Comparison of the effects of rapamycin and AZD8055 on colon cancer cells through UPLC-MS/MS-based metabolomics.

mTORC1/2 dual inhibitors may be more effective than mTORC1 inhibitor rapamycin. However, their metabolic impacts on colon cancer cells remain unexplored. We conducted a comparative analysis of the anti-proliferative effects of rapamycin and the novel AZD8055 in colon cancer cells HCT-116, evaluating their metabolic influences through ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS/MS). Our results demonstrate that AZD8055 more effectively inhibits colon cancer cell proliferation than rapamycin. Additionally, we identified nearly 600 metabolites from the spectra, revealing significant differences in metabolic patterns between cells treated with AZD8055 and rapamycin. Through variable importance in the projection (VIP) value screening, we pinpointed crucial metabolites contributing to these distinctions. The results indicate that both inhibitors suppress tumor cell growth by downregulating amino acid metabolism, inhibiting glucose metabolism, and enhancing oxidative stress, with AZD8055 exhibiting stronger anti-proliferative efficacy. Specifically, the AZD8055 group showed significantly reduced levels of glucose and lactate, suggesting a more potent suppression of aerobic oxidation and glycolysis. Concurrently, a marked increase in taurine levels was observed in the AZD8055 group, further enhancing its antioxidant and anti-tumor effects. Although both compounds similarly inhibited branched-chain amino acid (BCAA) metabolism, comprehensive metabolic analysis revealed that AZD8055 has greater potential in modulating tumor metabolic pathways, thereby providing new theoretical support for the translational development of mTORC1/2 dual inhibitors.