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
Alterations of the epigenome play an important role during the process of gastric carcinogenesis. Therefore, drugs like histone deacetylase inhibitors (HDACi) are being explored for their anti-tumor activity.
Identify alterations in the epigenetic milieu of gastric cancer, and check whether the concomitant usage of HDACi with chemotherapeutic drugs increases the drug’s efficacy.
This study aimed to reveal the most optimal combination of chemotherapeutic drugs, as well as HDACi type, dose and regime (pre, post and concurrent). The biochemical mechanism of action was investigated, and the combination was tested in an in vivo system.
This study utilized paired gastric cancer human samples, along with the gastric adenocarcinoma cell line AGS and immortalized normal counterpart HFE145. The efficacy of several chemotherapeutic agents and HDACi was tested in the AGS cell line, and the final combination was tested in an animal model of gastric cancer.
Gastric cancer patients showed differential HDAC activity and levels. Furthermore, pretreatment of valproic acid followed by cisplatin favors an open chromatin conformation via increased histone acetylation. These changes increase the binding of cisplatin to DNA at lower concentrations. In vivo studies suggest a better response with pretreatment regimes that do not cause toxicity.
This study described that decreased histone acetylation in human gastric cancer tumor samples may be attributed to differential/elevated histone deacetylase activity and expression. Additionally, pre-treatment with HDACi was the most optimal regime that maximally enhanced the cell killing potential of chemotherapeutic drugs. This was achieved by increased intercalation of the drug in chromatin post-HDACi treatment. The pre-treatment of HDACi valproic acid and cisplatin was able to decrease tumor volume in vivo compared to cisplatin alone.
This pre-clinical study provides evidence that pre-treatment of HDACi followed by standard chemotherapeutic agents enhances the effectiveness of the drug. Hence, clinical testing of such combinations may be explored for better management of gastric cancer.