Trichostatin A sensitizes hepatoma cells to Taxol more than 5-Aza-dC and dexamethasone

Thoria Donia; Sherien Khedr; Elsayed I Salim; Mohamed Hessien

doi:10.1515/dmdi-2020-0186

Trichostatin A sensitizes hepatoma cells to Taxol more than 5-Aza-dC and dexamethasone

Drug Metab Pers Ther. 2021 Apr 5. doi: 10.1515/dmdi-2020-0186. Online ahead of print.

Authors

Thoria Donia¹, Sherien Khedr¹, Elsayed I Salim², Mohamed Hessien¹

Affiliations

¹ Division of Biochemistry, Department of Chemistry, Faculty of Science, Tanta University, Tanta, Egypt.
² Department of Zoology, Faculty of Science, Tanta University, Tanta, Egypt.

PMID: 33818027
DOI: 10.1515/dmdi-2020-0186

Abstract

Objectives: This work was designed to compare the sensitizing effects of epigenetic modifiers on cancer cells vs. that of glucocorticoids. Also, to evaluate their effects on genes involved in epigenetic changes and drug metabolism.

Methods: Hepatoma cells (HepG2) were treated with the anticancer drug (Taxol), with a histone deacetylase inhibitor (Trichostatin A [TSA]), DNA methyltransferase inhibitor (5-Aza-dC) or dexamethasone (DEX). Cytotoxicity was assessed by MTT assay and the apoptosis was determined by Annexin V-FITC. The expression levels of HDAC1, HDAC3, Dnmt1, Dnmt3α, CYP1A2, CYP3A4, CYP2B6, CYP2C19 and CYP2D6 were monitored by qRT-PCR.

Results: TSA, synergistically enhanced cells sensitivity with the anticancer effect of Taxol more than 5-Aza-dC and DEX. This was evidenced by the relative decrease in IC₅₀ in cells cotreated with Taxol + TSA, Taxol + 5-Aza-dC or Taxol + DEX. Apoptosis was induced in 51.2, 16.9 and 41.3% of cells, respectively. In presence of Taxol, TSA induced four-fold increase in the expression of HDAC1 and downregulated Dnmt1&3α genes. CYP2D6 demonstrated progressive expression (up to 28-fold) with the increasing number of drugs. Moreover, the isoform overexpressed in cells treated with TSA + Taxol > DEX + Taxol > 5-Aza-dC + Taxol (6.4, 4.6 and 2.99, respectively). The investigated genes were clustered in two distinct subsets, where no coregulation was observed between HDAC1 and HDAC3. However, tight pairwise correlation-based cluster was seen between (CYP3A4/Dnmt3α and CYP2D6/CYP2C19).

Conclusions: The data reflects the sensitizing effect of acetylation modification by TSA on the responsiveness of hepatoma cells to anticancer therapy. The effect of histone deacetylase inhibition was more than hypomethylation and glucocorticoid effects. TSA exerts its role through its modulatory role on epigenetics and drugs metabolizing genes. Other modifiers (5-Aza-dC and DEX), however may adopt different mechanisms.

Keywords: 5-Aza-dC; CYPs; Taxol; Trichostatin A; dexamethasone; hepatoma cells; histone deacetylase inhibitors.