Hepoxilins in cancer and inflammation—use of hepoxilin antagonists

Abstract

Cancer is often accompanied with inflammatory, thrombotic, and diabetic complications. Alternatively, chronic inflammation is believed to be a causative factor in several cancers. This review article brings together reported biological actions in these areas of the unstable naturally derived hepoxilins (HX), metabolites of arachidonic acid formed through the 12-LO pathway, and those of their synthetically derived stable HX antagonists (PBT; proprietary bioactive therapeutics). Although the HX pathway has been known for some three decades since its discovery by the author with much data originating from the author's laboratory, studies by others over the past few years have confirmed early findings of the actions of HX as potent pro-inflammatory chemoattractant mediators and further showed HX to be involved in bacterial infection (Salmonella-induced intestinal inflammation and in bone inflammation caused by infection with the Lyme bacterium). The HX pathway appears to be an important early signal leading to inflammation. This provides important therapeutic potential for the PBTs as the only available selective antagonists of this pathway. The PBTs have shown benefit and efficacy in animal models of cancer and inflammation, which together with their known actions as anti-thrombotic (thromboxane (TPα) receptor antagonists) and hypoglycemic agents in vivo appears to make the PBTs suitable as therapeutics to control these disorders. The PBT structure is both stable in vivo and is essentially devoid of side effects in the animal models tested. The PBT structure serves as an important platform for selective HX and TX antagonists.

Pathophysiology of the hepoxilins

“…When infection with P. aeruginosa was carried out in vivo in mice through intranasal administration, and BAL fluid was collected 18 h thereafter, hepoxilin A 3 and 12-HETE were observed albeit in a 1:100 ratio, together with the appearance of abundant PMNs with significant monoamine oxidase activity reflecting the presence of an acute inflammatory response. Unfortunately in this report, the effect of the hepoxilin analogs on the in vivo characterization of inflammatory cells, arachidonic acid, 12-HETE and hepoxilin A 3 formation and release into the BAL fluid was not reported to determine whether the analogs studied are effective in vivo as already shown to be the case for the PBTs in a variety of animal models (recently reviewed in [53]). …”

“…For example 12(S)-HETE causes proliferation of cancer cells [48], it is implicated in diabetes [49], hypertension [50], and certain other diseases, whereas hepoxilin A 3 is a pro-inflammatory mediator and potentiates vascular reactivity of constrictor hormones [51,52]. The stable hepoxilin analogs are pro-apoptotic, anti-inflammatory, anti-thrombotic and antidiabetic (see review in [53]). Through their effects on inhibiting phospholipase A 2 [16] the hepoxilin analogs may very well prevent the formation of 12-HETE and actions of hepoxilins and other eicosanoids (such as in inflammation, cancer and other diseases, see sections below).…”

“…The hepoxilins had previously been shown to be formed by human neutrophils, to raise intracellular calcium in neutrophils, promote chemotaxis of human neutrophils, and promote skin vascular permeability, hallmarks of acute inflammation (reviewed in [53]). The hepoxilins act on intracellular calcium in a GPCR-coupled response, and neutrophils have specific hepoxilin binding, essential for hepoxilin's calcium mobilizing actions [75,83,84] and chemotaxis [85].…”

“…The PBTs displayed interesting actions in vivo as anti inflammatory and anti cancer drugs which will be described below. Other actions reviewed earlier relate to anti-thrombotic and anti-diabetic actions [53,138,139].…”

“…Importantly, after the 8-day treatment with PBT was stopped, tumor growth did not start immediately but was delayed until about 40 days into the study, and then the tumors grew rapidly as in the vehicle treated group. If, however, PBT treatment is started again for another 8-day period just before tumor growth began, a further cessation of growth is observed such that a delay in tumor growth is observed until approx 100 days [53,145]. Thus, 2 periods of PBT treatment (8-days each) could prevent tumor growth by 100 days as opposed to the 8-day uncontrolled rapid growth in the absence of PBT.…”