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

// Hua Zhu 1, 2, * , Jia-Hui Mao 3, * , Yin Wang 4, * , Dong-Hua Gu 2 , Xiao-Dong Pan 2 , Yuxi Shan 1 and Bing Zheng 2 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 * These authors have contributed equally to this work Correspondence to: Yuxi Shan, email: drshanyuxisd@163.com Bing Zheng, email: bingzhengnantong@163.com Keywords: renal cell carcinoma (RCC); BRD4; PI3K-AKT-mTOR; SF2523; molecule-targeted therapy Received: August 09, 2017 Accepted: August 28, 2017 Published: September 30, 2017 ABSTRACT 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-O 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-O 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 .