MDM2/X Inhibitors as Radiosensitizers for Glioblastoma Targeted Therapy
Inhibition of the MDM2/X-p53 interaction is recognized as a potential anti-cancer strategy, including the treatment of glioblastoma (GB). In response to cellular stressors, such as DNA damage, the tumor suppression protein p53 is activated and responds by mediating cellular damage through DNA repair...
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2021-07-01
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doaj-2b8c696d12f54f66b5a915ccb234379c2021-07-08T07:14:07ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-07-011110.3389/fonc.2021.703442703442MDM2/X Inhibitors as Radiosensitizers for Glioblastoma Targeted TherapyXanthene Miles0Charlot Vandevoorde1Alistair Hunter2Julie Bolcaen3Radiobiology, Radiation Biophysics Division, Nuclear Medicine Department, iThemba LABS, Cape Town, South AfricaRadiobiology, Radiation Biophysics Division, Nuclear Medicine Department, iThemba LABS, Cape Town, South AfricaRadiobiology Section, Division of Radiation Oncology, Department of Radiation Medicine, University of Cape Town and Groote Schuur Hospital, Cape Town, South AfricaRadiobiology, Radiation Biophysics Division, Nuclear Medicine Department, iThemba LABS, Cape Town, South AfricaInhibition of the MDM2/X-p53 interaction is recognized as a potential anti-cancer strategy, including the treatment of glioblastoma (GB). In response to cellular stressors, such as DNA damage, the tumor suppression protein p53 is activated and responds by mediating cellular damage through DNA repair, cell cycle arrest and apoptosis. Hence, p53 activation plays a central role in cell survival and the effectiveness of cancer therapies. Alterations and reduced activity of p53 occur in 25-30% of primary GB tumors, but this number increases drastically to 60-70% in secondary GB. As a result, reactivating p53 is suggested as a treatment strategy, either by using targeted molecules to convert the mutant p53 back to its wild type form or by using MDM2 and MDMX (also known as MDM4) inhibitors. MDM2 down regulates p53 activity via ubiquitin-dependent degradation and is amplified or overexpressed in 14% of GB cases. Thus, suppression of MDM2 offers an opportunity for urgently needed new therapeutic interventions for GB. Numerous small molecule MDM2 inhibitors are currently undergoing clinical evaluation, either as monotherapy or in combination with chemotherapy and/or other targeted agents. In addition, considering the major role of both p53 and MDM2 in the downstream signaling response to radiation-induced DNA damage, the combination of MDM2 inhibitors with radiation may offer a valuable therapeutic radiosensitizing approach for GB therapy. This review covers the role of MDM2/X in cancer and more specifically in GB, followed by the rationale for the potential radiosensitizing effect of MDM2 inhibition. Finally, the current status of MDM2/X inhibition and p53 activation for the treatment of GB is given. https://www.frontiersin.org/articles/10.3389/fonc.2021.703442/fullp53MDM2 & MDMXradiationglioblastomaradiosensitizerradiotherapy |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xanthene Miles Charlot Vandevoorde Alistair Hunter Julie Bolcaen |
spellingShingle |
Xanthene Miles Charlot Vandevoorde Alistair Hunter Julie Bolcaen MDM2/X Inhibitors as Radiosensitizers for Glioblastoma Targeted Therapy Frontiers in Oncology p53 MDM2 & MDMX radiation glioblastoma radiosensitizer radiotherapy |
author_facet |
Xanthene Miles Charlot Vandevoorde Alistair Hunter Julie Bolcaen |
author_sort |
Xanthene Miles |
title |
MDM2/X Inhibitors as Radiosensitizers for Glioblastoma Targeted Therapy |
title_short |
MDM2/X Inhibitors as Radiosensitizers for Glioblastoma Targeted Therapy |
title_full |
MDM2/X Inhibitors as Radiosensitizers for Glioblastoma Targeted Therapy |
title_fullStr |
MDM2/X Inhibitors as Radiosensitizers for Glioblastoma Targeted Therapy |
title_full_unstemmed |
MDM2/X Inhibitors as Radiosensitizers for Glioblastoma Targeted Therapy |
title_sort |
mdm2/x inhibitors as radiosensitizers for glioblastoma targeted therapy |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Oncology |
issn |
2234-943X |
publishDate |
2021-07-01 |
description |
Inhibition of the MDM2/X-p53 interaction is recognized as a potential anti-cancer strategy, including the treatment of glioblastoma (GB). In response to cellular stressors, such as DNA damage, the tumor suppression protein p53 is activated and responds by mediating cellular damage through DNA repair, cell cycle arrest and apoptosis. Hence, p53 activation plays a central role in cell survival and the effectiveness of cancer therapies. Alterations and reduced activity of p53 occur in 25-30% of primary GB tumors, but this number increases drastically to 60-70% in secondary GB. As a result, reactivating p53 is suggested as a treatment strategy, either by using targeted molecules to convert the mutant p53 back to its wild type form or by using MDM2 and MDMX (also known as MDM4) inhibitors. MDM2 down regulates p53 activity via ubiquitin-dependent degradation and is amplified or overexpressed in 14% of GB cases. Thus, suppression of MDM2 offers an opportunity for urgently needed new therapeutic interventions for GB. Numerous small molecule MDM2 inhibitors are currently undergoing clinical evaluation, either as monotherapy or in combination with chemotherapy and/or other targeted agents. In addition, considering the major role of both p53 and MDM2 in the downstream signaling response to radiation-induced DNA damage, the combination of MDM2 inhibitors with radiation may offer a valuable therapeutic radiosensitizing approach for GB therapy. This review covers the role of MDM2/X in cancer and more specifically in GB, followed by the rationale for the potential radiosensitizing effect of MDM2 inhibition. Finally, the current status of MDM2/X inhibition and p53 activation for the treatment of GB is given. |
topic |
p53 MDM2 & MDMX radiation glioblastoma radiosensitizer radiotherapy |
url |
https://www.frontiersin.org/articles/10.3389/fonc.2021.703442/full |
work_keys_str_mv |
AT xanthenemiles mdm2xinhibitorsasradiosensitizersforglioblastomatargetedtherapy AT charlotvandevoorde mdm2xinhibitorsasradiosensitizersforglioblastomatargetedtherapy AT alistairhunter mdm2xinhibitorsasradiosensitizersforglioblastomatargetedtherapy AT juliebolcaen mdm2xinhibitorsasradiosensitizersforglioblastomatargetedtherapy |
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