Mitigating Effect of 1-Palmitoyl-2-Linoleoyl-3-Acetyl-Rac-Glycerol (PLAG) on a Murine Model of 5-Fluorouracil-Induced Hematological Toxicity

Abstract

5-Fluorouracil (5-FU) is an antimetabolite chemotherapy widely used for the treatment of various cancers. However, many cancer patients experience hematological side effects following 5-FU treatment. Here, we investigated the protective effects of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) as a mitigator against 5-FU-induced hematologic toxicity, including neutropenia, monocytopenia, thrombocytopenia, and thrombocytosis, in Balb/c mice injected with 5-FU (100 mg/kg, i.p.). Administration of PLAG significantly and dose-dependently reduced the duration of neutropenia and improved the nadirs of absolute neutrophil counts (ANCs). Moreover, while the ANCs of all mice in the control fell to the severely neutropenic range, none of the mice in the PLAG 200 and 400 mg/kg-treated groups experienced severe neutropenia. Administration of PLAG significantly delayed the mean first day of monocytopenia and reduced the duration of monocytopenia. PLAG also effectively reduced extreme changes in platelet counts induced by 5-FU treatment, thus preventing 5-FU-induced thrombocytopenia and thrombocytosis. PLAG significantly decreased plasma levels of the chemokine (C–X–C motif) ligand 1 (CXCL1), CXCL2, interleukin (IL)-6, and C-reactive protein (CRP), which were elevated consistently with the occurrence time of neutropenia, monocytopenia, and thrombocytopenia. When compared with olive oil and palmitic linoleic hydroxyl glycerol (PLH), only PLAG effectively mitigated 5-FU-induced hematological toxicity, indicating that it has a distinctive mechanism of action. In conclusion, PLAG may have therapeutic potential as a mitigator for 5-FU-induced neutropenia and other hematological disorders.

Synergistic effect of folate-conjugated polymers and 5-fluorouracil in the treatment of colon cancer

“…In agreement with other studies, ~ 40% depletion of the ability of monocyte/macrophage cells to proliferate after treatment by 5-FU has been observed (Fig. 6F) (VanderVeen et al 2020;Jeong et al 2019;Farhat et al 2014). Interestingly, after the addition of our polymeric systems to the THP-1 cells, increased proliferation was noted (Fig.…”

Novel 5-Fluorouracil Carbonate-Loaded Liposome: Preparation, In Vitro, and In Vivo Evaluation as an Antitumor Agent

“…50 Interestingly, different from human modeling, it has been demonstrated that 5-FU induces a moderate reduction of platelet counts (thrombocytopenia), followed by a profound and prolonged increase of platelet counts (thrombocytosis) in mice, and thrombocytosis could result in increased risks of thrombosis. 51,52 In this work, we found that 5-FU caused an increase in platelets in mice after administration, which was consistent with the above literature reports, and at the same time, we also found that LipoXL-01 caused neither thrombocytopenia nor thrombocytosis, suggesting LipoXL-01 had less effect on platelets.…”

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

“…Therefore, we think that CXCL8 is also a good therapeutic target for the treatment of gouty inflammation. In addition, there were no reports of toxicity or adverse effects when high doses of PLAG were administered in the non-clinical toxicity test (49,66). Since PLAG is delivered via oral administration, it has an advantage in the way of drug delivery than other gout drugs.…”