Yangjiong Xiao1,2,3,4, Yang Yu5, Pengcheng Jiang6, Yuhong Li7, Chao Wang7, Rong Zhang8. 1. Department of Obstetrics and Gynecology, Shanghai Fengxian District Central Hospital, Southern Medical University, 201499, Shanghai, China. xiaoyangjiong@alumni.sjtu.edu.cn. 2. State Key Laboratory of Respiratory Disease, Guangzhou Medical University, 510182, Guangzhou, China. xiaoyangjiong@alumni.sjtu.edu.cn. 3. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. xiaoyangjiong@alumni.sjtu.edu.cn. 4. Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, 200241, China. xiaoyangjiong@alumni.sjtu.edu.cn. 5. Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, 200241, China. 6. Department of Gynecology, Changzhou Second People's Hospital Affiliated to Nanjing Medical University, Changzhou, 213004, China. 7. Department of Gynecology, The International Peace Maternity & Child Health Hospital, The China Welfare Institute, Shanghai Jiaotong University, Shanghai, 200030, China. 8. Department of Obstetrics and Gynecology, Shanghai Fengxian District Central Hospital, Southern Medical University, 201499, Shanghai, China. rongzhang@163.com.
Abstract
PURPOSE: The PI3K/AKT/mTOR pathway is one of the most highly activated cellular signaling pathways in advanced ovarian cancer. Although several PI3K/AKT/mTOR inhibitors have been developed to treat various types of cancer, the antitumor efficacy of many of these compounds against ovarian cancer has remained unclear. METHODS: Here, we tested and compared a panel of 16 PI3K/AKT/mTOR inhibitors (XL765, Miltefosine, Rapamycin, CCI-779, RAD001, FK506, XL147, GSK2110183, IPI-145, GSK2141795, BYL719, GSK458, CAL-101, XL765 analogue SAR245409, Triciribine, and GDC0941) that have entered clinical trials for antitumor activity against ovarian cancer, as well as the front line drug, paclitaxel. Antitumor efficacy was measured in both ovarian cancer cell lines and patient-derived ovarian primary tumor cell lines in vitro and in vivo. RESULTS: We identified the PI3K/mTOR dual inhibitor GSK458 as a potent inhibitor of proliferation in all cell lines tested at half maximal inhibitory concentrations (IC50) of approximately 0.01-1 µM, a range tens to hundreds fold lower than that of the other PI3K/AKT/mTOR inhibitors tested. Additionally, GSK458 showed the highest inhibitory efficacy against ovarian cancer cell migration. GSK458 also inhibited tumor growth and metastasis in nude mice intraperitoneally engrafted with SKOV3 cells or a patient-derived tumor cell xenograft (PDCX). Importantly, the inhibitory efficiency of GSK458 on cell proliferation and migration both in vitro and in vivo was comparable to that of paclitaxel. Mechanistically, the anti-tumor activity of GSK458 was found to be associated with inactivation of AKT and mTOR, and induction of cell cycle arrest at the G0/G1 phase. CONCLUSIONS: Based on our results, we conclude that GSK458 may serve as an attractive candidate to treat ovarian cancer.
PURPOSE: The PI3K/AKT/mTOR pathway is one of the most highly activated cellular signaling pathways in advanced ovarian cancer. Although several PI3K/AKT/mTOR inhibitors have been developed to treat various types of cancer, the antitumor efficacy of many of these compounds against ovarian cancer has remained unclear. METHODS: Here, we tested and compared a panel of 16 PI3K/AKT/mTOR inhibitors (XL765, Miltefosine, Rapamycin, CCI-779, RAD001, FK506, XL147, GSK2110183, IPI-145, GSK2141795, BYL719, GSK458, CAL-101, XL765 analogue SAR245409, Triciribine, and GDC0941) that have entered clinical trials for antitumor activity against ovarian cancer, as well as the front line drug, paclitaxel. Antitumor efficacy was measured in both ovarian cancer cell lines and patient-derived ovarian primary tumor cell lines in vitro and in vivo. RESULTS: We identified the PI3K/mTOR dual inhibitor GSK458 as a potent inhibitor of proliferation in all cell lines tested at half maximal inhibitory concentrations (IC50) of approximately 0.01-1 µM, a range tens to hundreds fold lower than that of the other PI3K/AKT/mTOR inhibitors tested. Additionally, GSK458 showed the highest inhibitory efficacy against ovarian cancer cell migration. GSK458 also inhibited tumor growth and metastasis in nude mice intraperitoneally engrafted with SKOV3 cells or a patient-derived tumor cell xenograft (PDCX). Importantly, the inhibitory efficiency of GSK458 on cell proliferation and migration both in vitro and in vivo was comparable to that of paclitaxel. Mechanistically, the anti-tumor activity of GSK458 was found to be associated with inactivation of AKT and mTOR, and induction of cell cycle arrest at the G0/G1 phase. CONCLUSIONS: Based on our results, we conclude that GSK458 may serve as an attractive candidate to treat ovarian cancer.
Authors: Jacob P Veenstra; Lucas Felipe Fernandes Bittencourt; Katherine M Aird Journal: Am J Physiol Cell Physiol Date: 2022-05-18 Impact factor: 5.282
Authors: Natasha Rinne; Elizabeth L Christie; Anastasia Ardasheva; Chun Hei Kwok; Nikita Demchenko; Caroline Low; Catherine Tralau-Stewart; Christina Fotopoulou; Paula Cunnea Journal: Cancer Drug Resist Date: 2021-04-14