The HSP90 and DNA topoisomerase VI inhibitor radicicol also inhibits human type II DNA topoisomerase.
Radicicol derivatives are currently investigated as promising antitumoral drugs because they inhibit the activity of the molecular chaperone heat shock protein (HSP90), causing the destabilization and eventual degradation of HSP90 client proteins that are often associated with tumor cells. These drugs interact with the ATP-binding site of HSP90 which is characterized by a structural element known as the Bergerat fold, also present in type II DNA topoisomerases (Topo II). We have previously shown that radicicol inhibits archaeal DNA topoisomerase VI, the prototype of Topo II of the B family (present in archaea, some bacteria and all the plants sequenced so far). We show here that radicicol also inhibits the human Topo II, a member of the A family (comprising the eukaryotic Topo II, bacterial gyrase, Topo IV and viral Topo II), which is a major target for antitumoral drugs. In addition, radicicol prevents in vitro induction of DNA cleavage by human Topo II in the presence of the antitumoral drug etoposide. The finding that radicicol can inhibit at least two different antitumoral drug targets in human, and interferes with drugs currently used in cancer treatment, could have implications in cancer therapy.
Gadelle
Danièle
D
Institut de Genetique et Microbiologie, UMR CNRS 8621, France. daniele.gadelle@igmors.u-psud.fr
Graille
Marc
M
Forterre
Patrick
P
D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D053837:DNA Cleavage / Q000187:drug effects; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors*; D018105:DNA, Kinetoplast / Q000187:drug effects; D004278:DNA, Superhelical / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D018942:Macrolides / Q000737:chemistry / Q000494:pharmacology*; D008969:Molecular Sequence Data; D010957:Plasmids; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D016415:Sequence Alignment; D059005:Topoisomerase II Inhibitors
D000970:Antineoplastic Agents; D018105:DNA, Kinetoplast; D004278:DNA, Superhelical; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D018942:Macrolides; D059005:Topoisomerase II Inhibitors; D027101:DNA Topoisomerase IV; C035359:monorden