Shen Gang, Jiang Minjun, Pu Jinxian
Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Department of Urology, Wujiang Hospital Affiliated to Nantong University, Suzhou, China.
Biochem Biophys Res Commun. 2018 Jan 1;495(1):567-573. doi: 10.1016/j.bbrc.2017.11.062. Epub 2017 Nov 10.
Bromodomain-containing protein 4 (BRD4) and phosphatidylinositol 3-kinase (PI3K) are both key oncogenic proteins in human prostate cancer. In the current study, we examined the anti-prostate cancer cell activity by SF2523, a BRD4 and PI3K dual inhibitor. We showed that SF2523 potently inhibited survival and proliferation of the primary human prostate cancer cells. SF2523 induced profound apoptosis activation in prostate cancer cells. The dual inhibitor was yet non-cytotoxic to the prostate epithelial cells. At the molecular level, SF2523 downregulated BRD4-regulated genes (cyclin D1, c-Myc and androgen receptor) and almost blocked AKT-S6K1 activation in prostate cancer cells. In vivo, SF2523 intraperitoneal administration at the well-tolerated dose inhibited human prostate cancer xenograft growth in severe combined immunodeficient (SCID) mice. BRD4-regulated genes (cyclin D1, c-Myc and androgen receptor) and AKT-S6K1 activation were inhibited in SF2523-treated tumors. Together, dual inhibition of BRD4 and PI3K by SF2523 suppresses human prostate cancer cell growth in vitro and in vivo.
含溴结构域蛋白4（BRD4）和磷脂酰肌醇3激酶（PI3K）都是人类前列腺癌中的关键致癌蛋白。在本研究中，我们检测了BRD4和PI3K双重抑制剂SF2523对前列腺癌细胞的抗癌活性。我们发现SF2523能有效抑制原代人前列腺癌细胞的存活和增殖。SF2523可诱导前列腺癌细胞发生深度凋亡激活。该双重抑制剂对前列腺上皮细胞无细胞毒性。在分子水平上，SF2523下调了BRD4调控的基因（细胞周期蛋白D1、c-Myc和雄激素受体），并几乎阻断了前列腺癌细胞中AKT-S6K1的激活。在体内，以耐受性良好的剂量腹腔注射SF2523可抑制严重联合免疫缺陷（SCID）小鼠体内人前列腺癌异种移植瘤的生长。在经SF2523处理的肿瘤中，BRD4调控基因（细胞周期蛋白D1、c-Myc和雄激素受体）以及AKT-S6K1的激活均受到抑制。总之，SF2523对BRD4和PI3K的双重抑制作用在体外和体内均能抑制人前列腺癌细胞的生长。
