Resorufin: a lead for a new protein kinase CK2 inhibitor.
Screening a natural compound library led to the identification of resorufin as a highly selective and potent inhibitor of protein kinase CK2. Out of 52 kinases tested, only CK2 was inhibited, in contrast to emodin, a structurally related, known CK2 inhibitor that, in addition to CK2, inhibited ten other kinases by 90%. The IC50 values determined for the CK2 holoenzymes were 1.5 mol/l and for the free catalytic subunits ca. 4 mol/l. Altogether four cell lines were subjected to resorufin and emodin treatment. In the case of the three prostate carcinoma cell lines (PC-3, DU-145, LNCaP), 24 h treatment with 40 mol/l resorufin led to 15-20% dead cells; however, no caspase-mediated apoptosis was observed. In the case of the colorectal carcinoma HCT116 cell line, a similar picture was obtained, yet, when resorufin was administered to cells treated with doxorubicin, apoptosis was strongly induced within 24 h. Endogenous protein kinase CK2 was inhibited by resorufin by ca. 80% in the three prostate cell lines. In the case of the HCT116 cells, the inhibition was only 40% supporting the notion of cell line-specific selectivity. Moreover, we analysed the effect of resorufin and emodin on selected signalling molecules in the cell lines under investigation.
Sandholt
Iben Skjøth
IS
Institute of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej Denmark.
Olsen
Birgitte Brinkmann
BB
Guerra
Barbara
B
Issinger
Olaf-Georg
OG
D017209:Apoptosis / Q000187:drug effects; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology; D004642:Emodin / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D010078:Oxazines / Q000008:administration & dosage / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
D010078:Oxazines; D047428:Protein Kinase Inhibitors; C014180:resorufin; D047390:Casein Kinase II; D004642:Emodin