1 Experiment Teaching Center of Clinical Medicine, Chengdu Medical College , Chengdu, China.
2 Department of Pathogen Biology, Chengdu Medical College , Chengdu, China.
Hum Gene Ther. 2018 Aug;29(8):916-926. doi: 10.1089/hum.2017.186. Epub 2018 Apr 5.
Cross-reacting material 197 (CRM197) is a mutant form of the diphtheria toxin. Recent studies have found that CRM197 exerts an experimental antitumor effect on several types of tumors. This study applied a novel treatment of adenovirus-mediated CRM197 (AdCRM197) to human ovarian cancer cells. Interestingly, it was found that A2780 cells were sensitive to AdCRM197, but SKOV3 cells were resistant to it. Since SKOV3 cells are p53 deletion cells, while A2780 cells are p53 wild-type cells, it was postulated that p53 might play a key role in AdCRM197-induced apoptosis. This presumption was demonstrated by means of knockdown of p53 of the A2780 cells through lentivirus-mediated RNA interference. This knockdown resulted in the A2780 cells becoming resistant to AdCRM197. To verify this presumption further, the wild-type p53 gene in the SKOV3 cells was replaced with adenovirus-mediated p53 (Adp53). As expected, AdCRM197 plus Adp53 resulted in apoptosis of the SKOV3 cells. The combined treatment of AdCRM197 plus Adp53 also showed a good antitumor effect in the in vivo experiment on nude mice with xenograft tumors. Taking these results together, it is concluded that AdCRM197 induces apoptosis of human ovarian cancer cells via the p53 pathway. Moreover, it was found that Adp53 can reverse the resistance of p53-deletion human ovarian cancer cells to AdCRM197. The combination of AdCRM197 and Adp53 may be a potentially effective method for overcoming the resistance of p53-deficient human ovarian cancer to AdCRM197.
CRM197 是白喉毒素的一种突变形式。最近的研究发现，CRM197 对几种类型的肿瘤具有实验性的抗肿瘤作用。本研究应用新型腺病毒介导 CRM197（AdCRM197）治疗人卵巢癌细胞。有趣的是，发现 A2780 细胞对 AdCRM197 敏感，而 SKOV3 细胞则对其有抗性。由于 SKOV3 细胞是 p53 缺失细胞，而 A2780 细胞是 p53 野生型细胞，因此推测 p53 可能在 AdCRM197 诱导的细胞凋亡中发挥关键作用。通过慢病毒介导的 RNA 干扰敲低 A2780 细胞中的 p53，证明了这一假设。这种敲低导致 A2780 细胞对 AdCRM197 产生抗性。为了进一步验证这一假设，用腺病毒介导的 p53（Adp53）取代 SKOV3 细胞中的野生型 p53 基因。正如预期的那样，AdCRM197 加 Adp53 导致 SKOV3 细胞凋亡。在裸鼠异种移植肿瘤的体内实验中，AdCRM197 加 Adp53 的联合治疗也显示出良好的抗肿瘤效果。综合这些结果，结论是 AdCRM197 通过 p53 途径诱导人卵巢癌细胞凋亡。此外，还发现 Adp53 可以逆转 p53 缺失的人卵巢癌细胞对 AdCRM197 的耐药性。AdCRM197 和 Adp53 的联合应用可能是克服 p53 缺失型人卵巢癌对 AdCRM197 耐药的一种潜在有效方法。
