Bcl-2/Bcl-xL inhibition predominantly synergistically enhances the anti-neoplastic activity of a low-dose CUSP9 repurposed drug regime against glioblastoma.

摘要: BACKGROUND AND PURPOSE Drug repurposing represents a promising approach to safely accelerate the clinical application of therapeutics with anti-cancer activity. In this study, we examined whether inhibition anti-apoptotic Bcl-2 family proteins and Bcl-xL enhances biological effects repurposed CUSP9 regimen in an vitro setting glioblastoma. EXPERIMENTAL APPROACH We applied 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assays assess cellular proliferation. Annexin V/propidium iodide tetramethylrhodamine, ethyl ester staining were used examine apoptosis. Western blotting, RT-PCR, specific knockdown experiments using siRNA employed molecular mechanisms action. KEY RESULTS Bcl-2/Bcl-xL exerted synergistic anti-proliferative across established, primary cultured, stem-like glioblastoma cells when combined which had been reduced only one tenth its proposed original concentration (CUSP9-LD). The combination treatment also led enhanced apoptosis loss mitochondrial membrane potential activation caspases. On level, CUSP9-LD counteracted ABT263-mediated up-regulation Mcl-1. Silencing Mcl-1 indicates that down-regulation is crucial for induction cell death by treatment. CONCLUSION IMPLICATIONS These data suggest susceptibility towards CUSP9, allowing dramatic dose reduction potentially decreased toxicity clinically. A trial involving CUSP doses (CUSP9v3) currently ongoing our institution (NCT02770378). inhibitor ABT263 trials might represent valuable adjunct CUSP.