Inhibition of Phosphatidylinositol 3-kinase (PI3K) Signaling Synergistically Potentiates Antitumor Efficacy of Paclitaxel and Overcomes Paclitaxel-Mediated Resistance in Cervical Cancer.

Oyoung Kim,Jing Jing Liu,Hye Won Lee,Youn Jin Choi,Soo Young Hur,Min Wha Baik,Jung Yoon Ho

doi:10.3390/ijms20143383

Abstract

Acquired paclitaxel (PTX) resistance limits its effectiveness and results in advanced cancer progression. This review investigated whether the inhibition of phosphatidylinositol 3-kinase (PI3K) signaling overcomes paclitaxel resistance in cervical cancer. It was established paclitaxel-resistant cell lines (PTX-R ME180/PTX-R HeLa) and determined the combination index for paclitaxel and PI3K inhibitors (BYL-719/ LY294002) by tetrazolium dye assay. Flow cytometry was used to detect the cell cycle and apoptosis. Migration and invasion were explored by wound healing and transwell assays. Genes related to multiple pathways were assessed by a western blot. It was found that the PI3K pathway was significantly activated in paclitaxel-resistant HeLa and ME180 cells compared to parental cells. PTX + PI3K inhibitor combined therapy showed a synergistic effect by strengthening paclitaxel-induced S and G2M arrest in PTX-R cell sublines by the inactivation of cyclin A1, cyclin B1, cyclin E, and Cdc2 expression. Moreover, combination therapy significantly enhanced drug sensitivity and apoptosis through the activation of Bax, and cleavage of poly-(ADP-ribose) polymerase compared with paclitaxel alone. In addition, PI3K inhibition also suppressed tumor migration and invasion by targeting β-catenin and matrix metalloproteinase-2/9. The authors suggest that the combination of a PI3K inhibitor with paclitaxel may enhance antitumor activity through a cascade of PI3K signaling events.

Highlights

Cervical cancer is the third most common gynecological malignancy and responsible for 10–15% of cancer-related deaths in women [1]
It was found that the PI3KCA mutation rate was 27.3%, ranking first place in the top 10 mutation gene list identified by Mutation Significance (MutSig) with q ≤ 0.1 (Figure 1C)
The authors attempted to characterize paclitaxel resistance in association with the phosphatidylinositol 3-kinase (PI3K) pathway by performing apoptosis and migration/invasion assays in cervical cancer cell lines

Summary

Introduction

Cervical cancer is the third most common gynecological malignancy and responsible for 10–15% of cancer-related deaths in women [1]. Even with surgery followed by aggressive front-line chemotherapy, which can yield cures in 80% to 90% of women with early stage I and II cervical cancers, the problem of advanced or recurrent cervical cancer failing to respond to conventional treatment remains unresolved [2,3,4]. Paclitaxel (PTX) is a microtubule-stabilizing agent widely employed as a front-line chemotherapeutic agent for cervical cancer (used alone or in combination with other therapeutic agents). It has a response rate of 29–63%, mainly due to acquired chemo-resistance, leading to a dismal prognosis [5,6]. The discovery of new resistance reversal agents with low toxicity that target resistance biomarkers is a major goal of cancer biologists and pharmacists

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Conclusion