20-HETE Mimetics or Inhibitors in the Treatment of Cancer Patients with Sepsis and Septic Shock

Abstract

Patients with a variety of malignancies have a greater tendency to acquire infections than patients with non-malignant disorders. Sepsis and septic shock are common complications in patients with cancer. As the most common causes of mor- bidity and mortality in intensive care units worldwide, the societal and economic costs of cancer, sepsis, and septic shock are staggering. The molecular pathophysiology of cancer, sepsis, and septic shock remains controversial despite decades of study. 20-Hydroxyeicosatetraenoic acid (20-HETE), a ω-hydroxylation product of arachidonic acid that is produced by cytochrome P450 (CYP) enzymes, mainly by CYP4A and CYP4F isoforms, has been implicated in the regulation of proto- oncogenic, mitogenic, and angiogenic responses both in vitro and in vivo as well as inflammation that can support tumor progression. Therefore, selective 20-HETE inhibitors has been suggested to be a new class of compounds with antitumor and antiangiogenic activity. On the other hand, studies from our laboratory and others have provided substantial evidence that administration of a synthetic analog of 20-HETE, N-(20-hydroxyeicosa-5(Z),14(Z)-dienoyl)glycine, a 20-HETE mi- metic, prevents vascular hyporeactivity, hypotension, tachycardia, inflammation, and mortality presumably due to increased CYP4A1 expression and formation of 20-HETE associated with decreased vasodilatory and proinflammatory mediator production in a rodent model of septic shock. This review will focus on the rationale for the use of 20-HETE mimetics or inhibitors for the treatment of cancer patients with sepsis and septic shock.