Intravesical Instillation of c-MYC Inhibitor KSI-3716 Suppresses Orthotopic Bladder Tumor Growth

No AccessJournal of UrologyInvestigative Urology1 Feb 2014Intravesical Instillation of c-MYC Inhibitor KSI-3716 Suppresses Orthotopic Bladder Tumor Growth Kyung-Chae Jeong, Kyung-Tae Kim, Hye-Hyun Seo, Seung-Pil Shin, Kyung-Ohk Ahn, Min-Ju Ji, Weon Seo Park, In-Hoo Kim, Sang-Jin Lee, and Ho Kyung Seo Kyung-Chae JeongKyung-Chae Jeong Biomolecular Function Research Branch, National Cancer Center, Gyeonggi-do, Republic of Korea , Kyung-Tae KimKyung-Tae Kim Molecular Epidemiology Branch, National Cancer Center, Gyeonggi-do, Republic of Korea , Hye-Hyun SeoHye-Hyun Seo Genitourinary Cancer Branch, National Cancer Center, Gyeonggi-do, Republic of Korea , Seung-Pil ShinSeung-Pil Shin Genitourinary Cancer Branch, National Cancer Center, Gyeonggi-do, Republic of Korea , Kyung-Ohk AhnKyung-Ohk Ahn Biomolecular Function Research Branch, National Cancer Center, Gyeonggi-do, Republic of Korea , Min-Ju JiMin-Ju Ji Molecular Epidemiology Branch, National Cancer Center, Gyeonggi-do, Republic of Korea , Weon Seo ParkWeon Seo Park Center for Prostate Cancer, National Cancer Center, Gyeonggi-do, Republic of Korea , In-Hoo KimIn-Hoo Kim Molecular Imaging and Therapy Branch, National Cancer Center, Gyeonggi-do, Republic of Korea , Sang-Jin LeeSang-Jin Lee Genitourinary Cancer Branch, National Cancer Center, Gyeonggi-do, Republic of Korea , and Ho Kyung SeoHo Kyung Seo Center for Prostate Cancer, National Cancer Center, Gyeonggi-do, Republic of Korea View All Author Informationhttps://doi.org/10.1016/j.juro.2013.07.019AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail 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. References 1 : Global cancer statistics. CA Cancer J Clin2011; 61: 69. Google Scholar 2 : Bladder cancer: epidemiology, staging and grading, and diagnosis. Urology2005; 66: 4. Google Scholar 3 : Intravesical bacillus Calmette-Guerin versus mitomycin C for Ta and T1 bladder cancer. Cochrane Database Syst Rev2003; : CD003231. 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Volume 191Issue 2February 2014Page: 510-518 Advertisement Copyright & Permissions© 2014 by American Urological Association Education and Research, Inc.Keywordsdrug therapyadministrationurinary bladder neoplasmsintravesicalheterograftsgene expressionAcknowledgmentsDr. Ozu, Tokyo Medical University, provided Ku19-19 and Ku7 cells.Metrics Author Information Kyung-Chae Jeong Biomolecular Function Research Branch, National Cancer Center, Gyeonggi-do, Republic of Korea Equal study contribution. More articles by this author Kyung-Tae Kim Molecular Epidemiology Branch, National Cancer Center, Gyeonggi-do, Republic of Korea Equal study contribution. More articles by this author Hye-Hyun Seo Genitourinary Cancer Branch, National Cancer Center, Gyeonggi-do, Republic of Korea More articles by this author Seung-Pil Shin Genitourinary Cancer Branch, National Cancer Center, Gyeonggi-do, Republic of Korea More articles by this author Kyung-Ohk Ahn Biomolecular Function Research Branch, National Cancer Center, Gyeonggi-do, Republic of Korea More articles by this author Min-Ju Ji Molecular Epidemiology Branch, National Cancer Center, Gyeonggi-do, Republic of Korea More articles by this author Weon Seo Park Center for Prostate Cancer, National Cancer Center, Gyeonggi-do, Republic of Korea More articles by this author In-Hoo Kim Molecular Imaging and Therapy Branch, National Cancer Center, Gyeonggi-do, Republic of Korea More articles by this author Sang-Jin Lee Genitourinary Cancer Branch, National Cancer Center, Gyeonggi-do, Republic of Korea More articles by this author Ho Kyung Seo Center for Prostate Cancer, National Cancer Center, Gyeonggi-do, Republic of Korea More articles by this author Expand All Advertisement PDF downloadLoading ...