title: Optical and radioiodinated tethered Hsp90 inhibitors reveal selective internalization of ectopic Hsp90 in malignant breast tumor cells.
abstract: Inhibitors of heat-shock protein 90 (Hsp90) have demonstrated an unusual selectivity for tumor cells despite its ubiquitous expression. This phenomenon has remained unexplained, but could be influenced by ectopically expressed Hsp90 in tumors. In this work, we synthesized Hsp90 inhibitors that can carry optical or radioiodinated probes via a polyethyleneglycol tether. We show that these tethered inhibitors selectively recognize cells expressing ectopic Hsp90 and become internalized. The internalization process is blocked by Hsp90 antibodies, suggesting that active cycling of the protein occurs at the plasma membrane. In mice, we observed exquisite accumulation of the fluor-tethered versions within breast tumors at very sensitive levels. Cell-based assays with the radiolabeled version showed picomolar detection in cells that express ectopic Hsp90. Our findings show that fluor-tethered or radiolabeled inhibitors that target ectopic Hsp90 can be used to detect breast cancer malignancies through noninvasive imaging.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
authors.forename: Jared J
authors.initials: JJ
authors.lastname: Barrott
authors.forename: Philip F
authors.initials: PF
authors.lastname: Hughes
authors.forename: Takuya
authors.initials: T
authors.lastname: Osada
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Yang
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: Hartman
authors.forename: David R
authors.initials: DR
authors.lastname: Loiselle
authors.forename: Neil L
authors.initials: NL
authors.lastname: Spector
authors.forename: Len
authors.initials: L
authors.lastname: Neckers
authors.forename: Narasimhan
authors.initials: N
authors.lastname: Rajaram
authors.forename: Fangyao
authors.initials: F
authors.lastname: Hu
authors.forename: Nimmi
authors.initials: N
authors.lastname: Ramanujam
authors.forename: Ganesan
authors.initials: G
authors.lastname: Vaidyanathan
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zalutsky
authors.forename: H Kim
authors.initials: HK
authors.lastname: Lyerly
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Haystead
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054879:Halogenation; D006801:Humans; D007457:Iodine Radioisotopes / Q000737:chemistry; D007553:Isotope Labeling; D061986:MCF-7 Cells; D051379:Mice; D016513:Mice, SCID; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D007457:Iodine Radioisotopes
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