Buparlisib is a novel inhibitor of daunorubicin reduction mediated by aldo-keto reductase 1C3
Jazyk angličtina Země Irsko Médium print-electronic
Typ dokumentu časopisecké články
PubMed
30703376
DOI
10.1016/j.cbi.2019.01.026
PII: S0009-2797(18)31496-0
Knihovny.cz E-zdroje
- Klíčová slova
- AKR1C3, Anthracyclines, Buparlisib, Cancer, HCT116 cell line, Multidrug resistance,
- MeSH
- aldo-keto reduktasy antagonisté a inhibitory genetika metabolismus MeSH
- aminopyridiny chemie metabolismus farmakologie MeSH
- daunomycin metabolismus MeSH
- HCT116 buňky MeSH
- inhibiční koncentrace 50 MeSH
- katalytická doména MeSH
- kinetika MeSH
- lidé MeSH
- morfoliny chemie metabolismus farmakologie MeSH
- protein AKR1C3 antagonisté a inhibitory chemie metabolismus MeSH
- rekombinantní proteiny biosyntéza izolace a purifikace metabolismus MeSH
- simulace molekulového dockingu MeSH
- vazebná místa MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- aldo-keto reduktasy MeSH
- aminopyridiny MeSH
- daunomycin MeSH
- morfoliny MeSH
- NVP-BKM120 MeSH Prohlížeč
- protein AKR1C3 MeSH
- rekombinantní proteiny MeSH
Buparlisib is a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor and is currently under clinical evaluation for the treatment of different cancers. Because PI3K signalling is related to cell proliferation and resistance to chemotherapy, new therapeutic approaches are focused on combining PI3K inhibitors with other anti-cancer therapeutics. Carbonyl-reducing enzymes catalyse metabolic detoxification of anthracyclines and reduce their cytotoxicity. In the present work, the effects of buparlisib were tested on six human recombinant carbonyl-reducing enzymes: AKR1A1, AKR1B1, AKR1B10, AKR1C3, and AKR7A2 from the aldo-keto reductase superfamily and CBR1 from the short-chain dehydrogenase/reductase superfamily, all of which participate in the metabolism of daunorubicin. Buparlisib exhibited the strongest inhibitory effect on recombinant AKR1C3, with a half-maximal inhibitory concentration (IC50) of 9.5 μM. Its inhibition constant Ki was found to be 14.0 μM, and the inhibition data best fitted a mixed-type mode with α = 0.6. The same extent of inhibition was observed at the cellular level in the human colorectal carcinoma HCT 116 cell line transfected with a plasmid encoding the AKR1C3 transcript (IC50 = 7.9 μM). Furthermore, we performed an analysis of flexible docking between buparlisib and AKR1C3 and found that buparlisib probably occupies a part of the binding site for a cofactor most likely via the trifluoromethyl group of buparlisib interacting with catalytic residue Tyr55. In conclusion, our results show a novel PI3K-independent effect of buparlisib that may improve therapeutic efficacy and safety of daunorubicin by preventing its metabolism by AKR1C3.
Citace poskytuje Crossref.org
