Strategic Perspectives on Improved Anti-Tumor Drug Effects in Combination with Clinically Equivalent or Lower Concentrations of Epigenetic Modifiers, DNA Methyltransferase Inhibitors, and Histone Deacetylase Inhibitors
Shuko Hakata, Kouji Okada, Jun Terashima, Toshie Gamou, Wataru Habano and Shogo Ozawa*
Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Nishitokuta, Yahaba-cho, Iwate 028-3694, Japan
- *Corresponding Author:
- Shogo Ozawa
Department of Pharmacodynamics and Molecular Genetics
School of Pharmacy, Iwate Medical University
Nishitokuta, Yahaba-cho, Shiwa-gun, Iwate 028-3694, Japan
Tel: 5262 19 651 5111
E-mail: [email protected]
Received Date: June 28, 2017; Accepted Date: July 12, 2017; Published Date: July 17, 2017
Citation: Hakata S, Okada K, Terashima J, Gamou T, Habano W, et al. (2017) Strategic Perspectives on Improved Anti-Tumor Drug Effects in Combination with Clinically Equivalent or Lower Concentrations of Epigenetic Modifiers, DNA Methyltransferase Inhibitors, and Histone Deacetylase Inhibitors. J Cancer Sci Ther 9: 541-544. doi: 10.4172/1948-5956.1000471
Copyright: © 2017 Hakata S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
The aim of this research is to facilitate the pursuit of improved chemotherapeutic drugs in combination with epigenetic modifiers. Both in vitro studies and a clinical study have described the combinations of DNA methyltransferase inhibitors with irinotecan and histone deacetylase inhibitors with 5-fluorouracil or gemcitabine to enhance their anti-cancer activities. The molecular mechanisms involved in the potentiation of anti-tumor activities were apoptosis regulation, cellular metabolism, DNA topoisomerase-I upregulation, cell-cell adhesion, regulation of transcription (DNA-templated), DNA repair, and the PI3K/AKT signaling pathway. More importantly, the priming effects and long-lasting effects induced by DNA methyltransferase inhibitors, when applied as a pretreatment, sensitized cancer cells to subsequent anti-cancer drug treatments. The combinations of 5-fluorouracil and gemcitabine with histone deacetylase inhibitors (depsipeptide and valproic acid, respectively), increased the expression of major histocompatibility complex class II, which may warrant further investigation for possible accurate biomarkers and therapeutic targets. As valproic acid downregulated histone deacetylase in patients recruited in a clinical phase I/II study, the activity of valproic acid may be associated with the enhanced anti-tumor activity in combination with 5-fluorouracil. This research provides a positive perspective on the combination therapy of anticancer drugs with epigenetic modifiers.