RRC ID 72426
Author Kikuya M, Furuichi K, Hirao T, Endo S, Toyooka N, Ito K, Aoki S.
Title Aldo-keto reductase inhibitors increase the anticancer effects of tyrosine kinase inhibitors in chronic myelogenous leukemia.
Journal J Pharmacol Sci
Abstract Tyrosine kinase inhibitors (TKIs) are widely utilized in clinical practice to treat carcinomas, but secondary tumor resistance during chronic treatment can be problematic. AKR1B1 and AKR1B10 of the aldo-keto reductase (AKR) superfamily are highly expressed in cancer cells and are believed to be involved in drug resistance. The aim of this study was to understand how TKI treatment of chronic myelogenous leukemia (CML) cells changes their glucose metabolism and if inhibition of AKRs can sensitize CML cells to TKIs. K562 cells were treated with the TKIs imatinib, nilotinib, or bosutinib, and the effects on glucose metabolism, cell death, glutathione levels, and AKR levels were assessed. To assess glucose dependence, cells were cultured in normal and low-glucose media. Pretreatment with AKR inhibitors, including epalrestat, were used to determine AKR-dependence. Treatment with TKIs increased intracellular glucose, AKR1B1/10 levels, glutathione oxidation, and nuclear translocation of nuclear factor erythroid 2-related factor 2, but with minimal cell death. These effects were dependent on intracellular glucose accumulation. Pretreatment with epalrestat, or a selective inhibitor of AKR1B10, exacerbated TKI-induced cell death, suggesting that especially AKR1B10 was involved in protection against TKIs. Thus, by disrupting cell protective mechanisms, AKR inhibitors may render CML more susceptible to TKI treatments.
Volume 147(1)
Pages 1-8
Published 2021-9-1
DOI 10.1016/j.jphs.2021.05.001
PII S1347-8613(21)00043-8
PMID 34294359
MeSH Aldehyde Reductase Aldo-Keto Reductases / antagonists & inhibitors* Aldo-Keto Reductases / metabolism Aldo-Keto Reductases / physiology Aniline Compounds / pharmacology Aniline Compounds / therapeutic use Drug Resistance, Neoplasm Drug Synergism* Enzyme Inhibitors / pharmacology* Enzyme Inhibitors / therapeutic use* Glucose / metabolism Humans Imatinib Mesylate / pharmacology Imatinib Mesylate / therapeutic use K562 Cells Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy* Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology* Nitriles / pharmacology Nitriles / therapeutic use Protein Kinase Inhibitors / pharmacology* Protein Kinase Inhibitors / therapeutic use* Protein-Tyrosine Kinases / antagonists & inhibitors* Quinolines / pharmacology Quinolines / therapeutic use Rhodanine / analogs & derivatives Rhodanine / pharmacology Rhodanine / therapeutic use Thiazolidines / pharmacology Thiazolidines / therapeutic use
IF 2.835
Human and Animal Cells K562