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

  • J Urol. 2014 Feb;191(2):510-8. doi: 10.1016/j.juro.2013.07.019.
Kyung-Chae Jeong  1 ,  Kyung-Tae Kim  2 ,  Hye-Hyun Seo  3 ,  Seung-Pil Shin  3 ,  Kyung-Ohk Ahn  1 ,  Min-Ju Ji  2 ,  Weon Seo Park  4 ,  In-Hoo Kim  5 ,  Sang-Jin Lee  6 ,  Ho Kyung Seo  7
Affiliations
  • 1. Biomolecular Function Research Branch, National Cancer Center, Gyeonggi-do, Republic of Korea.
  • 2. Molecular Epidemiology Branch, National Cancer Center, Gyeonggi-do, Republic of Korea.
  • 3. Genitourinary Cancer Branch, National Cancer Center, Gyeonggi-do, Republic of Korea.
  • 4. Center for Prostate Cancer, National Cancer Center, Gyeonggi-do, Republic of Korea.
  • 5. Molecular Imaging and Therapy Branch, National Cancer Center, Gyeonggi-do, Republic of Korea.
  • 6. Genitourinary Cancer Branch, National Cancer Center, Gyeonggi-do, Republic of Korea. Electronic address: [email protected].
  • 7. Center for Prostate Cancer, National Cancer Center, Gyeonggi-do, Republic of Korea. Electronic address: [email protected].
PMID: 23872029 DOI: 10.1016/j.juro.2013.07.019
Abstract

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.

Keywords
5-ethynyl-2′-deoxyuridine; CDK4; CRE; ChIP; DMSO; EdU; IC(50); PARP; PBS; PCR; PEG; RT-PCR; administration; chromatin immunoprecipitation; consensus response element; cyclin-dependent kinase 4; dimethyl sulfoxide; drug therapy; gene expression; hTERT; half inhibitory concentration; heterografts; human telomerase reverse transcriptase; intravesical; phosphate buffered saline; poly adenosine diphosphate ribose polymerase; polyethylene glycol; polymerase chain reaction; qRT-PCR; quantitative RT-PCR; reverse transcriptase-PCR; urinary bladder neoplasms.
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