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Absent in melanoma 2 enhances anti-tumour effects of CAIX promotor controlled conditionally replicative adenovirus in renal cancer.
Journal of Cellular and Molecular Medicine ( IF 5.3 ) Pub Date : 2020-07-29 , DOI: 10.1111/jcmm.15697
Dafei Chai 1, 2 , Dong Qiu 3 , Zichun Zhang 1, 2 , Shang Yuchen Shi 4 , Gang Wang 1, 2 , Lin Fang 1, 2 , Huizhong Li 1, 2 , Hailong Li 3 , Hui Tian 1, 2 , Junnian Zheng 2
Affiliation  

Conditionally replicative adenoviruses (CRAds) were promising approach for solid tumour treatment, but its oncolytic efficiency and toxicity are still not satisfactory for further clinical application. Here, we developed the CAIX promotor (CAIXpromotor)‐controlled CRAd armed with a tumour suppressor absent in melanoma 2 (AIM2) to enhance its oncolytic potency. The CAIXpromotor‐AIM2 adenoviruses (Ad‐CAIXpromotor‐AIM2) could efficiently express E1A and AIM2 in renal cancer cells. Compared with Ad‐CAIXpromotor, Ad‐CAIXpromotor‐AIM2 significantly inhibited cell proliferation and enhanced cell apoptosis and cell killing, thus resulting in the oncolytic efficiency in 786‐O cells or OSRC‐2 cells. To explore the therapeutic effect, various Ads were intratumourally injected into OSRC‐2‐xenograft mice. The tumour growth was remarkably inhibited in Ad‐CAIXpromotor‐AIM2‐treated group as demonstrated by reduced tumour volume and weight with a low toxicity. The inflammasome inhibitor YVAD‐CMK resulted in the reduction of anti‐tumour activity by Ad‐CAIXpromotor‐AIM2 in vitro or in vivo, suggesting that inflammasome activation response was required for the enhanced therapeutic efficiency. Furthermore, lung metastasis of renal cancer mice was also suppressed by Ad‐CAIXpromotor‐AIM2 treatment accompanied by the decreased tumour fossil in lung tissues. These results indicated that the tumour‐specific Ad‐CAIXpromotor‐AIM2 could be applied for human renal cancer therapy. The therapeutic strategy of AIM2‐based CRAds could be a potential and promising approach for the therapy of primary solid or metastasis tumours.

中文翻译:

黑色素瘤2缺失可增强CAIX启动子控制的条件复制型腺病毒在肾癌中的抗肿瘤作用。

条件复制型腺病毒(CRAds)是用于实体瘤治疗的有前途的方法,但是其溶瘤效率和毒性对于进一步的临床应用仍不令人满意。在这里,我们开发了配备有黑色素瘤2(AIM2)中不存在的抑癌剂的CAIX启动子(CAIX promotor)控制的CRAd,以增强其溶瘤作用。CAIX启动子-AIM2腺病毒(Ad-CAIX启动子-AIM2)可以在肾癌细胞中有效表达E1A和AIM2。与Ad-CAIX相比启动子,AD-CAIX启动子‐AIM2显着抑制细胞增殖并增强细胞凋亡和杀伤细胞,从而导致786-O细胞或OSRC-2细胞的溶瘤效率。为了探索治疗效果,将各种Ads瘤内注射到OSRC-2异种移植小鼠中。Ad‐CAIX启动子‐AIM2治疗组的肿瘤生长受到显着抑制,这表现为肿瘤体积和重量减少,毒性低。炎性体抑制剂YVAD-CMK导致Ad-CAIX启动子-AIM2在体外或体内的抗肿瘤活性降低,表明炎性体激活反应是提高治疗效率所必需的。此外,Ad‐CAIX启动子也抑制了肾癌小鼠的肺转移‐AIM2治疗伴随肺组织肿瘤化石减少。这些结果表明,肿瘤特异性Ad‐CAIX启动子‐AIM2可以用于人类肾癌治疗。基于AIM2的CRAd的治疗策略可能是治疗原发性实体瘤或转移瘤的一种潜在且有前途的方法。
更新日期:2020-09-28
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