Increased resistance of tumor cells to daunorubicin after transfection of cDNAs coding for anthracycline inactivating enzymes.
Carbonyl reduction is a main but undesired metabolic pathway of the anti-cancer drug daunorubicin (DRC). The resulting alcohol metabolite daunorubicinol has a far less anti-tumor potency and, in addition, is responsible for the life-threatening cardiac toxicity that limits the clinical use of DRC. Elevated levels of carbonyl-reducing enzymes in cancer cells may therefore contribute to the development of DRC chemoresistance and affect the clinical outcome. In the present investigation, human pancreas carcinoma cells were transfected with three important DRC reductases, namely carbonyl reductase (CBR1), aldehyde reductase (AKR1A1) and aldose reductase (AKR1B1), and levels of resistance towards DCR determined. Overexpression of all three reductases lead to a higher DRC inactivation and to an elevation of chemoresistance (7-fold for CBR1, 4.5-fold for AKR1A1 and 3.7-fold for AKR1B1), when IC(50)-values were considered. Coadministration of DRC reductase inhibitors in DRC chemotherapy may be desirable since this would reduce the formation of the cardiotoxic alcohol metabolite and prevent drug resistance.
Plebuch
Mariann
M
Institute of Toxicology and Pharmacology for Natural Scientists, University Medical School Schleswig-Holstein, Campus Kiel, Brunswiker Strasse 10, 24105, Kiel, Germany.
Soldan
Michael
M
Hungerer
Christoph
C
Koch
Lutz
L
Maser
Edmund
E
D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000449:Aldehyde Reductase / Q000378:metabolism; D000074408:Aldo-Keto Reductases; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D003630:Daunorubicin / Q000494:pharmacology*; D004351:Drug Resistance; D006801:Humans; D020128:Inhibitory Concentration 50; D010190:Pancreatic Neoplasms / Q000378:metabolism; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014162:Transfection
D000903:Antibiotics, Antineoplastic; D018076:DNA, Complementary; D013778:Tetrazolium Salts; D013844:Thiazoles; D000429:Alcohol Oxidoreductases; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase; C022616:thiazolyl blue; D003630:Daunorubicin