Chidamide Combined With Doxorubicin Induced p53-Driven Cell Cycle Arrest and Cell Apoptosis Reverse Multidrug Resistance of Breast Cancer.

Lixia Cao,Teng Pan,Dongdong Zhou,Jingjing Liu,Qianxi Yang,Jin Zhang,Shaorong Zhao,Zhendong Shi

doi:10.3389/fonc.2021.614458

Lixia Cao, Teng Pan + Show 6 more

Open Access

https://doi.org/10.3389/fonc.2021.614458

Copy DOI

Abstract

The multidrug-resistant (MDR) phenotype is usually accompanied by an abnormal expression of histone deacetylase (HDAC). Given that HDAC is vital in chromatin remodeling and epigenetics, inhibiting the role of HDAC has become an important approach for tumor treatment. However, the effect of HDAC inhibitors on MDR breast cancer has not been elucidated. This study aim to demonstrate the potential of chidamide (CHI) combined with the chemotherapy drug doxorubicin (DOX) to overcome chemotherapeutic resistance of breast cancer in vitro and in vivo, laying the experimental foundation for the next clinical application. The results showed that, CHI combined with DOX showed significant cytotoxicity to MDR breast cancer cells in vitro and in vivo compared with the CHI monotherapy. The cell cycle distribution results showed that CHI caused G0/G1 cell cycle arrest and inhibited cell growth regardless of the addition of DOX. At the same time, annexin V staining and TUNEL staining results showed that CHI enhanced the number of cell apoptosis in drug-resistant cells. The western blot analysis found that p53 was activated in the CHI-treated group and combined treatment group, and then the activated p53 up-regulated p21, apoptosis regulator recombinant protein (Puma), and pro-apoptotic protein Bax, down-regulated the apoptotic proteins Bcl-xL and Bcl-2, and activated the caspase cascade to induce apoptosis.

Highlights

Doxorubicin (DOX) is an anthracycline widely used as the firstline treatment of breast cancer [1, 2]
This study aim to demonstrate the potential of chidamide (CHI) combined with the chemotherapy drug doxorubicin (DOX) to overcome chemotherapeutic resistance of breast cancer in vitro and in vivo, laying the experimental foundation for the clinical application
The MDR breast cancer cells CALDOX and MCF-7/A02 were derived from chemosensitive cell lines Cal51 and MCF-7, respectively

Summary

Introduction

Doxorubicin (DOX) is an anthracycline widely used as the firstline treatment of breast cancer [1, 2]. The pharmacological effect of this drug is to intervene between gene base pairs of DNA, interfere with gene transcription, and inhibit the synthesis of DNA and RNA in tumor cells. The cancer cells become resistant to drugs. The effect of the drugs decreased significantly [3]. The drug resistance of breast cancer cells is the main reason for the failure of chemotherapy and the recurrence of the disease, and it is one of the problems that need to be solved urgently in clinical practice. The p53/p21 pathways are important factors for tumor cell resistance to chemotherapy drugs [7,8,9]

Methods

Results

Conclusion