Department of Immunology, Genetics & Pathology, Uppsala University, Uppsala, Sweden.
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
Cancer Res. 2018 Sep 1;78(17):5084-5093. doi: 10.1158/0008-5472.CAN-18-0440. Epub 2018 Jul 19.
Radiotherapy amplifies p53 expression in cancer cells with wild-type (wt) p53. Blocking the negative regulators MDM2 and MDMX stabilizes p53 and may therefore potentiate radiotherapy outcomes. In this study, we investigate the efficacy of the novel anti-MDM2/X stapled peptide PM2 alone and in combination with external gamma radiation and PM2 therapy combined with radiotherapy elicited synergistic therapeutic effects compared with monotherapy in cells with wt p53 in both and assays, whereas these effects did not manifest in p53 cells. Biodistribution and autoradiography of I-PM2 revealed high and retained uptake homogenously distributed throughout the tumor. In mice carrying wt p53 tumors, PM2 combined with radiotherapy significantly prolonged the median survival by 50%, whereas effects of PM2 therapy on mutant and p53 tumors were negligible. PM2-dependent stabilization of p53 was confirmed with immunohistochemistry. These data demonstrate the potential of the stapled peptide PM2 as a radiotherapy potentiator and suggest that clinical application of PM2 with radiotherapy in wt p53 cancers might improve tumor control. These findings contribute advances to cancer radiotherapy by using novel p53-reactivating stapled peptides as radiosensitizers in wild-type p53 cancers. .
放射治疗可增强野生型（wt）p53 癌细胞中的 p53 表达。抑制负调节因子 MDM2 和 MDMX 可稳定 p53，从而可能增强放射治疗效果。在这项研究中，我们研究了新型抗 MDM2/X 肽 PM2 单独使用以及与外部伽马辐射联合使用的效果。与单独治疗相比，PM2 联合放射治疗在具有 wt p53 的细胞中产生了协同治疗效果，而在 p53 细胞中则没有这些效果。I-PM2 的生物分布和放射自显影显示，高摄取均匀分布在整个肿瘤中，并保持摄取。在携带 wt p53 肿瘤的小鼠中，PM2 联合放射治疗使中位生存期显著延长了 50%，而 PM2 治疗对突变型和 p53 细胞的肿瘤几乎没有影响。通过免疫组化证实了 PM2 依赖性 p53 稳定。这些数据表明，作为放射治疗增强剂，肽 PM2 具有潜力，并提示在 wt p53 癌症中使用 PM2 联合放射治疗可能会改善肿瘤控制。这些发现通过使用新型 p53 激活肽作为放射增敏剂在野生型 p53 癌症中为癌症放射治疗带来了进步。
