Mechanism of topoisomerase II inhibition by staurosporine and other protein kinase inhibitors.
Topoisomerase II is an essential enzyme for proliferation of eukaryotic cells. It is also a target for many antineoplastic drugs that promote stabilization of covalent complexes between topoisomerase II and DNA. Topoisomerase II and protein kinases both catalyze the transfer of phosphoester bonds from nucleotides to proteins. This similarity suggests that inhibitors may affect both classes of enzymes. In the present study, we have examined the mechanism of topoisomerase II inhibition by three different classes of protein kinase inhibitors. We report that staurosporine inhibited the catalytic activity of topoisomerase II by blocking the transfer of phosphodiester bonds from DNA to the active tyrosine site, a mechanism of inhibition not previously reported for this enzyme. In contrast, other kinase inhibitors, such as methyl 2,5-dihydroxycinnamate, most likely inactivated topoisomerase II by alkylation of essential amino acids, whereas the mechanism of inhibition of bis-indolylmaleimide possibly involved a direct interaction with DNA.
Lassota
P
P
Oncology and Immunology Research Division, Wyeth-Ayerst Research, Pearl River, New York 10965, USA.
Singh
G
G
Kramer
R
R
D000255:Adenosine Triphosphate / Q000378:metabolism; D000266:Adenylyl Imidodiphosphate / Q000494:pharmacology; D000818:Animals; D002934:Cinnamates / Q000494:pharmacology; D016831:Crithidia fasciculata; D004247:DNA / Q000378:metabolism; D054659:Diketopiperazines; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D019311:Staurosporine / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors
D002934:Cinnamates; D054659:Diketopiperazines; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D059005:Topoisomerase II Inhibitors; C070899:4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione; D000266:Adenylyl Imidodiphosphate; C067472:methyl 2,5-dihydroxycinnamate; D005047:Etoposide; D000255:Adenosine Triphosphate; D004247:DNA; D019311:Staurosporine; C088060:bisindolylmaleimide