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Combinatorial Effect of PLK1 Inhibition with Temozolomide and Radiation in Glioblastoma
Arvind Pandey1,2, Satyendra C Tripathi3,4, Junhua Mai5
1Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX 77030, USA.
Abstract:
New strategies that improve median survivals of only ~15-20 months for glioblastoma (GBM) with the current standard of care (SOC) which is concurrent temozolomide (TMZ) and radiation (XRT) treatment are urgently needed. Inhibition of polo-like kinase 1 (PLK1), a multifunctional cell cycle regulator, overexpressed in GBM has shown therapeutic promise but has never been tested in the context of SOC. Therefore, we examined the mechanistic and therapeutic impact of PLK1 specific inhibitor (volasertib) alone and in combination with TMZ and/or XRT on GBM cells. We quantified the effects of volasertib alone and in combination with TMZ and/or XRT on GBM cell cytotoxicity/apoptosis, mitochondrial membrane potential (MtMP), reactive oxygen species (ROS), cell cycle, stemness, DNA damage, DNA repair genes, cellular signaling and in-vivo tumor growth. Volasertib alone and in combination with TMZ and/or XRT promoted apoptotic cell death, altered MtMP, increased ROS and G2/M cell cycle arrest. Combined volasertib and TMZ treatment reduced side population (SP) indicating activity against GBM stem-like cells. Volasertib combinatorial treatment also significantly increased DNA damage and reduced cell survival by inhibition of DNA repair gene expression and modulation of ERK/MAPK, AMPK and glucocorticoid receptor signaling. Finally, as observed in-vitro, combined volasertib and TMZ treatment resulted in synergistic inhibition of tumor growth in-vivo. Together these results identify new mechanisms of action for volasertib that provide a strong rationale for further investigation of PLK1 inhibition as an adjunct to current GBM SOC therapy.
Insights
New glioblastoma (GBM) treatments are needed. Volasertib, a polo-like kinase 1 (PLK1) inhibitor, combined with standard care (temozolomide and radiation), shows promise by enhancing cell death and reducing tumor growth.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Glioblastoma (GBM) median survival remains poor (~15-20 months) with current standard of care (SOC).
- Polo-like kinase 1 (PLK1), a cell cycle regulator overexpressed in GBM, presents a potential therapeutic target.
- PLK1 inhibitors have not been evaluated in combination with GBM SOC.
Purpose of the Study:
- To investigate the mechanistic and therapeutic effects of volasertib, a PLK1 inhibitor, alone and combined with temozolomide (TMZ) and/or radiation (XRT) in GBM.
- To assess the impact on GBM cell cytotoxicity, apoptosis, mitochondrial membrane potential, reactive oxygen species, cell cycle, stemness, DNA damage, and signaling pathways.
- To evaluate the in-vivo efficacy of volasertib in combination with TMZ and XRT.
Main Methods:
- Assessed cytotoxicity, apoptosis, mitochondrial membrane potential, reactive oxygen species, cell cycle progression, and stemness markers in GBM cells.
- Quantified DNA damage and expression of DNA repair genes.
- Analyzed cellular signaling pathways (ERK/MAPK, AMPK, glucocorticoid receptor).
- Evaluated in-vivo tumor growth inhibition in preclinical models.
Main Results:
- Volasertib alone and in combination with TMZ/XRT induced apoptosis, altered mitochondrial membrane potential, increased reactive oxygen species, and caused G2/M cell cycle arrest.
- Combined volasertib and temozolomide reduced glioblastoma stem-like cells (side population).
- Volasertib combination therapy significantly increased DNA damage and reduced cell survival by inhibiting DNA repair genes and modulating key signaling pathways.
- In-vivo studies demonstrated synergistic tumor growth inhibition with combined volasertib and temozolomide.
Conclusions:
- Volasertib exhibits potent anti-cancer activity against GBM, both alone and in combination with standard therapies.
- Combined volasertib and temozolomide demonstrate synergistic effects, offering a promising new therapeutic strategy for glioblastoma.
- PLK1 inhibition represents a viable approach to enhance current glioblastoma treatment protocols.
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