Phospholipase A(2) Isoforms as Novel Targets for Prevention and Treatment of Inflammatory and Oncologic Diseases

Phospholipase A(2)s (PLA(2)s) 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 PLA(2) prevents the liberation of AA and LPLs. Hence, researchers have been considering PLA(2)s could be a better therapeutic target than the downstream enzymes cyclooxygense and lipoxygenase. Several isoforms of PLA(2)s exist; they are mainly divided into secretory PLA(2)s (sPLA(2)), cytosolic PLA(2)s (cPLA(2)), and calcium independent PLA(2)s (iPLA(2)), platelet activating factor- acyl hydrolase (PAF-AH), lysosomal PLA(2) (LPLA(2)), adipose-specific PLA(2) (AdPLA). Each isoform of PLA(2)s is different in its chemical structure and physiological functions. sPLA(2)s (Groups IIA, V and X) are well characterized as proinflammatory mediating enzymes but their role in cancer is controversial. Groups IVA, IVB and IVC cPLA(2)s are present in humans but only Group IVA cPLA(2) plays key role in pathophysiology of various cancers and inflammation. The role of iPLA(2) in inflammation and cancer is limited. Lipoprotein associated PLA(2) (Group VIIA PLA(2)), a PAF-AH isoform, has key role in atherosclerosis. Several isoform specific PLA(2) inhibitors have been developed and some of the PLA(2)s 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 PLA(2)s are causally implicated in the pathobiology of cancer and inflammatory related disorders and discuss the potential utility of isoform specific PLA(2) inhibitors as preventive and/or therapeutic agents.