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posted on 2023-04-03, 15:22 authored by Yevgen Chornenkyy, Sameer Agnihotri, Man Yu, Pawel Buczkowicz, Patricia Rakopoulos, Brian Golbourn, Livia Garzia, Robert Siddaway, Stephie Leung, James T. Rutka, Michael D. Taylor, Peter B. Dirks, Cynthia Hawkins <p>A, B, MTT viability relative absorbance values of SJG2 and SF188 after being treated with an indicated concentration of Niraparib for 72h. C, Western blot for cleaved PARP1 in SJG2 and SF188 after being treated with an indicated concentration of Niraparib for 72h. D, E, Propidium Iodide DNA staining analysis in SJG2, SF188 cells, respectively, after a 72h incubation with an indicated concentration of Niraparib. *, ***, **** Denotes significance of p<0.05, p<0.001, p<0.0001, respectively. Error bars represent SEM.</p>
History
ARTICLE ABSTRACT
Pediatric high-grade astrocytomas (pHGA) and diffuse intrinsic pontine gliomas (DIPG) are devastating malignancies for which no effective therapies exist. We investigated the therapeutic potential of PARP1 inhibition in preclinical models of pHGA and DIPG. PARP1 levels were characterized in pHGA and DIPG patient samples and tumor-derived cell lines. The effects of PARP inhibitors veliparib, olaparib, and niraparib as monotherapy or as radiosensitizers on cell viability, DNA damage, and PARP1 activity were evaluated in a panel of pHGA and DIPG cell lines. Survival benefit of niraparib was examined in an orthotopic xenograft model of pHGA. About 85% of pHGAs and 76% of DIPG tissue microarray samples expressed PARP1. Six of 8 primary cell lines highly expressed PARP1. Interestingly, across multiple cell lines, some PARP1 protein expression was required for response to PARP inhibition; however, there was no correlation between protein level or PARP1 activity and sensitivity to PARP inhibitors. Niraparib was the most effective at reducing cell viability and proliferation (MTT and Ki67). Niraparib induced DNA damage (γH2AX foci) and induced growth arrest. Pretreatment of pHGA cells with a sublethal dose of niraparib (1 μmol/L) before 2 Gy of ionizing radiation (IR) decreased the rate of DNA damage repair, colony growth, and relative cell number. Niraparib (50 mg/kg) inhibited PARP1 activity in vivo and extended survival of mice with orthotopic pHGA xenografts, when administered before IR (20 Gy, fractionated), relative to control mice (40 vs. 25 days). Our data provide in vitro and in vivo evidence that niraparib may be an effective radiosensitizer for pHGA and DIPG. Mol Cancer Ther; 14(11); 2560–8. ©2015 AACR.
