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.
Keywords:
PP242
mTOR inhibitor
UHPLC-Orbitrap-MS
Metabolomics
Lipidomics
Colon cancer
Bullet Point Summary:
What is already known
PP242 is an ATP-competitive mTOR inhibitor that represents promising
anticancer activity against various cancers.
What this study adds
- The antitumor activity of PP242 is mainly associated with energy and
glycerophospholipid metabolism.
- Both the TCA cycle and fatty acid β-oxidation (β-FAO) for energy
metabolism were inhibited.
Clinical significance
This study can help to further understand the therapeutic effects of
PP242 in clinical applications.