TY - JOUR
T1 - Combinatorial effect of plk1 inhibition with temozolomide and radiation in glioblastoma
AU - Pandey, Arvind
AU - Tripathi, Satyendra C.
AU - Mai, Junhua
AU - Hanash, Samir M.
AU - Shen, Haifa
AU - Mitra, Sankar
AU - Rostomily, Robert C.
N1 - Funding Information:
Funding: This work was supported by funding by the NIH R01 CA 158910 (to SM), R01 NS091251 (to RCR) and John S. “Steve” Dunn, Jr. and Dagmar Dunn Pickens Gipe Chair in Brain Tumor Re‐ search.. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement per 18 U.S.C. Section 1734 solely indi‐ cates this fact.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/10/12
Y1 - 2021/10/12
N2 - 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 signal-ing. 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.
AB - 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 signal-ing. 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.
KW - Glioblastoma
KW - PLK1 inhibitor
KW - Radiation
KW - Side population
KW - Temozolomide
KW - Volasertib
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U2 - 10.3390/cancers13205114
DO - 10.3390/cancers13205114
M3 - Article
C2 - 34680264
AN - SCOPUS:85116755397
SN - 2072-6694
VL - 13
JO - Cancers
JF - Cancers
IS - 20
M1 - 5114
ER -