Alterations in eicosanoid levels during U937 bcl-xL tumour growth suppression and recovery in NU/NU mice in vivo—Involvement of phospholipase A2

Pathophysiology of the hepoxilins

“…In this study we used the leukemic U937 bcl-xL cell line and transplanted the cells subcutaneously as we did before with the leukemic K562 CML cell line. It was interesting to observe that 12-HETE was the major eicosanoid present in this tumor as well as its precursor, arachidonic acid [16]. All other eicosanoids including other HETEs, prostaglandins, EETs and hepoxilins were found in very small amounts.…”

“…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).…”

“…In this respect, the hepoxilin analogs inhibit platelet aggregation although while this effect may be coupled to inhibition of cyclic AMP formation, it could as well result from the demonstrated antagonistic effects on the thromboxane [55,56] receptor as well as phospholipase A 2 inhibition [16] thereby negatively affecting thromboxane A 2 formation. Hence it is probable that hepoxilins may play a significant role in melatonin synthesis through their stimulatory effects on calcium and cyclic AMP and NAT although direct measurement of melatonin production as influenced by hepoxilins is lacking.…”

“…In vitro studies have shown that the hepoxilin analogs cause apoptosis through a stimulation of the release of cytochrome c and activation of caspase-3 [74]. These studies suggest that the hepoxilins may be involved in the stress/HSP/anti-apoptosis pathways and that the hepoxilin analogs oppose this, probably directly as hepoxilin A 3 antagonists [75] or indirectly as phospholipase A 2 inhibitors [16], potentially leading to a novel therapeutic approach for cancer control (see later section on hepoxilin analogs in cancer).…”

“…In so doing, it was hoped that information could be obtained on the role of the endogenous hepoxilins. Indeed this review addresses the major findings from our group and those from several others showing the involvement of the hepoxilins in acute inflammation, the efficacy of the hepoxilin analogs as antagonists of the native hepoxilins, and to offer some insight as to the potential therapeutic interest generated by a recent finding that the hepoxilin analogs additionally cause some of their inhibitory effects in both the cancer animal model in vivo and on platelet aggregation in vitro through inhibition of the release of arachidonic acid, suggesting inhibition of an acyl hydrolase, likely a type of phospholipase A 2 [16].…”