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.