title: KU135, a novel novobiocin-derived C-terminal inhibitor of the 90-kDa heat shock protein, exerts potent antiproliferative effects in human leukemic cells.
abstract: The 90-kDa heat shock protein (Hsp90) assists in the proper folding of numerous mutated or overexpressed signal transduction proteins that are involved in cancer. Consequently, there is considerable interest in developing chemotherapeutic drugs that specifically disrupt the function of Hsp90. Here, we investigated the extent to which a novel novobiocin-derived C-terminal Hsp90 inhibitor, designated KU135, induced antiproliferative effects in Jurkat T-lymphocytes. The results indicated that KU135 bound directly to Hsp90, caused the degradation of known Hsp90 client proteins, and induced more potent antiproliferative effects than the established N-terminal Hsp90 inhibitor 17-allylamino-demethoxygeldanamycin (17-AAG). Closer examination of the cellular response to KU135 and 17-AAG revealed that only 17-AAG induced a strong up-regulation of Hsp70 and Hsp90. In addition, KU135 caused wild-type cells to undergo G(2)/M arrest, whereas cells treated with 17-AAG accumulated in G(1). Furthermore, KU135 but not 17-AAG was found to be a potent inducer of mitochondria-mediated apoptosis as evidenced, in part, by the fact that cell death was inhibited to a similar extent by Bcl-2/Bcl-x(L) overexpression or the depletion of apoptotic protease-activating factor-1 (Apaf-1). Together, these data suggest that KU135 inhibits cell proliferation by regulating signaling pathways that are mechanistically different from those targeted by 17-AAG and as such represents a novel opportunity for Hsp90 inhibition.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Shary N
authors.initials: SN
authors.lastname: Shelton
authors.forename: Mary E
authors.initials: ME
authors.lastname: Shawgo
authors.forename: Shawna B
authors.initials: SB
authors.lastname: Matthews
authors.forename: Yuanming
authors.initials: Y
authors.lastname: Lu
authors.forename: Alison C
authors.initials: AC
authors.lastname: Donnelly
authors.forename: Kristen
authors.initials: K
authors.lastname: Szabla
authors.forename: Mehmet
authors.initials: M
authors.lastname: Tanol
authors.forename: George A
authors.initials: GA
authors.lastname: Vielhauer
authors.forename: Roger A
authors.initials: RA
authors.lastname: Rajewski
authors.forename: Robert L
authors.initials: RL
authors.lastname: Matts
authors.forename: Brian S J
authors.initials: BS
authors.lastname: Blagg
authors.forename: John D
authors.initials: JD
authors.lastname: Robertson
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002846:Chromatography, Affinity; D005434:Flow Cytometry; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D019169:Jurkat Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009675:Novobiocin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D020349:Surface Plasmon Resonance
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; C545608:KU135; D009675:Novobiocin