Abstract 338: Inhibition of phosphatidylinositol 3-kinase signaling antagonizes paclitaxel-mediated resistance in cervical cancer

Abstract

Abstract Paclitaxel is used as an effective treatment against advanced cervical cancer. However, acquired resistance limits its success and results in cancer progression. We investigated whether the inhibition of phosphatidylinositol 3-kinase (PI3K) signaling overcomes paclitaxel resistance in cervical cancer. Two human cervical cancer cell lines (Me180 and HeLa) were used. We established paclitaxel-resistant cell lines (PTX-R Me180/PTX-R HeLa) and confirmed inhibitory concentrations (IC)50 and cell death rates by tetrazolium dye (MTT) and apoptosis assays, respectively, after exposure to a combination of paclitaxel with PI3K inhibitors (LY294002 and BYL-719). Migration and invasive abilities were explored by wound healing and transwell assays, respectively. Western blots were performed to determine the mechanism underlying the antitumor effects of PI3K inhibitors.PTX-R Me180 and PTX-R HeLa cells were gradually established from parental cell lines by stepwise exposure to paclitaxel over 7 months and with stable resistance at under 20 nM. We found that the activation of the PI3K pathway in paclitaxel-resistant lines increased tumor growth and invasiveness, and impeded cell apoptosis. The combination of LY294002 or BYL-719 with paclitaxel significantly enhanced drug sensitivity and synergistic apoptosis through the activation of Bax, caspase-3, and cleaved poly ADP ribose polymerase compared with paclitaxel alone. In addition, PI3K inhibition also suppressed tumor migration and invasive ability by targeting vimentin, matrix metalloproteinase-9 and vascular endothelial cell growth factor.We suggest that a combination of a PI3K inhibitor with paclitaxel may enhance antitumor activity through a cascade of PI3K signaling events. Note: This abstract was not presented at the meeting. Citation Format: Youn Jin Choi, Yoo Yeon Jung, Jing Jing Liu. Inhibition of phosphatidylinositol 3-kinase signaling antagonizes paclitaxel-mediated resistance in cervical cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 338.