Kyung-Chae Jeong1, Kyung-Tae Kim2, Hye-Hyun Seo3, Seung-Pil Shin3, Kyung-Ohk Ahn1, Min-Ju Ji2, Weon Seo Park4, In-Hoo Kim5, Sang-Jin Lee6, Ho Kyung Seo7. 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: leesj@ncc.re.kr. 7. Center for Prostate Cancer, National Cancer Center, Gyeonggi-do, Republic of Korea. Electronic address: seohk@ncc.re.kr.
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.
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.
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Authors: Ho Kyung Seo; Jeong Bin Seo; Jae-Kook Nam; Kyung-Chae Jeong; Seung-Pil Shin; In-Hoo Kim; Sang Don Lee; Sang-Jin Lee Journal: Oncotarget Date: 2014-07-30