17‑AAG synergizes with Belinostat to exhibit a negative effect on the proliferation and invasion of MDA‑MB‑231 breast cancer cells

Abstract

Breast cancer is one of the most common malignancies that threaten the health of women. Although there are a few chemotherapies for the clinical treatment of breast cancer, these therapies are faced with the problems of drug-resistance and metastasis. Drug combination can help to reduce the adverse side effects of chemotherapies using single drugs, and also help to overcome common drug-resistance during clinical treatment of breast cancer. The present study reported the synergistic effect of the heat shock protein 90 inhibitor 17-AAG and the histone deacetylase 6 inhibitor Belinostat in triple-negative breast cancer (TNBC) MDA-MB-231 cells, by detection of proliferation, apoptosis and cell cycle arrest following treatment with this combination. Subsequently, RNA sequencing (RNA-seq) data was collected and analyzed to investigate the synergistic mechanism of this combination. Based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways revealed by RNA-seq data analysis, a wound-healing assay was used to investigate the effect of this combination on the migration of MDA-MB-231 cells. Compared with treatment with 17-AAG or Belinostat alone, both the viability inhibition and apoptosis rate of MDA-MB-231 cells were significantly enhanced in the combination group. The combination index values were <1 in three concentration groups. Revealed by the RNA-seq data analysis, the most significantly enriched KEGG pathways in the combination group were closely associated with cell migration. Based on these findings, the anti-migration effect of this combination was investigated. It was revealed that the migration of MDA-MB-231 cells was significantly suppressed in the combination group compared with in the groups treated with 17-AAG or Belinostat alone. In terms of specific genes, the mRNA expression levels of TEA domain family proteins were significantly decreased in the combination group, whereas the phosphorylation of YY1 associated protein 1 and modulator of VRAC current 1 was significantly enhanced in the combination group. These alterations may help to explain the anti-migration effect of this combination. Belinostat has already been approved as a treatment for T-cell lymphoma and 17-AAG is undergoing clinical trials. These findings could provide a beneficial reference for the clinical treatment of patients with TNBC.

Vorinostat (SAHA) and Breast Cancer: An Overview

“…Since HDIs have proven insufficient to treat solid tumors alone, preclinical studies are ongoing to find appropriate drug combinations to make them suitable for use. Some HDIs have been successfully tested in combination in preclinical studies for many types of solid tumors, including larynx cancer [ 77 ], lung cancer [ 78 , 79 ], breast cancer [ 80 ], glioblastoma [ 81 ], and prostate cancer [ 82 ]. No sirtuin inhibitors have been approved by FDA so far.…”

Effects of Radiotherapy in Combination With Irinotecan and 17-AAG on Bcl-2 and Caspase 3 Gene Expression in Colorectal Cancer Cells

“…22 The 17-AAG binding affinity to HSP90 protein in cancerous cells is higher than in normal cells. 31 With the purpose of overcoming resistance in CRC therapies, the study of new treatments options is essential to recognize effective treatments including combinatorial treatments. 22,27 Consequently, in this study, the anti-cancer effects of irinotecan as the conventional chemotherapeutic agent, in comparison with 17-AAG as possible radiosensitizers, in the CRC cell line were investigated.…”

CXCL1 Clone Evolution Induced by the HDAC Inhibitor Belinostat Might Be a Favorable Prognostic Indicator in Triple-Negative Breast Cancer

“…Each treatment group was performed in duplicate. The mRNA expression profiles were determined using the Illumina HiSeq 2500 mRNA sequencing platform (Illumina Inc., USA) and normalized as fragments per kilobase of exons per million mapped reads (FPKM) data [ 27 ]. Among those sets, we chose the belinostat treatment group to probe the molecular alterations responding to HDAC inhibitors.…”