Introduction/Background Paclitaxel (PTX) 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.

Methodology Two human cervical cancer cell lines (Me180 and HeLa) and two PI3K inhibitors (BYL-719 and LY294002) were used. We established paclitaxel-resistant cell lines (PTX-R Me180/PTX-R HeLa) and confirmed inhibitory concentrations (IC) 50 for each chemicals and combination index (CI) for paclitaxel and PI3K inhibitors by tetrazolium dye (MTT). Flow cytometry with Annexin/PI double or PI single staining were used to detect cell cycle and apoptosis. Migration and invasive abilities were explored by wound healing and transwell assays. Meanwhile, genes related to multiple pathways were assessed by western blot.

Results 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 PI3K pathway was significantly activated in paclitaxel-resistant Hela and Me180 cells compared to its parental cells (p<0.01). PTX + PI3K inhibitors)combinatorial therapy potentiated synergistic effect to strengthen paclitaxel induced S and G2M arrest in paclitaxel resistance subline cells by inactivation of cyclin A1(CCNA1), cyclin B1(CCNB1), cyclin E (CCNE), cdc2 expression. Moreover, the combinatory therapy significantly enhanced drug sensitivity and apoptosis through the activation of Bax, cleaved-caspase-9, and cleaved poly ADP ribose polymerase (PARP) compared with paclitaxel alone. In addition, PI3K inhibition also suppressed tumor migration and invasive ability by targeting β-catenin, p-c-raf, matrix metalloproteinase-2 (MMP-2) and vascular endothelial cell growth factor (VEGF).

Conclusion We suggest that a combination of a PI3K inhibitor with paclitaxel may enhance antitumor activity through a cascade of PI3K signaling events.

Disclosure Nothing to disclose.