Abstract
Background and Objective: Alterations in gene expressions are often due to epigenetic modifications that can have a significant influence on cancer development, growth, and progression. Lately, histone deacetylase inhibitors (HDACi) such as suberoylanilide hydroxamic acid (SAHA, or vorinostat, MK0683) have been emerging as a new class of drugs with promising therapeutic benefits in controlling cancer growth and metastasis. The small molecule RG7388 (idasanutlin, R05503781) is a newly developed inhibitor that is specific for an oncogene-derived protein called MDM2, which is also in clinical trials for the treatment of various types of cancers. These two drugs have shown the ability to induce p21 expression through distinct mechanisms in MCF-7 and LNCaP cells, which are reported to have wild-type TP53. Our understanding of the molecular mechanism whereby SAHA and RG7388 can induce cell cycle arrest and trigger cell death is still evolving. In this study, we performed experiments to measure the cell cycle arrest effects of SAHA and RG7388 using MCF-7 and LNCaP cells. Materials and Methods: The cytotoxicity, cell cycle arrest, and apoptosis/necroptosis effects of the SAHA and RG7388 treatments were assessed using the Trypan Blue dye exclusion (TBDE) method, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, fluorescence assay with DEVD-amc substrate, and immunoblotting methods. Results: The RG7388 treatment was able to induce cell death by elevating p21WAF1/CIP1 through inhibition of MDM2 in LNCaP, but not in MCF-7 cells, even though there was evidence of p53 elevation. Hence, we suspect that there is some level of uncoupling of p53-mediated transcriptional induction of p21WAF1/CIP1 in MCF-7 cells. Conclusion: Our results from MCF-7 and LNCaP cells confirmed that SAHA and RG7388 treatments were able to induce cell death via a combination of cell cycle arrest and cytotoxic mechanisms. We speculate that our findings could lead to the development of newer treatments for breast and prostate cancers with drug combinations including HDACi.
Highlights
Breast cancer is one of the most common causes of cancer-related deaths worldwide
Our results suggest that the cell death caused by SAHA treatment in both cell lines was primarily through induction of p21WAF1/CIP1 and p27Kip1 levels, that is independent of p53
In support of this conclusion it has been reported in the literature that the elevated levels of acetylated histones (H2 and H3) and consequent activation of intracellular signals including p21WAF1/CIP1 elevation are responsible for the cell cycle arrest and cell death that are typically observed in cancer cells when
Summary
Breast cancer is one of the most common causes of cancer-related deaths worldwide. Despite the continued efforts around the globe, there has been only marginal improvements in breast-cancerrelated treatment success. The median survival time for patients with metastatic breast cancer is no more than 1 year [1]. The need for new drugs and efficient strategies for effectively treating aggressive cancers continues to exist. The development of cancer is triggered by a complex process of tumorigenesis, they are intimately linked to gene mutations and abnormal gene expressions. Epigenetic changes, which are known to affect the gene transcription without modifying the underlying DNA sequence, are very common and significant in the process of tumorigenesis. Acetylation of histone is one of the most common epigenetic modifications that is regulated largely by histone acetyltransferases (HATs), which transfer the hydrophobic acetyl group from acetyl coenzyme A to specific lysine residues on the N-terminal tails of histone H2A, H2B, H3 and H4 [4]
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