Inhibition of Hsp90 acts synergistically with topoisomerase II poisons to increase the apoptotic killing of cells due to an increase in topoisomerase II mediated DNA damage.
Topoisomerase II plays a crucial role during chromosome condensation and segregation in mitosis and meiosis and is a highly attractive target for chemotherapeutic agents. We have identified previously topoisomerase II and heat shock protein 90 (Hsp90) as part of a complex. In this paper we demonstrate that drug combinations targeting these two enzymes cause a synergistic increase in apoptosis. The objective of our study was to identify the mode of cell killing and the mechanism behind the increase in topoisomerase II mediated DNA damage. Importantly we demonstrate that Hsp90 inhibition results in an increased topoiosmerase II activity but not degradation of topoisomerase II and it is this, in the presence of a topoisomerase II poison that causes the increase in cell death. Our results suggest a novel mechanism of action where the inhibition of Hsp90 disrupts the Hsp90-topoisomerase II interaction leading to an increase in and activation of unbound topoisomerase II, which, in the presence of a topoisomerase II poison leads to the formation of an increased number of cleavable complexes ultimately resulting in rise in DNA damage and a subsequent increase cell death.
Barker
Catherine R
CR
The Henry Wellcome Laboratory of Molecular and Cellular Gastroenterology, Division of Gastroenterology, School of Clinical Sciences, University of Liverpool, Crown Street, Liverpool L69 3BX, UK.
McNamara
Anne V
AV
Rackstraw
Stephen A
SA
Nelson
David E
DE
White
Mike R
MR
Watson
Alastair J M
AJ
Jenkins
John R
JR
D017209:Apoptosis; D016227:Benzoquinones; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000633:toxicity; D005047:Etoposide / Q000633:toxicity; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D047029:Lactams, Macrocyclic; D011494:Protein Kinases / Q000378:metabolism; D011809:Quinones / Q000633:toxicity; D059005:Topoisomerase II Inhibitors
D016227:Benzoquinones; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011809:Quinones; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D004247:DNA; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; D004250:DNA Topoisomerases, Type II; C001277:geldanamycin