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Evaluating In Vitro DNA Damage Using Comet Assay
Published on: October 11, 2017
Enhanced efficacy of combined HDAC and PARP targeting in glioblastoma
Rikke D Rasmussen1, Madhavsai K Gajjar1, Kamilla E Jensen1
1Brain Tumor Biology Group, Danish Cancer Society Research Center, Strandboulevarden 49, 2100-DK, Copenhagen, Denmark.
Abstract:
Recent clinical trials have demonstrated that targeting chromatin remodeling factors is as a promising strategy for the treatment of glioblastoma (GBM). We and others have shown constitutive activation of DNA damage response (DDR) pathways in gliomas and suggested that targeting the DDR may improve the currently grim prognosis for patients. Based on our previous findings that inhibition of poly(ADP-ribose) polymerase (PARP) increases radio-sensitivity of the notoriously radio-resistant GBM cells, we hypothesized that epigenetic down-regulation of the DDR responses and induction of oxidative stress via HDAC inhibition would contribute to more efficient targeting of this deadly disease. Our data show that SAHA, an HDAC class I + II inhibitor, in combination with olaparib (PARP inhibitor): i) enhanced inhibition of GBM cell survival, ii) induced apoptosis, and iii) impaired cell cycle progression. These results provide a pre-clinical rationale for combined administration of SAHA and olaparib, which are already individually in clinical trials.
Insights
Combining HDAC and PARP inhibitors shows promise for glioblastoma (GBM) treatment. This epigenetic therapy enhances GBM cell death and halts cell cycle progression, offering a new strategy against this deadly brain cancer.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Glioblastoma (GBM) remains a challenging brain cancer with a poor prognosis.
- Targeting chromatin remodeling factors and DNA damage response (DDR) pathways are emerging therapeutic strategies for GBM.
- Constitutive activation of DDR pathways is observed in gliomas, suggesting therapeutic vulnerability.
Purpose of the Study:
- To investigate the combined efficacy of HDAC inhibition and PARP inhibition in GBM treatment.
- To determine if combining SAHA (HDAC inhibitor) and olaparib (PARP inhibitor) enhances anti-GBM effects.
Main Methods:
- Utilized SAHA (an HDAC class I + II inhibitor) in combination with olaparib (a PARP inhibitor).
- Assessed the effects on GBM cell survival, apoptosis, and cell cycle progression in pre-clinical models.
Main Results:
- The combination of SAHA and olaparib significantly enhanced the inhibition of GBM cell survival.
- Combined treatment induced apoptosis in GBM cells.
- The synergistic effect impaired GBM cell cycle progression.
Conclusions:
- Combined administration of SAHA and olaparib provides a pre-clinical rationale for treating glioblastoma.
- This combination therapy represents a promising strategy to overcome radio-resistance and improve outcomes in GBM patients.
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