Anti-glioblastoma study of YHP-836,a novel PARP1/2 inhibitor,in combination with temozolomide
The aim of this study was to investigate and evaluate the antitumor effects of a novel poly(ADP-ribose)polymerase(PARP)1/2 inhibitor,YHP-836,in combination with temozolomide(TMZ)for the treatment of glioblastoma(GBM).The cytotoxicity of YHP-836 was tested alone or in combination with TMZ using MTT assay.Immunoblotting and flow cytometry were also employed to assess the combination activity of YHP-836 and TMZ in multiply GBM cell lines.Further,the antitumor activity of YHP-836 and TMZ was evaluated using subcutaneous and orthotopic mice xenograft tumor models.All procedures were approved by the Ethics Committee for Animal Experiments of the Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College and conducted under the Guidelines for Animal Experiments of Peking Union Medical College.The approval number is 00009138.It was demonstrated that the combination of YHP-836 and TMZ increased the cytotoxicity against GBM cells and upregulated histone H2AX phosphorylation(yH2AX)expression levels compared to TMZ treatment alone.The combination also led to the S-phase cell cycle arrest.Moreover,YHP-836 significantly enhanced TMZ antitumor effects without significantly increasing chemotherapy drug toxicity in vivo,whereas YHP-836 alone showed limited therapeutic efficacy against GBM.In conclusion,the novel PARP1/2 inhibitor,YHP-836,sensitizes TMZ and provides a basis for further investigation into its mechanism of action.These findings suggest that YHP-836 may be a potential candidate for combination therapy with TMZ in patients with TMZ resistance.
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