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.
- 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
A gram-positive, slowly growing rod effectively utilizing morpholine as the sole source of organic carbon, nitrogen, and energy was isolated from a mixed culture in a laboratory reactor. The strain was tentatively identified as Mycobacterium aurum. Its growth characteristics at 20 degrees C and pH 6.5 were as follows: maximum specific growth rate, 0.052 h-1; half-velocity constant, 1.3 mg/liter; and yield, 0.37 g/g. The optimum temperature and pH were 31 degrees C and 6.0, respectively.
- MeSH
- biodegradace MeSH
- kinetika MeSH
- mikrobiologie vody * MeSH
- morfoliny metabolismus MeSH
- Mycobacterium růst a vývoj izolace a purifikace metabolismus MeSH
- teplota MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- morfoliny MeSH
- MeSH
- anestetika lokální metabolismus MeSH
- biotransformace MeSH
- cyklické N-oxidy biosyntéza MeSH
- cytochromreduktasy metabolismus MeSH
- endoplazmatické retikulum metabolismus MeSH
- fenylethery metabolismus MeSH
- isomerie MeSH
- jaterní mikrozomy enzymologie MeSH
- játra metabolismus MeSH
- krysa rodu Rattus MeSH
- morfoliny metabolismus MeSH
- NAD MeSH
- oxidace-redukce MeSH
- oxygenasy metabolismus MeSH
- techniky in vitro MeSH
- toluen metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- zvířata MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- Názvy látek
- anestetika lokální MeSH
- cyklické N-oxidy MeSH
- cytochromreduktasy MeSH
- fenylethery MeSH
- morfoliny MeSH
- NAD MeSH
- oxygenasy MeSH
- toluen MeSH
- MeSH
- anestetika lokální metabolismus moč MeSH
- chromatografie na tenké vrstvě MeSH
- ethery metabolismus MeSH
- koncentrace vodíkových iontů MeSH
- krysa rodu Rattus MeSH
- morčata MeSH
- morfoliny metabolismus MeSH
- toluen metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- morčata MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- anestetika lokální MeSH
- ethery MeSH
- morfoliny MeSH
- toluen MeSH
- MeSH
- aplikace orální MeSH
- chromatografie na tenké vrstvě MeSH
- hypoglykemika krev metabolismus moč MeSH
- intestinální absorpce MeSH
- krysa rodu Rattus MeSH
- morfoliny metabolismus MeSH
- psi MeSH
- spektrofotometrie MeSH
- ultrafialové záření MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- psi MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- hypoglykemika MeSH
- morfoliny MeSH
