The MDM2/MDMX-p53 Antagonist PM2 Radiosensitizes Wild-Type p53 Tumors

Cancer Research
Diana SpiegelbergMarika Nestor

Abstract

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 in vitro and in vivo PM2 therapy combined with radiotherapy elicited synergistic therapeutic effects compared with monotherapy in cells with wt p53 in both in vitro and in vivo assays, whereas these effects did not manifest in p53 -/- cells. Biodistribution and autoradiography of 125I-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 ex vivo immunohistochemistry. These data demonstrate the potential of the stapled peptide PM2 as a radiotherapy potentiator in vivo and suggest that clinical application of PM2 with radiotherapy in wt p53 cancers might improve tumor control.Significance: These findings contribute advances to c...Continue Reading

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Citations

Jul 20, 2019·The Journal of Pathology·Yuezhen XueDavid P Lane
May 23, 2019·Cancer Cell International·Yanzhu LinXinping Cao
Oct 17, 2019·Frontiers in Oncology·Anja Charlotte Lundgren MortensenMarika Nestor
Jun 14, 2020·Signal Transduction and Targeted Therapy·Ling ChenYongguang Tao
Jul 19, 2019·IET Systems Biology·Muhammad Rizwan AzamAamer Iqbal Bhatti
Feb 11, 2021·Nature Communications·Jacob Stewart-OrnsteinGalit Lahav
Jul 27, 2021·Frontiers in Oncology·Xanthene MilesJulie Bolcaen
Sep 29, 2021·Journal of Theoretical Biology·Sheher BanoAamer Iqbal Bhatti

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