title: Molecular chaperone Hsp90 as a target for oxidant-based anticancer therapies.
abstract: Hsp90 is a molecular chaperone involved in the stabilization of many oncoproteins that are required for the acquisition and maintenance of the so-called six major hallmarks of cancer cells. Various strategies have, therefore, been developed to inhibit the chaperone activity of Hsp90 and induce cancer cell death through the destabilization of its client proteins. Among these strategies, we have shown that generation of oxidative stress leads to the cleavage and deactivation of Hsp90. Because cancer cells are often deficient in antioxidant enzymes and exhibit higher basal levels of reactive oxygen species (ROS) than their normal counterparts, inducing a selective oxidative stress may be a promising approach for cancer treatment. Thus, many redox-modulating agents have, therefore, been developed or are undergoing clinical trials and Hsp90 represents a new target for oxidative stress-generating agents. The purpose of this article is to review the current state of knowledge about Hsp90 and the use of oxidative stress-generating agents in cancer treatment. We will illustrate the review with some of our results concerning the effects of oxidative stress on Hsp90 using various oxidative stress-generating systems based on different quinones in combination with a well-known reducing agent (i.e., ascorbate). Our results show that oxidative stress provokes the cleavage of Hsp90 in CML cells, as well as the degradation of its client protein Bcr-Abl and the deactivation of its downstream signaling pathways, namely MAPK and STAT5. Overall, these results highlight the potential interest of using oxidative stress to target Hsp90.
authors.affiliation: Toxicology and Cancer Biology Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, Belgium.
authors.forename: R
authors.initials: R
authors.lastname: Beck
authors.forename: N
authors.initials: N
authors.lastname: Dejeans
authors.forename: C
authors.initials: C
authors.lastname: Glorieux
authors.forename: R C
authors.initials: RC
authors.lastname: Pedrosa
authors.forename: D
authors.initials: D
authors.lastname: Vásquez
authors.forename: J A
authors.initials: JA
authors.lastname: Valderrama
authors.forename: P B
authors.initials: PB
authors.lastname: Calderon
authors.forename: J
authors.initials: J
authors.lastname: Verrax
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D018832:Molecular Chaperones / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016877:Oxidants / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D016877:Oxidants; D017382:Reactive Oxygen Species