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.
Highlights
Neutrophils are the most abundant white blood cell in circulation and play a key role in the first-line of defense against foreign substances and/or invading pathogens [1, 2]
PLAG maintains circulating neutrophils by down‐regulating cell surface expression of adhesion molecules in gemcitabine‐induced neutropenia model To investigate whether PLAG has an effect on gemcitabine-induced neutropenia, we orally administrated the mice with PLAG (50 and 250 mg/kg) just before gemcitabine treatment (i.p. injection; 50 mg/kg)
When neutropenia was induced by other chemotherapeutic agents, 5-fluorouacil or AC regimen, PLAG effectively preserved the number of circulating neutrophils (Additional file 1: Fig. S3a and b)
Summary
Neutrophils are the most abundant white blood cell in circulation and play a key role in the first-line of defense against foreign substances and/or invading pathogens [1, 2]. Cancer patients undergoing treatment with chemotherapeutics often suffer from a rapid decline of circulating neutrophils [3]. This complication, which is called chemotherapy-induced neutropenia (CIN), increases the patient’s susceptibility to infection, which necessitates dose reduction or cessation of chemotherapy [4]. Exact mechanisms of CIN remains unknown, for that reason, current treatment options rely mostly on promoting production of granulocytes and precursor cells in the bone marrow. Filgrastim, the recombinant human granulocyte-colony stimulating factor (rhG-CSF), is one of the few treatment options since its natural form is a key regulator of neutrophil differentiation and proliferation [5,6,7]. A better understanding of how neutropenia arises in response to chemotherapy would be the key for the development of new pharmaceuticals
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