Plant galactolipid dLGG suppresses lung metastasis of melanoma through deregulating TNF-α-mediated pulmonary vascular permeability and circulating oxylipin dynamics in mice

This study demonstrates the bioefficacy and gives mechanistic insights into a plant galactolipid 1,2‐di‐ O ‐linolenoyl‐3‐ O ‐β‐galactopyranosyl‐ sn ‐glycerol (dLGG) against metastatic melanoma using a syngeneic mouse model implanted with B16 COX‐2/Luc melanoma. dLGG‐20 ( p.o . dLGG 20 mg/kg) and anti‐cancer drug CP‐2 ( i.p . cisplatin 2 mg/kg) treatment significantly inhibited lung metastasis of melanoma in mice 91 and 57%, respectively, as determined by bioluminescence intensity. Moreover, dLGG‐20 and CP‐2 treatment prolonged mouse mean survival time. dLGG‐20 treatment significantly inhibited the expression levels of several molecular markers, that is, PCNA, MMP2, COX‐2, VEGF, vimentin, snail, TGF‐β, β‐catenin, TNF‐α, PD‐1 and PD‐L1 in mouse lung tissues compared to tumor control mice. Significant inhibition of macrophage and neutrophil infiltration and promotion of CD8 + Tc cell recruitment in the lung microenvironment was observed in dLGG‐20‐treated mice. A LC/MS‐based comparative oxylipin metabolomics study showed that dLGG‐20 treatment significantly induced (5.0‐ to 12.8‐fold) the 12/15‐LOX catalyzed oxylipin products in mouse serum including 17‐HDHA from DHA, 15‐HEPE from EPA, 8‐ and 12‐HETEs from AA, and CYP450‐derived 20‐HETE from AA. CP‐2 treatment increased 12/15‐LOX derived 8‐, 11‐ and 12‐HETEs from AA, and CYP450 derived 11,12‐EET from AA ad 9,10‐DHOME from LA by 5.3‐ to 8.1‐fold. Of note, dLGG and 17‐HDHA were more effective than CP in preventing B16 melanoma cell‐induced pulmonary vascular permeability in mice through inhibition of TNF‐α production, up‐regulation of tight junction proteins claudin1 and ZO‐2 and deregulation of Src activation. In conclusion, this study shows the novel therapeutic effect of phytoagent dLGG and suggests its potential as a therapeutic agent for metastatic melanoma.