PLK1 Inhibition Targets Myc-Activated Malignant Glioma Cells Irrespective of Mismatch Repair Deficiency-Mediated Acquired Resistance to Temozolomide.

ABSTRACT: Mismatch repair (MMR) deficiency through MSH6 inactivation has been identified in up to 30% of recurrent high-grade gliomas, and represents a key molecular mechanism underlying the acquired resistance to the alkylating agent temozolomide (TMZ). To develop a therapeutic strategy that could be effective in these TMZ-refractory gliomas, we first screened 13 DNA damage response modulators for their ability to suppress viability of MSH6-inactivated, TMZ-resistant glioma cells. We identified a PLK1 selective inhibitor, Volasertib, as the most potent in inhibiting proliferation of glioblastoma cells. PLK1 inhibition induced mitotic catastrophe, G₂-M cell-cycle arrest, and DNA damage, leading to caspase-mediated apoptosis in glioblastoma cells. Importantly, therapeutic effects of

SUBMITTER: Higuchi F 

PROVIDER: S-EPMC6279590 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature