As a regulator of cellular inflammation and proliferation, cytosolic phospholipase A₂ α (cPLA₂α) is a promising therapeutic target for psoriasis; indeed, the cPLA₂α inhibitor AVX001 has shown efficacy against plaque psoriasis in a phase I/IIa clinical trial. To improve our understanding of the anti-psoriatic properties of AVX001, we sought to determine how the compound modulates inflammation and keratinocyte hyperproliferation, key characteristics of the psoriatic epidermis. We measured eicosanoid release from human peripheral blood mononuclear cells (PBMC) and immortalized keratinocytes (HaCaT) and studied proliferation in HaCaT grown as monolayers and stratified cultures. We demonstrated that inhibition of cPLA₂α using AVX001 produced a balanced reduction of prostaglandins and leukotrienes; significantly limited prostaglandin E₂ (PGE₂) release from both PBMC and HaCaT in response to pro-inflammatory stimuli; attenuated growth factor-induced arachidonic acid and PGE₂ release from HaCaT; and inhibited keratinocyte proliferation in the absence and presence of exogenous growth factors, as well as in stratified cultures. These data suggest that the anti-psoriatic properties of AVX001 could result from a combination of anti-inflammatory and anti-proliferative effects, probably due to reduced local eicosanoid availability.

Cytosolic phospholipase A2α (cPLA2α) is the rate-limiting enzyme in releasing arachidonic acid and biosynthesis of its derivative eicosanoids. Thus, the catalytic activity of cPLA2α plays an important role in cellular metabolism in healthy as well as cancer cells. There is mounting evidence suggesting that cPLA2α is an interesting target for cancer treatment; however, it is unclear which cancers are most relevant for further investigation. Here we report the relative expression of cPLA2α in a variety of cancers and cancer cell lines using publicly available datasets. The profiling of a panel of cancer cell lines representing different tissue origins suggests that hematological malignancies are particularly sensitive to the growth inhibitory effect of cPLA2α inhibition. Several hematological cancers and cancer cell lines overexpressed cPLA2α, including multiple myeloma. Multiple myeloma is an incurable hematological cancer of plasma cells in the bone marrow with an emerging requirement of therapeutic approaches. We show here that two cPLA2α inhibitors AVX420 and AVX002, significantly and dose-dependently reduced the viability of multiple myeloma cells and induced apoptosis in vitro. Our findings implicate cPLA2α activity in the survival of multiple myeloma cells and support further studies into cPLA2α as a potential target for treating hematological cancers, including multiple myeloma.

Chronic kidney disease (CKD) is a significant global health burden and a leading cause of death in the United States. Chronic inflammation contributes to fibrosis and CKD progression. Here, we present evidence that a key pro-inflammatory group IVA phospholipase A₂ enzyme (cPLA₂α) is critical to the development of kidney inflammation and fibrosis and can be targeted pharmacologically to attenuate CKD in animal models. Consistent with a role in human disease, overexpression of cPLA₂α is seen in kidneys from patients suffering from CKD, and its expression is inversely correlated with the glomerular filtration rate. Genetic ablation of cPLA₂α or inhibition with 1-octadeca-3,6,9,12,15-pentaenylsulfanyl-propan-2-one (AVX002) reduced inflammation and ameliorated renal fibrosis in mouse and rat disease models. In addition, reduced levels of eleven arachidonic acid-derived plasma eicosanoids demonstrated inhibitor effectiveness and specificity. Furthermore, AVX002 dose-dependently reduced kidney fibroblast production of profibrotic, pro-inflammatory components leading to progressive fibrotic kidney failure. In conclusion, our results strongly suggest that inhibition of cPLA₂α holds promise as a novel therapeutic strategy for renal fibrosis and chronic kidney disease.