Md Mamunur Rashid

and 2 more

BACKGROUND AND PURPOSE PP242, an inhibitor of mechanistic target of rapamycin (mTOR), displays potent anticancer effects against various types of cancer. However, the underlying metabolic mechanism associated with the PP242 effects is not clearly understood. In this study, comprehensive metabolomics and lipidomics investigations were performed in plasma and tumor tissue to reveal the metabolic mechanism of PP242 in an LS174T cell-induced colon cancer xenograft mouse model. EXPERIMENTAL APPROACH A colon cancer xenograft model was developed in BALB/c nude mice and then treated with PP242 for three weeks. After the final dose, blood, tumor, liver and kidney tissues were collected. Plasma and tumor samples were analyzed through untargeted metabolomics and lipidomics approaches using ultra-high-performance chromatography-Orbitrap-mass spectrometry (UHPLC-Orbitrap-MS). KEY RESULTS PP242 treatment reduces tumor size without any critical toxicities. According to results, metabolic changes due to the effects of PP242 were not significant in plasma. In contrast, metabolic changes in tumor tissues were very significant in the PP242-treated group compared to the xenograft control (XC) group, and revealed that energy and lipid metabolism were mainly altered by PP242 treatment like other cancer inhibitors. Additionally, it this study it was discovered that not only TCA cycle but also fatty acid β-oxidation (β-FAO) for energy metabolism was inhibited and clear reduction in glycerophospholipid was observed. CONCLUSIONS AND IMPLICATIONS The findings of this study reveal new insights into the underlying anticancer mechanism of the dual mTOR inhibitor PP242, and could help further facilitate the understanding of the effects PP242 in the course of clinical application.