A role for oleoylethanolamide in chronic lymphocytic leukemia

Abstract

Oleoylethanolamide (OEA) is a bioactive lipid that stimulates nuclear and G protein-coupled receptors and regulates appetite and fat metabolism. It has not previously been shown to have a role in cancer. However, a mass spectrometry-based lipidomics platform revealed the presence of high amounts of OEA in the plasma of chronic lymphocytic leukemia (CLL) patients compared with normal donors. CLL cells produced OEA and the magnitude of plasma OEA levels was related directly to the circulating leukemic cell number. OEA from CLL cells was increased by URB-597, an inhibitor of fatty acid amide hydrolase (FAAH), and decreased by inflammatory mediators that downregulate expression of N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD). These enzymes degrade and synthesize OEA, respectively. Nonphysiologic doses of OEA prevented spontaneous apoptosis of CLL cells in a receptor-independent manner that was mimicked by its free fatty acid (FFA) derivative oleate. However, OEA-containing supernatants from CLL cells induced lipolysis in adipocytes, lipid products from adipocytes protected CLL cells from cytotoxic chemotherapy, and increased levels of FFAs were found in CLL plasma that correlated with OEA. We suggest OEA is a lipolytic factor produced by CLL cells to fuel their growth with a potential role in drug resistance and cancer cachexia.

To treat or not to treat: metabolomics reveals biomarkers for treatment indication in chronic lymphocytic leukaemia patients

“…PPAR-α is also closely associated to the metabolism of fatty acid amides. For example PPAR-α agonist oleoylethanolamide was observed to be significantly high in patients such that its plasma concentration was directionally related to the number of circulating leukemic cells [47]. In that study, it was suggested that oleoylethanolamide is produced in CLL cells as a lipolytic factor that later plays a role in drug resistance as well as cachexia.…”

Structure of Human N -Acylphosphatidylethanolamine-Hydrolyzing Phospholipase D: Regulation of Fatty Acid Ethanolamide Biosynthesis by Bile Acids

“…In mammals, monounsaturated and saturated FAEs (e.g., oleoylethanolamide and palmitoylethanolamide) are agonists for peroxisome proliferator-activated nuclear receptors (PPAR-α) (Fu et al, 2003) and G protein-coupled receptors (GPR119 and GPR55) (Godlewski et al, 2009). Oleylethanolamide regulates satiety, body weight, and cancer cell proliferation (Piomelli, 2013; Masoodi et al, 2014); palmitoylethanolamide serves as an early stop signal that contrasts the progress of inflammation (Solorzano et al, 2009). On the other hand, polyunsaturated FAEs (e.g., anandamide) activate cannabinoid receptors (CBs) – the same G protein-coupled receptors targeted by the psychotropic component Δ 9 -tetrahydrocannabinol in marijuana – and contribute in important ways to the regulation of food intake, stress and pain response, and synaptic function (Kathuria et al, 2003; Hohmann et al, 2005; Di Marzo and Matias, 2005; Di Marzo, 2008; Piomelli and Sasso, 2014).…”

Pharmacometabolomics identifies dodecanamide and leukotriene B4 dimethylamide as a predictor of chemosensitivity for patients with acute myeloid leukemia treated with cytarabine and anthracycline

“…Peroxisome proliferator activated receptor (PPAR) could be activated by fatty acid amides and was thought to aid in leukemic cell survival against cytotoxic stressors such as chemotherapeutic drugs [ 28 ]. For example, oleoylethanolamide, an endogenous PPAR-α agonist, was significantly high level in the plasma of chronic lymphocytic leukemia patients such that its plasma concentration was directionally related to the number of circulating leukemic cells [ 29 ]. In that study, it was suggested that oleoylethanolamide was produced by leukemic cells as a lipolytic factor to fuel their growth with a potential role in drug resistance and cancer cachexia [ 29 ], which could give an clue to the physiological functions of dodecanamide, decanamide, and oleamide in this study.…”

“…For example, oleoylethanolamide, an endogenous PPAR-α agonist, was significantly high level in the plasma of chronic lymphocytic leukemia patients such that its plasma concentration was directionally related to the number of circulating leukemic cells [ 29 ]. In that study, it was suggested that oleoylethanolamide was produced by leukemic cells as a lipolytic factor to fuel their growth with a potential role in drug resistance and cancer cachexia [ 29 ], which could give an clue to the physiological functions of dodecanamide, decanamide, and oleamide in this study. This was the possible reason that the AML patients with a low level of dodecanamide have better chemosensitivity than those with a high level of dodecanamide.…”