Selectivity analysis of protein kinase CK2 inhibitors DMAT, TBB and resorufin in cisplatin-induced stress responses.
Targeting protein kinases as a therapeutic approach to treat various diseases, especially cancer is currently a fast growing business. Although many inhibitors are available, exhibiting remarkable potency, the major challenge is their selectivity. Here we show that the protein kinase CK2 inhibitors DMAT, TBB and resorufin differ in their selectivity against PI3K family members, since PI3K and DNA-PK are subject to inhibition by DMAT and TBB, however, not by resorufin. TBB and DMAT treatment together with cisplatin lead to an inhibition of cisplatin-induced stress signaling (as detected by phosphorylation of JNK and H2AX). In the case of resorufin no interference with the stress-signaling pathway is observed, supporting the notion that TBB and DMAT interfere with upstream molecules involved in genotoxic stress signaling. We have also tested the protein kinase CK2 inhibitors with respect to cell viability and inhibition of endogenous CK2 activity in the absence and presence of the anti-cancer drug cisplatin. The strongest effect on viability was observed with resorufin. In contrast to resorufin, TBB protected cells from cisplatin-induced cell killing. Furthermore, the inhibition of endogenous CK2 activity was cell type-dependent as endogenous CK2 was inhibited to different degrees in the cell lines.
Department of Toxicology, University of Mainz, D-55131 Mainz, Germany.
Gerhard
G
Fritz
Olaf-Georg
OG
Issinger
Birgitte Brinkmann
BB
Olsen
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D015153:Blotting, Western; D047390:Casein Kinase II / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D010078:Oxazines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology*
C492322:2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole; C405354:4,5,6,7-tetrabromobenzotriazole; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D010078:Oxazines; D014230:Triazoles; C014180:resorufin; D047390:Casein Kinase II; D002945:Cisplatin