Phospholipase A2 Isoforms as Novel Targets for Prevention and Treatment of Inflammatory and Oncologic Diseases

Abstract

Phospholipase A2s (PLA2s) are group of enzymes, which cleave phospholipids specifically at sn-2 position to liberate free fatty acid, mostly arachidonic acid (AA) and lysophospholipids (LPLs). Inhibition of PLA2 prevents the liberation of AA and LPLs. Hence, researchers have been considering PLA2s could be a better therapeutic target than the downstream enzymes cyclooxygense and lipoxygenase. Several isoforms of PLA2s exist; they are mainly divided into secretory PLA2s (sPLA2), cytosolic PLA2s (cPLA2), and calcium independent PLA2s (iPLA2), platelet activating factor- acyl hydrolase (PAF-AH), lysosomal PLA2 (LPLA2), adipose-specific PLA2 (Ad- PLA). Each isoform of PLA2s is different in its chemical structure and physiological functions. sPLA2s (Groups IIA, V and X) are well characterized as proinflammatory mediating enzymes but their role in cancer is controversial. Groups IVA, IVB and IVC cPLA2s are present in humans but only Group IVA cPLA2 plays key role in pathophysiology of various cancers and inflammation. The role of iPLA2 in inflammation and cancer is limited. Lipoprotein associated PLA2 (Group VIIA PLA2), a PAF-AH isoform, has key role in atherosclerosis. Several isoform specific PLA2 inhibitors have been developed and some of the PLA2s inhibitors are currently under clinical trials for various inflammatory and oncologic diseases. This review focuses on the recent experimental evidences to support the notion that PLA2s are causally implicated in the pathobiology of cancer and inflammatory related disorders and discuss the potential utility of isoform specific PLA2 inhibitors as preventive and/or therapeutic agents.

Edema Induced by sPLA2 from Crotalus durissus terrificus Involves PLC and PKC Signaling, Activation of cPLA2, and Oxidative Stress

“…sPLA2 is considered a simple and primitive enzyme, acting as an inducer of the inflammatory process, besides being able to act as a pseudohormone. In addition to generating AA directly, this enzyme can also increase the activity of cPLA2 [9]. Furthermore, the produced AA usually follows one of three distinct enzymatic pathways involving cyclooxygenase, lipoxygenase, and cytochrome P450.…”

Phospholipid Cyclosporine Prodrugs Targeted at Inflammatory Bowel Disease (IBD) Treatment: Design, Synthesis, and in Vitro Validation

“…[21][22][23][24][25] PLA 2 is a family of enzymes that catalyze the hydrolysis of the sn-2 fatty acyl bond of phospholipids (PL) thereby liberating a free fatty acid (FA) and a lysophospholipid (LPL). [26] We envision that elevated PLA 2 levels in the diseased tissue could hydrolyze PL-cyclosporine prodrugs and lead to increased amounts of the cyclosporine in the actual diseased tissues, and at the same time decrease drug levels in non-diseased tissues, providing an extended therapeutic index and improved drug therapy (Figure 1c). This novel strategy whereby a PL is linked to an efficacious drug molecule is studied here for the first time with cyclosporine ( Figure 1b), which is in clinical use for patients with IBD but suffers the drawback of systemic application described above.…”

Lipoprotein‐associated phospholipase A2: The story continues

“…In the past decade, a number of reviews have been published with respect to the structure, genetic aspects, biological roles, disease implications, and specific inhibitors of Lp‐PLA2 . In addition, Lp‐PLA2 has been reviewed as a part of the PLA2 superfamily or PAF‐AHs . Nevertheless, in this review, we comprehensively summarize the Lp‐PLA2 studies on the gene, regulation of expression, biological functions, indications, crystal structures, and inhibitors.…”