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Activated protein C: a promising drug with multiple effects?

S T B G Loubele1, H M H Spronk, H Ten Cate

  • 1Maastricht University Medical Center+, Departments of Internal Medicine and Biochemistry, Laboratory for Clinical Thrombosis and Haemostasis, P.O. Box 616, Uns 50: Box 8, 6200 MD Maastricht, The Netherlands. sarah.loubele@bioch.unimaas.nl

Mini Reviews in Medicinal Chemistry
|May 22, 2009
PubMed

Insights

Activated protein C (APC) offers cytoprotective effects against apoptosis and inflammation by engaging PAR-1 and EPCR. While clinical trials show reduced mortality in severe sepsis, bleeding risks limit broader therapeutic use, prompting research into APC mutants.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Activated protein C (APC) is an anticoagulant with known cytoprotective functions.
  • These functions involve mechanisms of apoptosis and inflammation.
  • Key cellular receptors, protease-activated receptor-1 (PAR-1) and endothelial protein C receptor (EPCR), mediate APC's cytoprotective effects.

Purpose of the Study:

  • To summarize the cytoprotective mechanisms of APC.
  • To highlight clinical evidence supporting APC's role in severe sepsis.
  • To discuss limitations and future research directions for APC therapeutics.

Main Methods:

  • Review of in vitro and animal studies on APC's cytoprotective properties.
  • Analysis of clinical trial data, specifically the PROWESS trial.
  • Examination of research into APC mutants for improved therapeutics.

Main Results:

  • APC inhibits inflammatory gene expression and down-regulates p53 and Bax.
  • The PROWESS trial demonstrated reduced mortality in severe sepsis patients treated with APC.
  • APC's therapeutic potential is currently limited by an associated risk of bleeding.

Conclusions:

  • APC exhibits significant cytoprotective properties mediated by PAR-1 and EPCR.
  • Clinical data supports APC's efficacy in severe sepsis, but bleeding complications are a concern.
  • Ongoing research focuses on developing specific APC mutants to enhance therapeutic benefits while mitigating risks.

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