Abstract
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.
Highlights
Hematologic malignancies, which are cancers of the blood, bone marrow, and lymph nodes, account for approximately 8% of all cancers [1]
To get a better overview of whether certain cancers may be more reliant on Cytosolic phospholipase A2α (cPLA2α) activity than others, we explored gene expression data from publicly available clinical cancer patient and cell line databases using Genevestigator and the Cancer Cell Line Encyclopedia (CCLE), respectively
We showed that cell lines of hematological origin were highly susceptible to the effects of cPLA2α inhibition on cell viability
Summary
Hematologic malignancies, which are cancers of the blood, bone marrow, and lymph nodes, account for approximately 8% of all cancers [1]. Arachidonyl trifluoromethyl ketone (AACOCF3), for example, was reported to sensitize tumors to radiation therapy via effects on the tumor vasculature [24] and was reported to inhibit the migration and invasion of lung cancer cells in vitro [27] Another cPLA2 inhibitor, 4-[2-[5-chloro-1-(diphenylmethyl)-2-methyl-1H-indol-3-yl]-ethoxy]benzoic acid (CDIBA), has been used to demonstrate key regulatory roles of cPLA2 and lysophospholipids in brain and lung cancers in vivo [25], and cPLA2α inhibitors (e.g., AVX001, AVX002, AVX235) developed by Avexxin, Coegin Pharma, were previously shown to inhibit inflammation [28,29,30,31,32,33], tumor progression, and angiogenesis both in vitro and in vivo [34,35]. 2-(2-(4-heptyloxy)-phenoxy)-acetyl)thiazole-4-carboxylate) [36,37] to investigate cPLA2α as a potential target for treating the hematological cancer multiple myeloma
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