors, has a potential as a monotherapy or in combination with CDDP for NPC treatment.
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着丝粒蛋白F表达在人鼻咽癌中的预后意义和治疗意义
影响因子：
37.3
作者：
Cao JY;Liu L;Chen SP;Zhang X;Mi YJ;Liu ZG;Li MZ;Zhang H;Qian CN;Shao JY;Fu LW;Xia YF;Zeng MS
通讯作者：
Zeng MS
DOI：
10.1158/1078-0432.ccr-11-0933
发表时间：
2011-10-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Jin N;Jiang T;Rosen DM;Nelkin BD;Ball DW
通讯作者：
Ball DW
有效使用 PI3K 和 MEK 抑制剂治疗突变型 Kras G12D 和 PIK3CA H1047R 小鼠肺癌。
影响因子：
82.9
作者：
通讯作者：
--
抗癌药物诱导细胞凋亡过程中 c-Jun-NH2 末端激酶通路介导的乙酰胆碱酯酶表达
影响因子：
8
作者：
Deng, R.;Li, W.;Zhu, X-F
通讯作者：
Zhu, X-F
影响因子：
9.2
作者：
Cai MB;Han HQ;Bei JX;Liu CC;Lei JJ;Cui Q;Feng QS;Wang HY;Zhang JX;Liang Y;Chen LZ;Kang TB;Shao JY;Zeng YX
通讯作者：
Zeng YX