The hydrogel‐encapsulated liver X receptor ligand, T0901317, enhances its antitumorigenic effects but eliminates lipogenesis

Abstract

The anti‐tumorigenic functions of liver X receptor (LXR) ligands have been confirmed in several types of tumors. We previously reported that LXR ligand, T0901317 (T317), inhibited growth of inoculated LLC1 carcinoma and urethane‐induced pulmonary carcinomas by activating IFN‐γ expression in tissues, particularly in macrophages. However, T317 activates fatty acid synthesis to result in severe hepatic lipogenesis and fatty liver. Tissue‐specific activation of LXR, such as in antigen‐presenting cells (APCs) but not in liver, by ligand can enhance inhibition of tumor growth without activation of lipogenesis. Injected naphthylacetic acid modified D‐glycine‐phenylalanine‐phenylalanine‐tyrosine tetra‐peptide (GFFY) can be selectively delivered to APCs, macrophages and dendritic cells (DCs). In this study, we encapsulated T317 with GFFY hydrogel (GFFY‐T317) and determined its effect on tumor growth and hepatic lipogenesis. Compared with oral administration of T317, subcutaneous injection of GFFY‐T317 more potently inhibited LLC1 tumor growth in mice. The inhibition was dependent on induction of IFN‐γ expression in APCs by activating LXR. We further determined that GFFY‐T317 increased M1 type macrophages while reducing M2 cells in the tumor. Meanwhile, GFFY‐T317 enhanced DC maturation and infiltration to tumors. Both CD3+ and CD8+ cells in tumors were also increased, which was associated with activation of IFN‐γ expression. In contrast, tumor angiogenesis was clearly inhibited by GFFY‐T317 in an IFN‐γ‐dependent manner. In addition, GFFY‐T317 had more potent inhibitory effects on urethane‐induced lung tumor than oral administration of T317. More importantly, in these two tumor models, compared with severe liver steatosis by oral administration of T317, injection of GFFY‐T317 had little effect on lipid synthesis/metabolism in the liver, while eliminating T317‐induced liver injury. Taken together, our study demonstrates that the hydrogel‐encapsulated T317 can inhibit lung tumor growth without adverse effect of lipogenesis, indicating the hydrogel‐encapsulated LXR ligand might be a novel therapy for tumor treatment.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.