Characterization of a novel AICARFT inhibitor which potently elevates ZMP and has anti-tumor activity in murine models
| Autor: | Harold B. Brooks, Shuang Luo, Timothy I. Meier, Kwame Frimpong, Timothy B. Durham, Matthew Lee, Kevin Robert Fales, Kenneth Jeff Thrasher, Philip W. Iversen, Robert T. Foreman, Yu-Hua Hui, Charles D. Spencer, Sandaruwan Geeganage, Kenneth D. Roth, Alicia Torrado, Yong Wang, Chong Si, Jefferson R. Mc Cowan, Stefan Jon Thibodeaux, Zhipei Wu, Timothy Alan Shepherd, James Lee Toth, Tao Wang, Yue-Wei Qian, Robert Dean Dally, Njoroge F George, Susan A. Konicek |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Purine Hydroxymethyl and Formyl Transferases Lung Neoplasms Mice Nude lcsh:Medicine Antineoplastic Agents Article 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Downregulation and upregulation Multienzyme Complexes Cell Line Tumor Animals Humans Enzyme Inhibitors lcsh:Science Nucleotide salvage Hypoxanthine Multidisciplinary Cell growth lcsh:R AMPK Ribonucleotides Aminoimidazole Carboxamide Xenograft Model Antitumor Assays Neoplasm Proteins 030104 developmental biology chemistry Cell culture Nucleotide Deaminases 030220 oncology & carcinogenesis Cancer research Female lcsh:Q Growth inhibition |
| Zdroj: | Scientific Reports, Vol 8, Iss 1, Pp 1-12 (2018) Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-018-33453-4 |
| Popis: | AICARFT is a folate dependent catalytic site within the ATIC gene, part of the purine biosynthetic pathway, a pathway frequently upregulated in cancers. LSN3213128 is a potent (16 nM) anti-folate inhibitor of AICARFT and selective relative to TS, SHMT1, MTHFD1, MTHFD2 and MTHFD2L. Increases in ZMP, accompanied by activation of AMPK and cell growth inhibition, were observed with treatment of LY3213128. These effects on ZMP and proliferation were dependent on folate levels. In human breast MDA-MB-231met2 and lung NCI-H460 cell lines, growth inhibition was rescued by hypoxanthine, but not in the A9 murine cell line which is deficient in purine salvage. In athymic nude mice, LSN3213128 robustly elevates ZMP in MDA-MB-231met2, NCI-H460 and A9 tumors in a time and dose dependent manner. Significant tumor growth inhibition in human breast MDA-MB231met2 and lung NCI-H460 xenografts and in the syngeneic A9 tumor model were observed with oral administration of LSN3213128. Strikingly, AMPK appeared activated within the tumors and did not change even at high levels of intratumoral ZMP after weeks of dosing. These results support the evaluation of LSN3213128 as an antineoplastic agent. |
| Databáze: | OpenAIRE |
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