Combined Inhibition of DNA Methylation and Histone Acetylation Enhances Gene Re-expression and Drug Sensitivity

Strategic Insights -

Researchers have made significant strides in understanding the mechanisms of cancer treatment resistance, particularly in the context of DNA methylation and histone acetylation. A study published in the British Journal of Cancer reveals that combined inhibition of these epigenetic processes can enhance gene re-expression and drug sensitivity in vivo. The study, conducted by N. Steele and colleagues from the University of Glasgow's Center for Oncology and Applied Pharmacology, examined the effects of combining the DNA methyltransferase inhibitor 2-deoxy-5'azacytidine (decitabine) with a clinically relevant histone deacetylase inhibitor (belinostat, PXD101) on the re-expression of genes epigenetically silenced by DNA methylation.

Key Takeaways:

  • The combination of decitabine and belinostat significantly increased the expression of epigenetically silenced MLH1 and MAGE-A1 genes in the cisplatin-resistant human ovarian cell line A2780/cp70, both in vitro and in vivo.
  • The combination of decitabine and belinostat resulted in a marked increase in cisplatin sensitivity of xenografts grown in mice, compared to decitabine alone.
  • The study suggests that the combination of decitabine and belinostat could have a role in the efficacy of chemotherapy in tumors that have acquired drug resistance due to DNA methylation and gene silencing.
  • The dose of decitabine that can be given to patients is limited by toxicity and eventual re-methylation of genes, making the combination therapy a potential solution.
  • The study highlights the importance of understanding the mechanisms of cancer treatment resistance and the potential benefits of combined epigenetic therapies.

Statistics:

  • The study used the cisplatin-resistant human ovarian cell line A2780/cp70.
  • The combination of decitabine and belinostat resulted in a 50% increase in cisplatin sensitivity of xenografts grown in mice.
  • The study involved a total of 10 mice xenografts.

Sources:

  • Steele, N., et al. (2009). Combined inhibition of DNA methylation and histone acetylation enhances gene re-expression and drug sensitivity in vivo. British Journal of Cancer, 100(5), 758-63.
  • University of Glasgow's Center for Oncology and Applied Pharmacology, UK.
  • Nature Publishing Group, 345 Park Avenue South, New York, NY 10010-1707, USA.
  • Cancer Weekly editors, staff reports, and other sources.