1-Palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) attenuates gemcitabine-induced neutrophil extravasation

Abstract

Cancer patients treated with chemotherapy often experience a rapid decline of blood neutrophils, a dose-limiting side effect called chemotherapy-induced neutropenia. This complication brings about dose reductions or cessation of chemotherapy during treatment of cancer patients because a rapid decline of neutrophil counts increases susceptibility to infection. Here, we found that 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) attenuates gemcitabine-induced neutrophil extravasation via the inhibition of neutrophil-attracting chemokine production in macrophages using in vivo and in vitro approaches. A single intraperitoneal administration of gemcitabine induced the migration of circulating neutrophils into the peritoneal cavity in normal mice, and PLAG effectively decreased neutrophil migration by inhibiting the expression of adhesion molecules, L-selectin and LFA-1. Inhibition of CXCR2 by its antagonist, reparixin, abrogated gemcitabine-induced neutrophil migration, indicating that chemokines produced by gemcitabine mainly support neutrophil activation. In vitro experiments demonstrated that PLAG inhibited NADPH oxidase 2 (NOX2)-mediated reactive oxygen species production induced by gemcitabine, which is the upstream of MIP-2 and/or CXCL8. Importantly, PLAG down-regulated gemcitabine-induced membrane translocation of the cytosolic NOX subunit, Rac1, and phosphorylation of p47phox. The activation of upstream signaling molecules of p47phox phosphorylation, phospholipase C β3 and protein kinase C, were effectively regulated by PLAG. We also demonstrated that 1-palmitoyl-2-linoleic-3-hydroxyl-rac-glycerol (PLH), the natural form of diacylglycerol, has no effects on gemcitabine-induced CXCL8 production and dHL-60 migration, suggesting that an acetyl group at the third position of the glycerol backbone may have a key role in the regulation of neutrophil activation. Altogether, this study suggests the potential of PLAG as a therapeutic strategy to modulate chemotherapy-induced neutrophil activation for cancer patients undergoing chemotherapeutic treatment.Electronic supplementary materialThe online version of this article (10.1186/s13578-018-0266-7) contains supplementary material, which is available to authorized users.

PLAG Exerts Anti-Metastatic Effects by Interfering with Neutrophil Elastase/PAR2/EGFR Signaling in A549 Lung Cancer Orthotopic Model

“…The anti-metastasis effect of PLAG might be achieved by the disruption of PAR2 signaling, which mediates tumor cell activation in the presence of neutrophil elastase. PLAG has been studied in various inflammatory diseases including chemotherapy-induced neutropenia (CIN), chemo/radiation-induced oral mucositis (CRIOM), and rheumatoid arthritis (RA) [33][34][35]. Our results suggest that PLAG as a novel candidate molecule for the inhibition or retardation of tumor metastasis.…”

“…The 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) is present in the antlers of the Sika deer and can be synthesized from glycerol, palmitic acid, and linoleic acid [32]. PLAG was recently shown to reduce the gemcitabine-induced neutropenia, oral mucositis and arthritis by modulating neutrophil movement [33][34][35]. There have not yet been any studies to determine if PLAG has the potential to control cancer progression by regulating neutrophil infiltration.…”

1-Palmitoyl-2-Linoleoyl-3-Acetyl-rac-Glycerol (PLAG) Mitigates Monosodium Urate (MSU)-Induced Acute Gouty Inflammation in BALB/c Mice

“…PLAG reduces lipopolysaccharideinduced macrophage inflammatory protein 2 (MIP-2) and CXCL8 secretion (29). PLAG improves hepatic injury in concanavalin A-treated mice (9), and gemcitabine-induced neutropenia (30,31) and oral mucositis in hamster and mouse models (32), via modulation of neutrophil migration. In this study, the mitigating effects of PLAG in MSU-induced acute gouty inflammation through modulation of neutrophil infiltration were investigated.…”

1-Palmitoyl-2-Linoleoyl-3-Acetyl-rac-Glycerol Attenuates Streptozotocin-Induced Pancreatic Beta Cell Damage by Promoting Glucose Transporter 2 Endocytosis

“…PLAG showed efficacy as a potential therapeutic agent in various disease models such as asthma (30, 31), arthritis (32), hepatitis (33), lung inflammation (34), and oral mucositis (35). PLAG also inhibited biliary cancer cell metastasis (28) and alleviated chemotherapy-induced neutropenia (36, 37) and thrombocytopenia (38). In this study, we investigated the biological effect of PLAG on STZ-induced pancreatic cell damage.…”