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Lack of cross‐resistance to FF‐10501, an inhibitor of inosine‐5′‐monophosphate dehydrogenase, in azacitidine‐resistant cell lines selected from SKM‐1 and MOLM‐13 leukemia cell lines
- Source :
- Pharmacology Research & Perspectives
- Publication Year :
- 2016
- Publisher :
- John Wiley and Sons Inc., 2016.
-
Abstract
- Resistance to azacitidine is a major issue in the treatments of myelodysplastic syndrome and acute myeloid leukemia, and previous studies suggest that changes in drug metabolism are involved in the resistance. Therefore, drugs with mechanisms resistant or alternative to such metabolic changes have been desired for the treatment of resistant disease. We generated azacitidine‐resistant cells derived from SKM‐1 and MOLM‐13 leukemia cell lines in vitro, analyzed the mechanisms, and examined the impact on the efficacy of other antimetabolic drugs. It appeared that the cell growth‐inhibitory effect of azacitidine, expression levels of uridine–cytidine kinase 2, and the concentrations of azacitidine triphosphate were remarkably decreased in the resistant cells compared with those in parent cells. These results were consistent with previous observations that azacitidine resistance is derived from metabolic changes. Cross‐resistance of greater than 10‐fold (shift in IC50 value) was observed in azacitidine‐resistant cells for decitabine and for cytarabine, but not for gemcitabine or the inosine‐5′‐monophosphate dehydrogenase (IMPDH) inhibitors FF‐10501 and mycophenolate mofetil (cross‐resistance to 5‐fluorouracil was cell line dependent). The IMPDH inhibitors maintained their cell growth‐inhibitory activities in the azacitidine‐resistant cell lines, in which the levels of adenine phosphoribosyltransferase (which converts FF‐10501 to its active form, FF‐10501 ribosylmonophosphate [FF‐10501RMP]), FF‐10501RMP, and the target enzyme, IMPDH, were equivalent to those in the parent cell lines. These results suggest that an IMPDH inhibitor such as FF‐10501 could be an alternative therapeutic treatment for leukemia patients with acquired resistance to azacitidine.
- Subjects :
- 0301 basic medicine
Azacitidine
IMPDH inhibitor
Decitabine
Pharmacology
Mycophenolate
resistance
03 medical and health sciences
0302 clinical medicine
FF‐10501
medicine
General Pharmacology, Toxicology and Pharmaceutics
Inosine-5′-monophosphate dehydrogenase
biology
business.industry
Myeloid leukemia
Original Articles
medicine.disease
Leukemia
030104 developmental biology
Neurology
Cell culture
030220 oncology & carcinogenesis
biology.protein
Cytarabine
Original Article
business
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 20521707
- Volume :
- 4
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Pharmacology Research & Perspectives
- Accession number :
- edsair.doi.dedup.....d2c10926fbbe12469f020665e18d77f9