title: Extracellular Hsp90 (eHsp90) as the actual target in clinical trials: intentionally or unintentionally.
abstract: Despite extensive investigative studies and clinical trials over the past two decades, we still do not understand why cancer cells are more sensitive to the cellular toxicity of Hsp90 inhibitors than normal cells. We still do not understand why only some cancer cells are sensitive to the Hsp90 inhibitors. Based on studies of the past few years, we argue that the selected sensitivity of cancer cells to Hsp90 inhibitors, such as 17-N-allylamino-17-demethoxygeldanamycin, is due to inhibition of the extracellular Hsp90 (eHsp90) rather than intracellular Hsp90 by these inhibitors. Because not all tumor cells utilize eHsp90 for motility, invasion and metastasis, only the group of "eHsp90-dependent" cancer cells is sensitive to Hsp90 inhibitors. If these notions prove to be true, pharmaceutical agents that selectively target eHsp90 should be more effective on tumor cells and less toxic on normal cells than current inhibitors that nondiscriminatively target both extracellular and intracellular Hsp90.
authors: Department of Dermatology, USC-Norris Comprehensive Cancer Center, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA. wli@usc.edu
authors: Wei
authors: W
authors: Li
authors: Fred
authors: F
authors: Tsen
authors: Divya
authors: D
authors: Sahu
authors: Ayesha
authors: A
authors: Bhatia
authors: Mei
authors: M
authors: Chen
authors: Gabriele
authors: G
authors: Multhoff
authors: David T
authors: DT
authors: Woodley
mesh_terms: D001775:Blood Circulation; D002465:Cell Movement; D002986:Clinical Trials as Topic; D005110:Extracellular Space / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism
chemical_list: D018841:HSP90 Heat-Shock Proteins