Roscovitine and purvalanol A effectively reverse anthracycline resistance mediated by the activity of aldo-keto reductase 1C3 (AKR1C3): A promising therapeutic target for cancer treatment

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11160%2F18%3A10383093" target="_blank" >RIV/00216208:11160/18:10383093 - isvavai.cz</a>

Výsledek na webu

<a href="http://www.sciencedirect.com/science/article/pii/S0006295218303204" target="_blank" >http://www.sciencedirect.com/science/article/pii/S0006295218303204</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.bcp.2018.08.001" target="_blank" >10.1016/j.bcp.2018.08.001</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Roscovitine and purvalanol A effectively reverse anthracycline resistance mediated by the activity of aldo-keto reductase 1C3 (AKR1C3): A promising therapeutic target for cancer treatment

Popis výsledku v původním jazyce

Members of the short-chain dehydrogenase/reductase (SDR) and aldo-keto reductase (AKR) superfamilies mediate the reduction of anthracyclines to their less potent C-13 alcohol metabolites. This reductive metabolism has been recognized as one of the most important factors that trigger anthracycline resistance in cancer cells. In our study, two purine analogues, purvalanol A and roscovitine, were identified as effective inhibitors of aldoketo reductase 1C3 (AKR1C3), an enzyme that is overexpressed in many cancer types and is also a key player in tumour cell resistance to anthracyclines. Purvalanol A and roscovitine potently inhibited human recombinant AKR1C3 (Ki = 5.5 mu M and 1.4 mu M, respectively) and displayed similar activity in experiments with intact cells. Ligand-protein docking calculations suggested that both inhibitors occupied a part of the cofactor-binding site. Furthermore, we demonstrated that the combination of daunorubicin with purvalanol A or roscovitine exhibited a synergistic effect in AKR1C3 overexpressing cells. Based on these findings, it is possible to presume that purvalanol A and roscovitine may have the potential to enhance the therapeutic effectiveness and safety of anthracyclines via inhibition of AKR1C3.

Název v anglickém jazyce

Roscovitine and purvalanol A effectively reverse anthracycline resistance mediated by the activity of aldo-keto reductase 1C3 (AKR1C3): A promising therapeutic target for cancer treatment

Popis výsledku anglicky

Members of the short-chain dehydrogenase/reductase (SDR) and aldo-keto reductase (AKR) superfamilies mediate the reduction of anthracyclines to their less potent C-13 alcohol metabolites. This reductive metabolism has been recognized as one of the most important factors that trigger anthracycline resistance in cancer cells. In our study, two purine analogues, purvalanol A and roscovitine, were identified as effective inhibitors of aldoketo reductase 1C3 (AKR1C3), an enzyme that is overexpressed in many cancer types and is also a key player in tumour cell resistance to anthracyclines. Purvalanol A and roscovitine potently inhibited human recombinant AKR1C3 (Ki = 5.5 mu M and 1.4 mu M, respectively) and displayed similar activity in experiments with intact cells. Ligand-protein docking calculations suggested that both inhibitors occupied a part of the cofactor-binding site. Furthermore, we demonstrated that the combination of daunorubicin with purvalanol A or roscovitine exhibited a synergistic effect in AKR1C3 overexpressing cells. Based on these findings, it is possible to presume that purvalanol A and roscovitine may have the potential to enhance the therapeutic effectiveness and safety of anthracyclines via inhibition of AKR1C3.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Biochemical Pharmacology

ISSN

0006-2952

e-ISSN

—

Svazek periodika

156

Číslo periodika v rámci svazku

October

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

10

Strana od-do

22-31

Kód UT WoS článku

000448491500003

EID výsledku v databázi Scopus

2-s2.0-85051117986