Autophagic Vacuole Secretion Triggered by Chidamide Participates in TRAIL Apoptosis Effect in Breast Cancer Cells

Author(s): Weiqiang Zhou*, Han Han, Junnan Xu, Tao Sun*, Xiuyan Feng*

Journal Name: Current Pharmaceutical Design

Volume 27 , Issue 20 , 2021


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Abstract:

Background: Breast cancer is one of the most prevalent diseases threatening women's health today. Indepth research on breast cancer (BC) pathogenesis and prevention and treatment methods are gradually receiving attention. Chidamide is a novel histone deacetylase inhibitor (HDACi) that depresses the function of histone deacetylase, consequently affecting the growth of BC cells through epigenetic modification. However, preclinical and clinical studies show that chidamide is ineffective in long-term treatment. We demonstrated in previous experiments that TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in BC cells and is significantly less non-toxic to normal cells than chidamide. Therefore, in this study, we treated BC cells with chidamide and TRAIL to explore a novel option to reduce the clinical toxicity through augmenting the sensitivity for BC cells.

Methods and Results: Results from the MTT and cell viability assays indicated that the combination of chidamide and TRAIL in MCF-7 and MDA-MB-231 cells induced BC cell death, while maintaining a reduced concentration of chidamide. Autophagy assay and annexin V analysis showed that the autophagosome microtubuleassociated protein1light chain3-II (LC3-II) was abnormally increased and much more early and late phase of apoptotic cells appeared during chidamide and TRAIL induction. Anti-tumor assays in a BC tumor xenograft model displayed that the mixture of chidamide and TRAIL exhibited stronger effects on inhibiting tumor growth. The data from real-time PCR and western blotting showed that the cytotoxic effect correlated with the expressions of related apoptosis and autophagy factors.

Conclusion: Our data are the first to demonstrate the synergistic effects of chidamide and TRAIL in BC cells, specifically, the pharmacological effects on cell death induction. These results lay a solid experimental and theoretical basis to solve the clinical resistance of chidamide.

Keywords: Chidamide, TRAIL, apoptosis, drug resistance, breast cancer, HDACi.

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Article Details

VOLUME: 27
ISSUE: 20
Year: 2021
Published on: 11 August, 2020
Page: [2366 - 2380]
Pages: 15
DOI: 10.2174/1381612826666200811175513
Price: $65

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