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Protein arginine deiminase 4: a target for an epigenetic cancer therapy

Jessica L Slack1, Corey P Causey, Paul R Thompson

  • 1Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC, 29208, USA.

Cellular and Molecular Life Sciences : CMLS
|August 14, 2010
PubMed

Insights

Protein arginine deiminase 4 (PAD4) inhibitors, F- and Cl-amidine, show promise as novel epigenetic cancer treatments. These compounds exhibit cytotoxicity against cancer cells and potentiate doxorubicin

Area of Science:

  • Epigenetics and its role in human diseases
  • Cancer biology and therapeutic targets
  • Drug discovery and development

Background:

  • Epigenetic modifications are increasingly recognized as crucial in human diseases.
  • Histone deacetylases and DNA methyltransferases are validated epigenetic drug targets.
  • Protein arginine deiminase 4 (PAD4) influences gene expression similarly to other epigenetic regulators.

Purpose of the Study:

  • To investigate PAD4 as a novel epigenetic drug target for cancer therapy.
  • To evaluate the efficacy of PAD4 inhibitors, F- and Cl-amidine, against cancer cell lines.
  • To explore the potential of PAD4 inhibition in combination with existing chemotherapeutics.

Main Methods:

  • Cytotoxicity assays on various human cancerous and noncancerous cell lines.
  • Cell differentiation induction studies.
  • Combination studies with doxorubicin to assess synergistic effects.

Main Results:

  • F- and Cl-amidine demonstrated micromolar cytotoxic effects on HL-60, MCF7, and HT-29 cancer cells.
  • No significant cytotoxicity was observed in noncancerous NIH 3T3 and HL-60 granulocyte cell lines.
  • PAD4 inhibitors induced differentiation in HL-60 and HT29 cells.
  • Compounds synergistically enhanced the cytotoxic effects of doxorubicin.

Conclusions:

  • PAD4 inhibition represents a novel epigenetic strategy for cancer treatment.
  • F- and Cl-amidine are potential therapeutic candidates for cancer therapy.
  • Targeting PAD4 offers a promising avenue for developing new epigenetic drugs.

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