Isoquinoline alkaloids as a novel type of AKR1C3 inhibitors.
AKR1C3 is an important human enzyme that participates in the reduction of steroids and prostaglandins, which leads to proliferative signalling. In addition, this enzyme also participates in the biotransformation of xenobiotics, such as drugs and procarcinogens. AKR1C3 is involved in the development of both hormone-dependent and hormone-independent cancers and was recently demonstrated to confer cell resistance to anthracyclines. Because AKR1C3 is frequently upregulated in various cancers, this enzyme has been suggested as a therapeutic target for the treatment of these pathological conditions. In this study, nineteen isoquinoline alkaloids were examined for their ability to inhibit a recombinant AKR1C3 enzyme. As a result, stylopine was demonstrated to be the most potent inhibitor among the tested compounds and exhibited moderate selectivity towards AKR1C3. In the follow-up cellular studies, stylopine significantly inhibited the AKR1C3-mediated reduction of daunorubicin in intact cells without considerable cytotoxic effects. This inhibitor could therefore be used as a model AKR1C3 inhibitor in research or evaluated as a possible therapeutic anticancer drug. Furthermore, based on our results, stylopine can serve as a model compound for the design and future development of structurally related AKR1C3 inhibitors.
Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic.
Lucie
L
Skarydova
Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic.
Jakub
J
Hofman
ADINACO Research Group, Department of Pharmaceutical Botany and Ecology, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic.
Jakub
J
Chlebek
Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic.
Jana
J
Havrankova
Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic.
Katerina
K
Kosanova
Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic.
Adam
A
Skarka
ADINACO Research Group, Department of Pharmaceutical Botany and Ecology, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic.
Anna
A
Hostalkova
Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic.
Tomas
T
Plucha
ADINACO Research Group, Department of Pharmaceutical Botany and Ecology, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic.
Lucie
L
Cahlikova
Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic. Electronic address: wsol@faf.cuni.cz.
Vladimir
V
Wsol
D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D000074425:Aldo-Keto Reductase Family 1 Member C3; D001600:Berberine Alkaloids / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000037:antagonists & inhibitors*; D013739:Testosterone / Q000378:metabolism; D014407:Tumor Cells, Cultured
D001600:Berberine Alkaloids; D004791:Enzyme Inhibitors; D013739:Testosterone; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3; C014212:stylopine
AKR1C3; Alkaloids; Cancer; Inhibitor; Isoquinoline; Natural