Effects of PI3K inhibitor NVP-BKM120 on overcoming drug resistance and eliminating cancer stem cells in human breast cancer cells.

Y Hu,J Liu,R Guo,W Ji,X Zhi,J Wei,J Zhang,Y Zhou

doi:10.1038/cddis.2015.363

Abstract

The multidrug resistance (MDR) phenotype often accompanies activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, which renders a survival signal to withstand cytotoxic anticancer drugs and enhances cancer stem cell (CSC) characteristics. As a result, PI3K/AKT-blocking approaches have been proposed as antineoplastic strategies, and inhibitors of PI3K/AKT are currently being trailed clinically in breast cancer patients. However, the effects of PI3K inhibitors on MDR breast cancers have not yet been elucidated. In the present study, the tumorigenic properties of three MDR breast cancer cell lines to a selective inhibitor of PI3K, NVP-BKM120 (BKM120), were assessed. We found that BKM120 showed a significant cytotoxic activity on MDR breast cancer cells both in vitro and in vivo. When doxorubicin (DOX) was combined with BKM120, strong synergistic antiproliferative effect was observed. BKM120 activity induced the blockage of PI3K/AKT signaling and NF-κB expression, which in turn led to activate caspase-3/7 and caspase-9 and changed the expression of several apoptosis-related gene expression. Furthermore, BKM120 effectively eliminated CSC subpopulation and reduced sphere formation of these drug-resistant cells. Our findings indicate that BKM120 partially overcomes the MDR phenotype in chemoresistant breast cancer through cell apoptosis induction and CSC abolishing, which appears to be mediated by the inhibition of the PI3K/AKT/NF-κB axis. This offers a strong rationale to explore the therapeutic strategy of using BKM120 alone or in combination for chemotherapy-nonresponsive breast cancer patients.

Highlights

The activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway is frequently implicated in resistance to anticancer therapies
The Multidrug resistance (MDR) breast cancer cell lines MCF-7/A02 and CALDOX were derived from chemosensitive cell lines MCF-7 and Cal[51], respectively
These results demonstrate that BKM120 is a potent cytotoxic agent to MDR breast cancer cells

Summary

Introduction

The activation of the PI3K/AKT pathway is frequently implicated in resistance to anticancer therapies. AKT can phosphorylate multiple substrates and downstream effectors, such as mTOR family, caspase family, cell cycle protein family and nuclear factor-κB (NF-κB), which contribute collectively to promote cell proliferation, survival, metastasis and chemoresistance.[10,11,12] As this signaling cascade has a central role in human breast cancer, development of novel strategies to overcome resistance and eliminate. NVP-BKM120 (referred hereafter as BKM120) is a potent and highly selective pan-class I PI3K inhibitor, which belongs to the 2,6-dimorpholino pyrimidine derivatives.[14] It selectively inhibits wild type and mutant PI3K p110 α, β, δ, γ isoforms and exerts a strong antiproliferative effect to induce apoptosis in several cancers by inhibiting the PI3K/AKT signaling pathway.[15,16,17] Phase I clinical trials show that overall.

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Conclusion