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Optical and radioiodinated tethered Hsp90 inhibitors reveal selective internalization of ectopic Hsp90 in malignant breast tumor cells.

Publication ,  Journal Article
Barrott, JJ; Hughes, PF; Osada, T; Yang, X-Y; Hartman, ZC; Loiselle, DR; Spector, NL; Neckers, L; Rajaram, N; Hu, F; Ramanujam, N; Lyerly, HK ...
Published in: Chem Biol
September 19, 2013

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.

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Published In

Chem Biol

DOI

EISSN

1879-1301

Publication Date

September 19, 2013

Volume

20

Issue

9

Start / End Page

1187 / 1197

Location

United States

Related Subject Headings

  • Transplantation, Heterologous
  • Organic Chemistry
  • Mice, SCID
  • Mice
  • MCF-7 Cells
  • Isotope Labeling
  • Iodine Radioisotopes
  • Humans
  • Halogenation
  • HSP90 Heat-Shock Proteins
 

Citation

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Barrott, J. J., Hughes, P. F., Osada, T., Yang, X.-Y., Hartman, Z. C., Loiselle, D. R., … Haystead, T. A. (2013). Optical and radioiodinated tethered Hsp90 inhibitors reveal selective internalization of ectopic Hsp90 in malignant breast tumor cells. Chem Biol, 20(9), 1187–1197. https://doi.org/10.1016/j.chembiol.2013.08.004
Barrott, Jared J., Philip F. Hughes, Takuya Osada, Xiao-Yi Yang, Zachary C. Hartman, David R. Loiselle, Neil L. Spector, et al. “Optical and radioiodinated tethered Hsp90 inhibitors reveal selective internalization of ectopic Hsp90 in malignant breast tumor cells.Chem Biol 20, no. 9 (September 19, 2013): 1187–97. https://doi.org/10.1016/j.chembiol.2013.08.004.
Barrott JJ, Hughes PF, Osada T, Yang X-Y, Hartman ZC, Loiselle DR, et al. Optical and radioiodinated tethered Hsp90 inhibitors reveal selective internalization of ectopic Hsp90 in malignant breast tumor cells. Chem Biol. 2013 Sep 19;20(9):1187–97.
Barrott, Jared J., et al. “Optical and radioiodinated tethered Hsp90 inhibitors reveal selective internalization of ectopic Hsp90 in malignant breast tumor cells.Chem Biol, vol. 20, no. 9, Sept. 2013, pp. 1187–97. Pubmed, doi:10.1016/j.chembiol.2013.08.004.
Barrott JJ, Hughes PF, Osada T, Yang X-Y, Hartman ZC, Loiselle DR, Spector NL, Neckers L, Rajaram N, Hu F, Ramanujam N, Vaidyanathan G, Zalutsky MR, Lyerly HK, Haystead TA. Optical and radioiodinated tethered Hsp90 inhibitors reveal selective internalization of ectopic Hsp90 in malignant breast tumor cells. Chem Biol. 2013 Sep 19;20(9):1187–1197.

Published In

Chem Biol

DOI

EISSN

1879-1301

Publication Date

September 19, 2013

Volume

20

Issue

9

Start / End Page

1187 / 1197

Location

United States

Related Subject Headings

  • Transplantation, Heterologous
  • Organic Chemistry
  • Mice, SCID
  • Mice
  • MCF-7 Cells
  • Isotope Labeling
  • Iodine Radioisotopes
  • Humans
  • Halogenation
  • HSP90 Heat-Shock Proteins