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

  • Thoria Donia ORCID logo , Sherien Khedr ORCID logo , Elsayed I. Salim ORCID logo and Mohamed Hessien ORCID logo EMAIL logo
Published/Copyright: April 5, 2021
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Drug Metabolism and Personalized Therapy
From the journal Drug Metabolism and Personalized Therapy Volume 36 Issue 4

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; dexamethasone; hepatoma cells; histone deacetylase inhibitors; Taxol; Trichostatin A
Corresponding author: Mohamed Hessien, Division of Biochemistry, Department of Chemistry, Faculty of Science, Tanta University, Tanta, Egypt, E-mail:

  1. Research funding: None declared.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Authors state no conflict of interest.

  4. Informed consent: Not applicable.

  5. Ethical approval: Not applicable.

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Received: 2020-12-05
Accepted: 2021-03-16
Published Online: 2021-04-05

© 2021 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Review
  3. Oxy+ (arthrospira) and its medicinal importance: an appraisal
  4. Original Articles
  5. In vitro inhibitory effects of glucosamine, chondroitin and diacerein on human hepatic CYP2D6
  6. Efficacy of Majoon-e-Seer Alvi Khan in dyslipidemia: a single blind randomized standard controlled clinical trial
  7. Prevalence of alcohol-drug interactions in community-dwelling older patients with polypharmacy
  8. Evaluation of the need for pharmacogenomics testing among physicians in the West Bank of Palestine
  9. Habitual khat chewing alters urinary inorganic profile in adult healthy males
  10. Trichostatin A sensitizes hepatoma cells to Taxol more than 5-Aza-dC and dexamethasone
  11. Ocimum gratissimum leaf extract ameliorates phenylhydrazine-induced anaemia and toxicity in Wistar rats
  12. Lactobacillus plantarum mitigates sexual-reproductive deficits by modulating insulin receptor expression in the hypothalamic-pituitary-testicular axis of hyperinsulinemic mice
  13. Consumption of Ashtanga Ghrita (clarified cow butter added with herb extracts) improves cognitive dysfunction induced by scopolamine in rats via regulation of acetylcholinesterase activity and oxidative stress
  14. Letter to the Editor
  15. Fatal thiopurine toxicity: pre-emptive testing of NUDT15 415C>T polymorphism may be life saving in South Asian population
https://doi.org/10.1515/dmpt-2020-0186
Keywords for this article
5-Aza-dC; CYPs; dexamethasone; hepatoma cells; histone deacetylase inhibitors; Taxol; Trichostatin A

Articles in the same Issue

  1. Frontmatter
  2. Review
  3. Oxy+ (arthrospira) and its medicinal importance: an appraisal
  4. Original Articles
  5. In vitro inhibitory effects of glucosamine, chondroitin and diacerein on human hepatic CYP2D6
  6. Efficacy of Majoon-e-Seer Alvi Khan in dyslipidemia: a single blind randomized standard controlled clinical trial
  7. Prevalence of alcohol-drug interactions in community-dwelling older patients with polypharmacy
  8. Evaluation of the need for pharmacogenomics testing among physicians in the West Bank of Palestine
  9. Habitual khat chewing alters urinary inorganic profile in adult healthy males
  10. Trichostatin A sensitizes hepatoma cells to Taxol more than 5-Aza-dC and dexamethasone
  11. Ocimum gratissimum leaf extract ameliorates phenylhydrazine-induced anaemia and toxicity in Wistar rats
  12. Lactobacillus plantarum mitigates sexual-reproductive deficits by modulating insulin receptor expression in the hypothalamic-pituitary-testicular axis of hyperinsulinemic mice
  13. Consumption of Ashtanga Ghrita (clarified cow butter added with herb extracts) improves cognitive dysfunction induced by scopolamine in rats via regulation of acetylcholinesterase activity and oxidative stress
  14. Letter to the Editor
  15. Fatal thiopurine toxicity: pre-emptive testing of NUDT15 415C>T polymorphism may be life saving in South Asian population
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