BACKGROUND: Pharmacological inhibition of the phosphoinositide 3-kinase (PI3K)/Akt pathway prevents G(1) cell cycle progression into S, resulting in G(1) accumulation. The hypothesis that this arrest might negatively impact on chemotherapeutic agents primarily effective in S, G(2) or M-phase was investigated. MATERIALS AND METHODS: Inhibition of PI3K/Akt pathway signaling via LY294002 and Akti-1/2 was demonstrated by immunoblotting. Cell cycle progression was determined by flow cytometric analysis. Cell proliferation was assayed using the XTT cell viability assay. The Chou and Talalay median effect principal was used to evaluate drug interaction. RESULTS: In SKOV3 and IGROV1 human ovarian cancer cells, LY294002 and Akti-1/2 increased the percentage of cells in G(1) and reversed the cell cycle effects of cisplatin, paclitaxel, gemcitabine and topotecan. Pathway blockade synergistically enhanced the cytotoxicity of cisplatin and paclitaxel, but antagonized gemcitabine and topotecan effects. CONCLUSION: Pharmacological PI3K/Akt inhibition antagonizes the efficacy of chemotherapeutic agents primarily effective in the S or G(2)-phase of the cell cycle.
BACKGROUND: Pharmacological inhibition of the phosphoinositide 3-kinase (PI3K)/Akt pathway prevents G(1) cell cycle progression into S, resulting in G(1) accumulation. The hypothesis that this arrest might negatively impact on chemotherapeutic agents primarily effective in S, G(2) or M-phase was investigated. MATERIALS AND METHODS: Inhibition of PI3K/Akt pathway signaling via LY294002 and Akti-1/2 was demonstrated by immunoblotting. Cell cycle progression was determined by flow cytometric analysis. Cell proliferation was assayed using the XTT cell viability assay. The Chou and Talalay median effect principal was used to evaluate drug interaction. RESULTS: In SKOV3 and IGROV1 human ovarian cancer cells, LY294002 and Akti-1/2 increased the percentage of cells in G(1) and reversed the cell cycle effects of cisplatin, paclitaxel, gemcitabine and topotecan. Pathway blockade synergistically enhanced the cytotoxicity of cisplatin and paclitaxel, but antagonized gemcitabine and topotecan effects. CONCLUSION: Pharmacological PI3K/Akt inhibition antagonizes the efficacy of chemotherapeutic agents primarily effective in the S or G(2)-phase of the cell cycle.
Authors: Dejan Juric; Johann S de Bono; Patricia M LoRusso; John Nemunaitis; Elisabeth I Heath; Eunice L Kwak; Teresa Macarulla Mercadé; Elena Geuna; Maria Jose de Miguel-Luken; Chirag Patel; Keisuke Kuida; Serap Sankoh; Eric H Westin; Fabian Zohren; Yaping Shou; Josep Tabernero Journal: Clin Cancer Res Date: 2017-05-10 Impact factor: 12.531
Authors: Chi Hang Wong; Herbert H Loong; Connie W C Hui; Cecilia P Y Lau; Edwin P Hui; Brigette B Y Ma; Anthony T C Chan Journal: Invest New Drugs Date: 2013-08-24 Impact factor: 3.850
Authors: Timon A Bloedjes; Guus de Wilde; Chiel Maas; Eric Eldering; Richard J Bende; Carel J M van Noesel; Steven T Pals; Marcel Spaargaren; Jeroen E J Guikema Journal: Blood Adv Date: 2020-09-08
Authors: Xi Wang; Ping Gao; Fang Lin; Min Long; Yuanyuan Weng; Yongri Ouyang; Li Liu; Junxia Wei; Xi Chen; Ting He; Huizhong Zhang; Ke Dong Journal: Cancer Cell Int Date: 2013-11-14 Impact factor: 5.722