Xiaohong Zhang1, Tingting Qin2, Zhengyan Zhu3, Fan Hong2, Yang Xu2, Xiongjie Zhang1, Xiaohong Xu1, Aiping Ma4. 1. Department of Obstetrics and Gynecology, The People's Hospital of Hanchuan, Hanchuan, Hubei Province, China. 2. Department of Integrated Traditional Chinese and Western Medicine, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan, Hubei Province, China. 3. Department of Obstetrics and Gynecology, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan, Hubei Province, China. 4. Department of Obstetrics and Gynecology, The People's Hospital of Hanchuan, Hanchuan, Hubei Province, China. Electronic address: aipingma@aliyun.com.
Abstract
BACKGROUND: The poor outcomes in epithelial ovarian cancer necessitate new treatments. In this work, we systematically analyzed the inhibitory effects of ivermectin and the molecular mechanism of its action in ovarian cancer. METHODS: The effects of ivermectin alone and its combination with cisplatin on growth and survival were examined using cultured ovarian cancer cells and a xenograft mouse model. The molecular mechanism of action of ivermectin, focusing on Akt/mTOR signaling, was elucidated. RESULTS: Ivermectin arrested growth in the G2/M phase and induced caspase-dependent apoptosis in ovarian cancer, regardless of specific cellular and molecular differences. Ivermectin significantly augmented the inhibitory effect of cisplatin on ovarian cancer cells in a dose-dependent manner. Mechanistically, ivermectin suppressed the phosphorylation of key molecules in the Akt/mTOR signaling pathway in ovarian cancer cells. In addition, overexpression of constitutively active Akt restored ivermectin-induced inhibition of Akt/mTOR, growth arrest and apoptosis. In an ovarian cancer xenograft mouse model, ivermectin alone significantly inhibited tumor growth. In combination with cisplatin, tumor growth was completely reversed over the entire duration of drug treatment without any toxicity. Furthermore, the concentrations of ivermectin used in our study are pharmacologically achievable. CONCLUSIONS: Our work suggests that ivermectin may be a useful addition to the treatment armamentarium for ovarian cancer and that targeting Akt/mTOR signaling is a therapeutic strategy to increase chemosensitivity in ovarian cancer.
BACKGROUND: The poor outcomes in epithelial ovarian cancer necessitate new treatments. In this work, we systematically analyzed the inhibitory effects of ivermectin and the molecular mechanism of its action in ovarian cancer. METHODS: The effects of ivermectin alone and its combination with cisplatin on growth and survival were examined using cultured ovarian cancer cells and a xenograft mouse model. The molecular mechanism of action of ivermectin, focusing on Akt/mTOR signaling, was elucidated. RESULTS:Ivermectin arrested growth in the G2/M phase and induced caspase-dependent apoptosis in ovarian cancer, regardless of specific cellular and molecular differences. Ivermectin significantly augmented the inhibitory effect of cisplatin on ovarian cancer cells in a dose-dependent manner. Mechanistically, ivermectin suppressed the phosphorylation of key molecules in the Akt/mTOR signaling pathway in ovarian cancer cells. In addition, overexpression of constitutively active Akt restored ivermectin-induced inhibition of Akt/mTOR, growth arrest and apoptosis. In an ovarian cancer xenograft mouse model, ivermectin alone significantly inhibited tumor growth. In combination with cisplatin, tumor growth was completely reversed over the entire duration of drug treatment without any toxicity. Furthermore, the concentrations of ivermectin used in our study are pharmacologically achievable. CONCLUSIONS: Our work suggests that ivermectin may be a useful addition to the treatment armamentarium for ovarian cancer and that targeting Akt/mTOR signaling is a therapeutic strategy to increase chemosensitivity in ovarian cancer.
Authors: Jamila Mammadova; Anna Redden; Rachel Cruz; Maryssa Ellison; Tyra Gatewood; Carla Duff; Anthony Canella; Charurut Somboonwit; Chakrapol Sriaroon; Joseph F Dasso; Terry Harville; Roohi Ismail-Khan; Jolan E Walter; Sumai Gordon Journal: Front Oncol Date: 2022-06-29 Impact factor: 5.738
Authors: Maritza P Garrido; Allison N Fredes; Lorena Lobos-González; Manuel Valenzuela-Valderrama; Daniela B Vera; Carmen Romero Journal: Biomedicines Date: 2021-12-31