Inhibitors of intracellular phosphatidic acid production: novel therapeutics with broad clinical applications

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Abstract
Phosphatidic acids (PAs) are a molecularly diverse group of phospholipids. Certain species of PA are highly active intracellular signaling molecules associated with cellular activation and mitogenesis. Not surprisingly, the PA species active in signaling are not produced by normal cells under homeostatic conditions. Recently the molecular species of PA associated with specific cellular activating events have been identified and compounds that inhibit the formation of specific PA species have been synthesised. We have characterised four classes of PA not derived from phosphatidylinositol hydrolysis that are involved in intracellularsignaling. PA1α is produced following exposure of cells to lipopolysaccharide, IL-1, hypoxia-reoxygenation, IL-8, or platelet activating factor. Lisofylline, a functional inhibitor of PA1a formation, is in Phase II-III trials as a therapeutic to reduce toxicities of anti-cancer therapies and for cytokine-mediated acute systemic inflammatory conditions. PA1α, PA1β and PA2 are produced following binding of the platelet-derived growth factor (PDGF) family of cytokines and tumour necrosis factor-α (TNFα) to their specific receptors. CT-3501, an inhibitor of PA1α, and β and PA2 formation, suppresses mitogenesis of smooth muscle cells, fibroblasts, and endothelial cells induced by PDGF, fibroblast growth factors (FGF) and vascular endotheiial growth factor (VEGF) as well as expression of certain TNFα-induced endothelial cell adhesion molecules. PA3 is associated with signaling by IL-2, CT-2576, a representative PA3 inhibitor suppresses mitogenesis of B- and T-cells induced by IL-2, IL-4, TNFα and IL-7. PA4 is produced in normal cells in response to the stimuli that induce PA1α. It is constitutively produced in cancer cells. Inhibition of PA4 by CT-2584, a compound which also inhibits PAs 1α and β PA2 and PA3, selectively kills malignant cells. Inhibition of PA formation thus appears to be a new target for therapeutic intervention.