Evaluation of the antitumor effects of PP242 in a colon cancer xenograft mouse model using comprehensive metabolomics and lipidomics

Md Mamunur Rashid,Byung Hwa Jung,Hyunbeom Lee

doi:10.1038/s41598-020-73721-w

Abstract

PP242, an inhibitor of mechanistic target of rapamycin (mTOR), displays potent anticancer effects against various cancer types. However, the underlying metabolic mechanism associated with the PP242 effects is not clearly understood. In this study, comprehensive metabolomics and lipidomics investigations were performed using ultra-high-performance chromatography-Orbitrap-mass spectrometry (UHPLC-Orbitrap-MS) in plasma and tumor tissue to reveal the metabolic mechanism of PP242 in an LS174T cell-induced colon cancer xenograft mouse model. After 3 weeks of PP242 treatment, a reduction in tumor size and weight was observed 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, in 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. This study reveals new insights into the underlying anticancer mechanism of the dual mTOR inhibitor PP242, and could help further to facilitate the understanding of PP242 effects in the clinical application.

Highlights

The body weights of the PP242-treated mice decreased significantly and quickly in the first couple of days after treatment compared to the Normal Control (NC) group, and later, the body weights gradually recovered
Tumor-bearing mice were treated with vehicle and/or PP242 over the course of 21 days, and the size of the tumor in the right flank region was measured at two days interval using digital caliper in the LS174T xenograft groups (XC and PP242-treated) in order to evaluate the drug therapeutic effects in vivo
The tumors were separated after sacrifice and weighed, which further displayed the significant decrease in tumor weight for the PP242 treatment compared to the Xenograft Control (XC) group mice (Fig. 2C)

Summary

Introduction

In order to evaluate the underlying mechanism of action of the dual mTOR inhibitor PP242, the LS174T xenograft mouse model was treated with PP242 for 3 weeks, and plasma and tumor samples were analyzed via metabolomics and lipidomics approaches. In tumor tissue, compared to the XC group, a total of 93 significantly altered metabolites were identified in the PP242-treated group via metabolomics and lipidomics analyses.

Results

Conclusion