Oncotarget published " Creation of a new class of radiosensitizers for glioblastoma based on the mibefradil pharmacophore " which reported that this group previously identified a calcium channel blocker, mibefradil , as a potential GBM radiosensitizer. They discovered that mibefradil selectively inhibits a key DNA repair pathway, alternative non-homologous end joining.
Then, they initiated a phase I clinical trial that revealed promising initial efficacy of mibefradil, but further development was hampered by dose-limiting toxicities, including CCB-related cardiotoxicity, off-target hERG channel and cytochrome P450 enzymes interactions.
Here, the authors show that mibefradil inhibits DNA repair independent of its CCB activity, and report a series of mibefradil analogues which lack CCB activity and demonstrate reduced hERG and CYP activity while retaining potency as DNA repair inhibitors. They also report a targeted siRNA-based screen which suggests a possible role for mTOR and Akt in DNA repair inhibition by this class of drugs.
Taken together, these Oncotarget data reveal a new class of mibefradil-based DNA repair inhibitors which can be further advanced into pre-clinical testing and eventually clinical trials, as potential GBM radiosensitizers.
Dr. Yulia V. Surovtseva and Dr. Ranjit S. Bindra from Yale University said, " Glioblastoma (GBM) is the most common primary malignant tumor of the central nervous system (CNS). "
Cells utilize several DNA double-strand break repair pathways to repair DNA damage induced by irradiation.
This pathway repairs only 0.5–1% of total DSBs, but serves as a crucial back-up pathway for both NHEJ and HR and for the repair of complex DNA lesions arising from IR-induced damage .
The EJ-DR assay was utilized in a high-throughput chemical screen for novel DNA repair inhibitors, which identified the T-type and L-type calcium channel blocker, mibefradil, as a selective inhibitor of alt-NHEJ repair.
Based on these findings, the authors sought to create a new class of radiosensitizers which retained mibefradil's activity as a DNA repair inhibitor, but showed reduced hERG and CYP450 enzyme inhibition.
Finally, through the knockdown of DNA damage response proteins in the high-throughput imaging-based assay, we identified potential targets or regulators of mibefradil, which phenocopied the selective inhibition of alt-NHEJ over HR.
The Surovtseva/Bindra Research Team concluded in their Oncotarget Research Output that, the use of DNA repair inhibitors as radiosensitizers in GBM could represent a viable approach to achieve better response owing to the range of DDR pathways activated in response to radiation-induced DNA damage.
Additionally, the identification of selective inhibitors of alt-NHEJ could also be tested in other settings where alt-NHEJ activity is critical, such as in HR-deficient tumors.
The synthesis and validation of the mibefradil analogue, YU252386, shows great promise towards the development of a potent and selective radiosensitizer for GBMs and beyond, and warrants further in vivo study in clinically relevant GBM models.
###
Sign up for free Altmetric alerts about this article
DOI - https://doi.org/10.18632/oncotarget.27933
Full text - https://www.oncotarget.com/article/27933/text/
Correspondence to - Yulia V. Surovtseva - yulia.surovtseva@yale.edu and Ranjit S. Bindra - ranjit.bindra@yale.edu
Keywords - lioblastoma , radiosensitizers , mibefradil , DNA repair , alternative non-homologous end joining
About Oncotarget
Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.
To learn more about Oncotarget , please visit https://www.oncotarget.com or connect with:
SoundCloud - https://soundcloud.com/oncotarget
Facebook - https://www.facebook.com/Oncotarget/
Twitter - https://twitter.com/oncotarget
LinkedIn - https://www.linkedin.com/company/oncotarget
Pinterest - https://www.pinterest.com/oncotarget/
Reddit - https://www.reddit.com/user/Oncotarget/
Oncotarget is published by Impact Journals, LLC please visit https://www.ImpactJournals.com or connect with @ImpactJrnls
Media Contact
MEDIA@IMPACTJOURNALS.COM
18009220957x105
Copyright © 2021 Impact Journals, LLC
Impact Journals is a registered trademark of Impact Journals, LLC
Oncotarget