GDC-0084 inhibits cutaneous squamous cell carcinoma cell growth
GDC-0084 inhibits cutaneous squamous cell carcinoma cell growth
复制标题
GDC-0084 抑制皮肤鳞状细胞癌细胞生长
DOI：
10.1016/j.bbrc.2018.07.139
复制
发表时间：
2018-09-10
影响因子：
3.1
通讯作者：
Zhao, Tian-lan
中科院分区：
文献类型：
--
作者：
Ding, Ling-tao;Zhao, Peng;Zhao, Tian-lan
GDC-0084是一种新型且有效的小分子PI 3 K-mTOR双重抑制剂。本研究检测了其在皮肤鳞状细胞癌（cSCC）细胞中的潜在活性。我们的结果显示，纳摩尔浓度的GDC-0084处理有效地抑制了建立的（A431、SCC-13和SCL-1系）和原代人cSCC细胞的存活和增殖。GDC-0084在cSCC细胞中诱导凋亡活化和细胞周期停滞。它在杀死cSCC细胞方面比其他已知的PI 3 K-Akt-mTOR抑制剂更有效，但对正常人皮肤成纤维细胞/角质形成细胞无细胞毒性。在A431细胞和原代cSCC细胞中，GDC-0084阻断关键PI 3 K-Akt-mTOR组分（包括p85、Akt、S6 K1和S6）的磷酸化。⑶ C-0084还抑制cSCC细胞中的DNA-PKcs活化。值得注意的是，通过组成性激活的DNA-PKcs（S2056 D）恢复DNA-PKcs激活部分抑制了GDC-0084诱导的A431细胞中的细胞死亡和凋亡。在体内，GDC-0084每日管饲有效地抑制小鼠中的A431异种移植肿瘤生长。在GDC-0084处理的肿瘤组织中，PI 3 K-Akt-mTOR和DNA-PKcs活化被显著抑制。总之，GDC-0084通过阻断PI 3 K-Akt-mTOR和DNA-PKcs信号传导在体外和体内抑制人cSCC细胞生长。(C)2018爱思唯尔公司All rights reserved.
GDC-0084 is a novel and potent small-molecule PI3K-mTOR dual inhibitor. The present study examined its potential activity in cutaneous squamous cell carcinoma (cSCC) cells. Our results show that GDC-0084 treatment at nanomole concentrations potently inhibited survival and proliferation of established (A431, SCC-13 and SCL-1 lines) and primary human cSCC cells. GDC-0084 induced apoptosis activation and cell cycle arrest in the cSCC cells. It was more efficient than other known PI3K-Akt-mTOR inhibitors in killing cSCC cells, but was non-cytotoxic to the normal human skin fibroblasts/keratinocytes. In A431 cells and primary cSCC cells, GDC-0084 blocked phosphorylation of key PI3K-Akt-mTOR components, including p85, Akt, S6K1 and S6. GDC-0084 also inhibited DNA-PKcs activation in cSCC cells. Significantly, restoring DNA-PKcs activation by a constitutively active-DNA-PKcs (S2056D) partially inhibited GDC-0084-induced cell death and apoptosis in A431 cells. In vivo, GDC-0084 daily gavage potently inhibited A431 xenograft tumor growth in mice. In GDC-0084-treated tumor tissues PI3K-Akt-mTOR and DNA-PKcs activation were significantly inhibited. In summary, GDC-0084 inhibits human cSCC cell growth in vitro and in vivo through blocking PI3K-Akt-mTOR and DNA-PKcs signalings. (C) 2018 Elsevier Inc. All rights reserved.