Histone deacetylase inhibitor reverses multidrug resistance by attenuating the nucleophosmin level through PI3K/Akt pathway in breast cancer

Chen,Si-Ying; Zheng,Xiao-Wei; Cai,Jiang-Xia; Zhang,Wei-Peng; You,Hai-Sheng; Xing,Jian-Feng; Dong,Ya-Lin

doi:10.3892/ijo.2016.3528

Histone deacetylase inhibitor reverses multidrug resistance by attenuating the nucleophosmin level through PI3K/Akt pathway in breast cancer

Authors:
- Si-Ying Chen
- Xiao-Wei Zheng
- Jiang-Xia Cai
- Wei-Peng Zhang
- Hai-Sheng You
- Jian-Feng Xing
- Ya-Lin Dong
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Affiliations: Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, P.R. China, School of Pharmacy, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, P.R. China
Published online on: May 17, 2016 https://doi.org/10.3892/ijo.2016.3528
Pages: 294-304

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Abstract

The development of multidrug resistance (MDR) is the major obstacle in the chemotherapy of breast cancer, and it restricts the application of antitumor drugs in the clinic. Therefore it is urgent to search for ways to reverse MDR and restore sensitivity to chemotherapeutics in breast carcinoma. Currently, histone deacetylase inhibitors (HDACIs) offer a promising strategy for tumor therapy as the effective anticancer drugs. Based on the potential resistant target of nucleophosmin (NPM), the purpose of this study was to explore the reversal effect of a new synthetic histone deacetylase inhibitor, FA17, on MDR in methotrexate-resistant breast cancer cells (MCF-7/MTX) and xenograft tumors. It was shown that the abnormal expression of NPM induced MDR and inhibited downstream mitochondrial apoptotic pathway by activating PI3K/Akt signaling pathway in MCF-7/MTX cells. The reversal effect and molecular mechanism of FA17 were investigated both in vitro and in vivo. We found that FA17 could significantly reverse resistance and sensitize MCF-7/MTX cells to methotrexate. FA17 obviously enhanced resistant cell apoptosis, inhibited expressions of NPM and efflux transporters. Additionally, FA17 could reverse MDR via inactivating PI3K/Akt pathway and accelerating mitochondrial apoptotic pathway both in MCF-7/MTX cells and in xenograft tumors. Taken together, the novel histone deacetylase inhibitor could effectively reverse drug resistance due to suppressing the activity of NPM and drug efflux pumps by PI3K/Akt and mitochondrial apoptotic pathway. The above not only indicated the potential applied value of FA17 in reversing MDR and enhancing the sensitivity of chemotherapy, but also confirmed the role of NPM in the development of MDR in breast cancer.

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