Journal
CELL DEATH & DISEASE
Volume 12, Issue 6, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/s41419-021-03805-6
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Funding
- National Natural Science Foundation of China [81673464, 82073890, 8201101056]
- Major Project of Tianjin for New Drug Development [17ZXXYSY00050]
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This study demonstrated synergistic anticancer effects of PARP inhibitor and PI3K inhibitor on GBM cells, affecting HR molecule expression, repair efficiency, and apoptosis induction. The combination therapy showed significantly increased anti-tumor efficacy in cell and animal models, with complemented DNA damage response and drug accumulation. This combination therapy might represent a promising therapeutic approach for GBM.
PARP inhibitors have been approved for the therapy of cancers with homologous recombination (HR) deficiency based on the concept of synthetic lethality. However, glioblastoma (GBM) patients have gained little benefit from PARP inhibitors due to a lack of BRCA mutations. Herein, we demonstrated that concurrent treatment with the PARP inhibitor rucaparib and the PI3K inhibitor BKM120 showed synergetic anticancer effects on GBM U251 and U87MG cells. Mechanistically, BKM120 decreased expression of HR molecules, including RAD51 and BRCA1/2, and reduced HR repair efficiency in GBM cells, therefore increasing levels of apoptosis induced by rucaparib. Furthermore, we discovered that the two compounds complemented each other in DNA damage response and drug accumulation. Notably, in the zebrafish U87MG-RFP orthotopic xenograft model, nude mouse U87MG subcutaneous xenograft model and U87MG-Luc orthotopic xenograft model, combination showed obviously increased antitumor efficacy compared to each monotherapy. Immunohistochemical analysis of tumor tissues indicated that the combination obviously reduced expression of HR repair molecules and increased the DNA damage biomarker gamma -H2AX, consistent with the in vitro results. Collectively, our findings provide new insight into combined blockade of PI3K and PARP, which might represent a promising therapeutic approach for GBM.
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