Published online Feb 14, 2020. doi: 10.3748/wjg.v26.i6.598
Peer-review started: October 15, 2019
First decision: December 4, 2019
Revised: December 20, 2019
Accepted: January 15, 2020
Article in press: January 15, 2020
Published online: February 14, 2020
The prognosis of gastric cancer continues to remain poor, and epigenetic drugs like histone deacetylase inhibitors (HDACi) have been envisaged as potential therapeutic agents. Nevertheless, clinical trials are facing issues with toxicity and efficacy against solid tumors, which may be partly due to the lack of patient stratification for effective treatments.
To study the need of patient stratification before HDACi treatment, and the efficacy of pre-treatment of HDACi as a chemotherapeutic drug sensitizer.
The expression activity of class 1 HDACs and histone acetylation was examined in human gastric cancer cells and tissues. The potential combinatorial regime of HDACi and chemotherapy drugs was defined on the basis of observed drug binding assays, chromatin remodeling and cell death.
In the present study, the data suggest that the differential increase in HDAC activity and the expression of class 1 HDACs are associated with hypo-acetylation of histone proteins in tumors compared to normal adjacent mucosa tissue samples of gastric cancer. The data highlights for the first time that pre-treatment of HDACi results in an increased amount of DNA-bound drugs associated with enhanced histone acetylation, chromatin relaxation and cell cycle arrest. Fraction-affected plots and combination index-based analysis show that pre-HDACi chemo drug combinatorial regimes, including valproic acid with cisplatin or oxaliplatin and trichostatin A with epirubicin, exhibit synergism with maximum cytotoxic potential due to higher cell death at low combined doses in gastric cancer cell lines.
Expression or activity of class 1 HDACs among gastric cancer patients present an effective approach for patient stratification. Furthermore, HDACi therapy in pre-treatment regimes is more effective with chemotherapy drugs, and may aid in predicting individual patient prognosis.
Core tip: Our study suggests that pre-treatment with histone deacetylase inhibitors (HDACi) in a pre-clinical model of gastric cancer increases acetylation, opens chromatin and favors synergistic binding of DNA-interacting chemotherapeutic drugs. This enhances the cytotoxic potential of chemotherapeutic drugs at low therapeutic doses, and reduces toxicity. The dose response studies using Fa plots and median curve analysis proposes valproic acid as the most synergistic and effective HDACi in combination with platinum-based drugs. Furthermore, HDAC expression, or activity-based patient stratification prior to HDACi therapy, has been put forth for better clinical outcomes of chemotherapeutic drugs in solid tumors.