Study on the effects of rapamycin and the mTORC1/2 dual inhibitor OSI-027 on the metabolism of colon cancer cells based on UPLC-MS/MS metabolomics.

Publisher: Springer Country of Publication: United States NLM ID: 8309330 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1573-0646 (Electronic) Linking ISSN: 01676997 NLM ISO Abbreviation: Invest New Drugs Subsets: MEDLINE

Publication: New York : Springer
Original Publication: Boston : M. Nijhoff, 1983-

Colonic Neoplasms*/drug therapy ; Colonic Neoplasms*/metabolism ; Imidazoles*/pharmacology ; Imidazoles*/therapeutic use ; Mechanistic Target of Rapamycin Complex 1*/antagonists & inhibitors ; Mechanistic Target of Rapamycin Complex 1*/metabolism ; Mechanistic Target of Rapamycin Complex 2*/antagonists & inhibitors ; Mechanistic Target of Rapamycin Complex 2*/metabolism ; Metabolomics*/methods ; Sirolimus*/pharmacology ; Sirolimus*/therapeutic use ; Triazines*/pharmacology ; Triazines*/therapeutic use; Humans ; Cell Proliferation/drug effects ; HCT116 Cells ; Liquid Chromatography-Mass Spectrometry ; Tandem Mass Spectrometry

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 OSI-027 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 OSI-027 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 OSI-027 and rapamycin. Through VIP value screening, we pinpointed crucial metabolites contributing to these distinctions. For inhibiting glycolysis and reducing glucose consumption, OSI-027 was likely to be more potent than rapamycin. For amino acids metabolism, although OSI-027 has a broad effect as rapamycin, their effects in degrees were not exactly the same. These findings address the knowledge gap regarding mTORC1/2 dual inhibitors and lay a foundation for their further development and research.
(© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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SKYXD2022022 Suzhou Municipal Science and Technology Bureau; SKYXD2022022 Suzhou Pharmaceutical Association

Keywords: Colon cancer; Metabolism; OSI-027; mTORC1/2

0 (Imidazoles)
EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
0 (OSI 027)
W36ZG6FT64 (Sirolimus)
0 (Triazines)

Date Created: 20240625 Date Completed: 20240815 Latest Revision: 20240819

20240820

10.1007/s10637-024-01438-y

38916794