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Dual inhibition of BRD4 and PI3K-AKT by SF2523 suppresses human renal cell carcinoma cell growth

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机构: [1]The Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, China [2]The Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, China [3]Department of Pathophysiology, Nantong University School of Medicine, Nantong, China [4]Institute of Neuroscience, Soochow University, Suzhou, China
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关键词: renal cell carcinoma (RCC) BRD4 Pl3K-AKT-mTOR SF2523 molecule-targeted therapy

摘要:
Bromodomain-containing protein 4 (BRD4) and PI3K-AKT are both important for renal cell carcinoma (RCC) development and progression. SF2523 is a BRD4 and PI3K-AKT dual inhibitor. The present study demonstrated that SF2523 was cytotoxic and anti-proliferative to established RCC cell lines (786-0 and A498) and primary human RCC cells. SF2523 induced activation of caspase and apoptosis in RCC cells. Further, SF2523 disrupted RCC cell cycle progression and inhibited cell migration in vitro. At the signaling level, SF2523 in-activated PI3K-AKT-mTOR, and downregulated BRD4-dependent proteins, Bcl-2 and Myc, in RCC cells. Remarkably, SF2523 was more efficient than Wortmannin (the PI3K inhibitor) and JQ1 (the BRD4 specific inhibitor) in killing RCC cells. In vivo, SF2523 administration at well-tolerated doses suppressed 786-0 xenograft tumor growth in severe combined immunodeficient (SCID) mice. Together, our results suggest that concurrent blockage of BRD4 and PI3K-AKT signalings by SF2523 efficiently inhibits RCC cell growth in vitro and in vivo.

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出版当年[2016]版:
大类 | 1 区 医学
小类 | 2 区 细胞生物学 2 区 肿瘤学
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出版当年[2015]版:
Q1 CELL BIOLOGY Q1 ONCOLOGY
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第一作者机构: [1]The Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, China [2]The Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, China
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通讯机构: [1]The Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, China [2]The Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, China
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