Tran Arthur-Quan, Sullivan Stephanie A, Chan Leo Li-Ying, Yin Yajie, Sun Wenchuan, Fang Ziwei, Dugar Sundeep, Zhou Chunxiao, Bae-Jump Victoria
Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Department of Advanced Technology R&D, Nexcelom Bioscience LLC, Lawrence, MA, United States.
Front Oncol. 2021 Feb 15;10:624498. doi: 10.3389/fonc.2020.624498. eCollection 2020.
SPR965 is an inhibitor of PI3K and mTOR C1/C2 and has demonstrated anti-tumorigenic activity in a variety of solid tumors. We sought to determine the effects of SPR965 on cell proliferation and tumor growth in human serous ovarian cancer cell lines and a transgenic mouse model of high grade serous ovarian cancer (KpB model) and identify the underlying mechanisms by which SPR965 inhibits cell and tumor growth. SPR965 showed marked anti-proliferative activity by causing cell cycle arrest and inducing cellular stress in ovarian cancer cells. Treatment with SPR965 significantly inhibited tumor growth in KpB mice, accompanied by downregulation of Ki67 and VEGF and upregulation of Bip expression in ovarian tumors. SPR965 also inhibited adhesion and invasion through induction of the epithelial-mesenchymal transition process. As expected, downregulation of phosphorylation of AKT and S6 was observed in SPR965-treated ovarian cancer cells and tumors. Our results suggest that SPR965 has significant anti-tumorigenic effects in serous ovarian cancer . Thus, SPR965 should be evaluated as a promising targeted agent in future clinical trials of ovarian cancer.
SPR965是一种PI3K和mTOR C1/C2的抑制剂，已在多种实体瘤中显示出抗肿瘤活性。我们试图确定SPR965对人浆液性卵巢癌细胞系和高级别浆液性卵巢癌转基因小鼠模型（KpB模型）中细胞增殖和肿瘤生长的影响，并确定SPR965抑制细胞和肿瘤生长的潜在机制。SPR965通过使卵巢癌细胞周期停滞并诱导细胞应激，表现出显著的抗增殖活性。用SPR965处理可显著抑制KpB小鼠的肿瘤生长，同时卵巢肿瘤中Ki67和VEGF表达下调，Bip表达上调。SPR965还通过诱导上皮-间质转化过程抑制黏附和侵袭。正如预期的那样，在经SPR965处理的卵巢癌细胞和肿瘤中观察到AKT和S6磷酸化水平下调。我们的结果表明，SPR965在浆液性卵巢癌中具有显著的抗肿瘤作用。因此，在未来的卵巢癌临床试验中，应将SPR965作为一种有前景的靶向药物进行评估。
