Combinatorial Effect of PLK1 Inhibition with Temozolomide and Radiation in Glioblastoma

Cancers

Satyendra C. Tripathi¹  Samir M. Hanash²  Junhua Mai³  Haifa Shen³  Arvind Pandey⁴  Robert C. Rostomily⁴  Sankar Mitra⁵ 

[1] Department of Biochemistry, All India Institute of Medical Sciences, Nagpur 440003, India;Department of Clinical Cancer Prevention, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA;Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA;Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX 77030, USA;Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX 77030, USA;

关键词: glioblastoma;    side population;    PLK1 inhibitor;    volasertib;    temozolomide;    radiation;   

DOI  :  10.3390/cancers13205114

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown