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

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 A...

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Autores principales: Zhu, Hua, Mao, Jia-Hui, Wang, Yin, Gu, Dong-Hua, Pan, Xiao-Dong, Shan, Yuxi, Zheng, Bing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716743/
https://www.ncbi.nlm.nih.gov/pubmed/29228703
http://dx.doi.org/10.18632/oncotarget.21432
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author Zhu, Hua
Mao, Jia-Hui
Wang, Yin
Gu, Dong-Hua
Pan, Xiao-Dong
Shan, Yuxi
Zheng, Bing
author_facet Zhu, Hua
Mao, Jia-Hui
Wang, Yin
Gu, Dong-Hua
Pan, Xiao-Dong
Shan, Yuxi
Zheng, Bing
author_sort Zhu, Hua
collection PubMed
description 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.
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spelling pubmed-57167432017-12-08 Dual inhibition of BRD4 and PI3K-AKT by SF2523 suppresses human renal cell carcinoma cell growth Zhu, Hua Mao, Jia-Hui Wang, Yin Gu, Dong-Hua Pan, Xiao-Dong Shan, Yuxi Zheng, Bing Oncotarget Research Paper 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. Impact Journals LLC 2017-09-30 /pmc/articles/PMC5716743/ /pubmed/29228703 http://dx.doi.org/10.18632/oncotarget.21432 Text en Copyright: © 2017 Zhu et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Research Paper
Zhu, Hua
Mao, Jia-Hui
Wang, Yin
Gu, Dong-Hua
Pan, Xiao-Dong
Shan, Yuxi
Zheng, Bing
Dual inhibition of BRD4 and PI3K-AKT by SF2523 suppresses human renal cell carcinoma cell growth
title Dual inhibition of BRD4 and PI3K-AKT by SF2523 suppresses human renal cell carcinoma cell growth
title_full Dual inhibition of BRD4 and PI3K-AKT by SF2523 suppresses human renal cell carcinoma cell growth
title_fullStr Dual inhibition of BRD4 and PI3K-AKT by SF2523 suppresses human renal cell carcinoma cell growth
title_full_unstemmed Dual inhibition of BRD4 and PI3K-AKT by SF2523 suppresses human renal cell carcinoma cell growth
title_short Dual inhibition of BRD4 and PI3K-AKT by SF2523 suppresses human renal cell carcinoma cell growth
title_sort dual inhibition of brd4 and pi3k-akt by sf2523 suppresses human renal cell carcinoma cell growth
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716743/
https://www.ncbi.nlm.nih.gov/pubmed/29228703
http://dx.doi.org/10.18632/oncotarget.21432
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