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The polo-like kinase 1 inhibitor volasertib synergistically increases radiation efficacy in glioma stem cells.

ABSTRACT: Despite the availability of hundreds of cancer drugs, there is insufficient data on the efficacy of these drugs on the extremely heterogeneous tumor cell populations of glioblastoma (GBM).The PKIS of 357 compounds was initially evaluated in 15 different GSC lines which then led to a more focused screening of the 21 most highly active compounds in 11 unique GSC lines using HTS screening for cell viability. We further validated the HTS result with the second-generation PLK1 inhibitor volasertib as a single agent and in combination with ionizing radiation (IR). In vitro studies showed that volasertib inhibited cell viability, and high levels of the anti-apoptotic protein Bcl-xL expression were highly correlated with volasertib resistance. Volasertib sensitized GSCs to radiation therapy by enhancing G2/M arrest and by inducing apoptosis. Colony-formation assay demonstrated that volasertib plus IR synergistically inhibited colony formation. In intracranial xenograft mouse models, the combination of volasertib and radiation significantly inhibited GSC tumor growth and prolonged median survival compared with radiation treatment alone due to inhibition of cell proliferation, enhancement of DNA damage, and induction of apoptosis.Our results reinforce the potential therapeutic efficacy of volasertib in combination with radiation for the treatment of GBM.We used high-throughput screening (HTS) to identify drugs, out of 357 compounds in the published Protein Kinase Inhibitor Set, with the greatest efficacy against a panel of glioma stem cells (GSCs), which are representative of the classic cancer genome atlas (TCGA) molecular subtypes.

SUBMITTER: Dong J

PROVIDER: S-EPMC5828226 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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The polo-like kinase 1 inhibitor volasertib synergistically increases radiation efficacy in glioma stem cells.

Dong Jianwen J Park Soon Young SY Nguyen Nghi N Ezhilarasan Ravesanker R Martinez-Ledesma Emmanuel E Wu Shaofang S Henry Verlene V Piao Yuji Y Tiao Ningyi N Brunell David D Stephan Clifford C Verhaak Roel R Sulman Erik E Balasubramaniyan Veerakumar V de Groot John F JF

Oncotarget 20180108 12

<h4>Background</h4>Despite the availability of hundreds of cancer drugs, there is insufficient data on the efficacy of these drugs on the extremely heterogeneous tumor cell populations of glioblastoma (GBM).<h4>Results</h4>The PKIS of 357 compounds was initially evaluated in 15 different GSC lines which then led to a more focused screening of the 21 most highly active compounds in 11 unique GSC lines using HTS screening for cell viability. We further validated the HTS result with the second-gene ...[more]

PMID: 29535822

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Project description:Polo-like kinase 1 (Plk1), a master regulator of mitosis and the DNA damage response, is considered to be an intriguing target in the research field of mitotic intervention. The observation that Plk1 is overexpressed in multiple human malignancies, including non-small-cell lung cancer (NSCLC), gave rise to the development of several small-molecule inhibitors. Volasertib, presently the most extensively studied Plk1 inhibitor, has been validated to efficiently reduce tumor growth in preclinical settings. Unfortunately, only modest antitumor activity against solid tumors was reported in clinical trials. This discrepancy prompted research into the identification of predictive biomarkers. In this study, we investigated the therapeutic effect of volasertib monotherapy (i.e., cytotoxicity, cell cycle distribution, apoptotic cell death, cellular senescence, and migration) in a panel of NSCLC cell lines differing in p53 status under both normal and reduced oxygen tension (<0.1% O2 ). A strong growth inhibitory effect was observed in p53 wild-type cells (A549 and A549-NTC), with IC50 values significantly lower than those in p53 knockdown/mutant cells (A549-920 and NCI-H1975) (P < 0.001). While mitotic arrest was significantly greater in cells with nonfunctional p53 (P < 0.005), apoptotic cell death (P < 0.026) and cellular senescence (P < 0.021) were predominantly induced in p53 wild-type cells. Overall, the therapeutic effect of volasertib was reduced under hypoxia (P < 0.050). Remarkably, volasertib inhibited cell migration in all cell lines tested (P < 0.040), with the exception of for the NCI-H1975 p53 mutant cell line. In conclusion, our results show an important difference in the therapeutic effect of Plk1 inhibition in NSCLC cells with versus without functional p53. Overall, the p53 wild-type cell lines were more sensitive to volasertib treatment, suggesting that p53 might be a predictive biomarker for Plk1 inhibition in NSCLC. Moreover, our results pave the way for new combination strategies with Plk1 inhibitors to enhance antitumor activity.

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The polo-like kinase 1 inhibitor volasertib synergistically increases radiation efficacy in glioma stem cells.

Publications

The polo-like kinase 1 inhibitor volasertib synergistically increases radiation efficacy in glioma stem cells.

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