PURPOSE: c-MYC is a promising target for cancer therapy but its utilization is restricted by unwanted and 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 utilized as an intravesical chemotherapeutic agent. The action of KSI-3716 was assessed by electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), transcription reporter assay and quantitative RT-PCR. Inhibition of cell proliferation and its mechanism were monitored by cell cytotoxicity assay, EdU incorporation assay and flow cytometry. The in vivo efficacy of KSI-3716 was examined by non-invasive 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 #x03BC;M, and the expression of c-MYC target genes such as cyclin D2, CDK4, and hTERT were markedly reduced. KSI-3716 was demonstrated to exert 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 chemotherapeutic agent for bladder cancer.
Written by:
Jeong KC, Kim KT, Seo HH, Shin SP, Ahn KO, Ji MJ, Park WS, Kim IH, Lee SJ, Seo HK. Are you the author?
Biomolecular Function Research Branch, National Cancer Center, Gyeonggi-do, Korea.
Reference: J Urol. 2013 Jul 17. pii: S0022-5347(13)04895-7.
doi: 10.1016/j.juro.2013.07.019
PubMed Abstract
PMID: 23872029
UroToday.com Investigative Urology Section
