title: Efficacy of the HSP90 inhibitor 17-AAG in human glioma cell lines and tumorigenic glioma stem cells.
abstract: Glioblastoma multiforme (GBM) arises from genetic and signaling abnormalities in components of signal transduction pathways involved in proliferation, survival, and the cell cycle axis. Studies to date with single-agent targeted molecular therapy have revealed only modest effects in attenuating the growth of these tumors, suggesting that targeting multiple aberrant pathways may be more beneficial. Heat-shock protein 90 (HSP90) is a molecular chaperone that is involved in the conformational maturation of a defined group of client proteins, many of which are deregulated in GBM. 17-allylamino-17-demethoxygeldanamycin (17-AAG) is a well-characterized HSP90 inhibitor that should be able to target many of the aberrant signal transduction pathways in GBM. We assessed the ability of 17-AAG to inhibit the growth of glioma cell lines and glioma stem cells both in vitro and in vivo and assessed its ability to synergize with radiation and/or temozolomide, the standard therapies for GBM. Our results reveal that 17-AAG is able to inhibit the growth of both human glioma cell lines and glioma stem cells in vitro and is able to target the appropriate proteins within these cells. In addition, 17-AAG can inhibit the growth of intracranial tumors and can synergize with radiation both in tissue culture and in intracranial tumors. This compound was not found to synergize with temozolomide in any of our models of gliomas. Our results suggest that HSP90 inhibitors like 17-AAG may have therapeutic potential in GBM, either as a single agent or in combination with radiation.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115. claire_sauvageot@dfci.harvard.edu
authors.forename: Claire Marie-Elisabeth
authors.initials: CM
authors.lastname: Sauvageot
authors.forename: Jessica Leigh
authors.initials: JL
authors.lastname: Weatherbee
authors.forename: Santosh
authors.initials: S
authors.lastname: Kesari
authors.forename: Susan Elizabeth
authors.initials: SE
authors.lastname: Winters
authors.forename: Jessica
authors.initials: J
authors.lastname: Barnes
authors.forename: Jamie
authors.initials: J
authors.lastname: Dellagatta
authors.forename: Naren Raj
authors.initials: NR
authors.lastname: Ramakrishna
authors.forename: Charles Dean
authors.initials: CD
authors.lastname: Stiles
authors.forename: Andrew Li-Jen
authors.initials: AL
authors.lastname: Kung
authors.forename: Mark W
authors.initials: MW
authors.lastname: Kieran
authors.forename: Patrick Yung Chih
authors.initials: PY
authors.lastname: Wen
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D016227:Benzoquinones / Q000494:pharmacology*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004359:Drug Therapy, Combination; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D011836:Radiation Tolerance; D013234:Stem Cells / Q000502:physiology*; D000077204:Temozolomide; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D016159:Tumor Suppressor Protein p53; C112765:tanespimycin; D003606:Dacarbazine; C512478:EGFR protein, human; D066246:ErbB Receptors; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D000077204:Temozolomide