Intravesical instillation of c-MYC inhibitor KSI-3716 suppresses orthotopic bladder tumor growth

Purpose: c-Myc is a promising target for Cancer therapy but its use is restricted by unwanted, devastating side effects. We explored whether intravesical instillation of the c-Myc Inhibitor KSI-3716 could suppress tumor growth in murine orthotopic bladder xenografts.

Materials and methods: The small molecule KSI-3716, which blocks c-Myc/MAX binding to target gene promoters, was used as an intravesical chemotherapy agent. KSI-3716 action was assessed by electrophoretic mobility shift assay, chromatin immunoprecipitation, transcription reporter assay and quantitative reverse transcriptase-polymerase chain reaction. Inhibition of cell proliferation and its mechanism was monitored by cell cytotoxicity assay, EdU incorporation assay and flow cytometry. The in vivo efficacy of KSI-3716 was examined by noninvasive luminescence imaging and histological analysis after intravesical instillation of KSI-3716 in murine orthotopic bladder xenografts.

Results: KSI-3716 blocked c-Myc/MAX from forming a complex with target gene promoters. c-Myc mediated transcriptional activity was inhibited by KSI-3716 at concentrations as low as 1 μM. The expression of c-Myc target genes, such as cyclin D2, CDK4 and hTERT, was markedly decreased. KSI-3716 exerted cytotoxic effects on bladder Cancer cells by inducing cell cycle arrest and Apoptosis. Intravesical instillation of KSI-3716 at a dose of 5 mg/kg significantly suppressed tumor growth with minimal systemic toxicity.

Conclusions: The c-Myc Inhibitor KSI-3716 could be developed as an effective intravesical chemotherapy agent for bladder Cancer.