Inhibition of gastric tumor growth by a novel Hsp90 inhibitor

Chunwan Lu, Di Liu, Jing Jin, Hemantkumar Deokar, Yi Zhang, John K. Buolamwini, Xiaoming Yu, Chunhong Yan, Xiaoguang Chen

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Heat shock protein 90 (Hsp90) is a molecular chaperone engaging in multiple cellular signaling by stabilizing oncoproteins (e.g. Akt and c-Raf) in tumor cells. Whereas Hsp90 inhibitors such as 17-AAG exert promising antitumor effects in clinical trials, current efforts focus on developing agents targeting Hsp90 with improved efficacy and lower toxicity. Using a fluorescence polarization assay, we screened over a hundred of synthetic small molecules and identified a resorcinol derivative LD053 that bound the Hsp90 ATP-binding pocket. The binding of LD053 to Hsp90 dissociated the co-chaperone protein cdc37 from Hsp90, resulting in destabilization of Akt and c-Raf and subsequent inhibition of PI3K/Akt and c-Raf/Mek/Erk signaling in BGC823 gastric cancer cells. As a consequence, LD053 decreased cancer cell viability and induced apoptosis evidenced by increased subG0/G1 cell population and increased cleavage of caspase 3 and PARP. Interestingly, normal human cells appeared insensitive to LD053 treatments. Consistent with its in vitro anticancer activities, LD053 significantly inhibited growth of BGC823 xenografts in nude mice without apparent body weight loss. These results thus demonstrate that LD053 is a novel Hsp90 inhibitor and has potential to be used to treat gastric cancer.

Original languageEnglish (US)
Pages (from-to)1246-1256
Number of pages11
JournalBiochemical Pharmacology
Volume85
Issue number9
DOIs
StatePublished - May 1 2013
Externally publishedYes

Keywords

  • Cancer therapy
  • Gastric cancer
  • Hsp90
  • Hsp90 inhibitor
  • Molecular chaperone

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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  • Cite this

    Lu, C., Liu, D., Jin, J., Deokar, H., Zhang, Y., Buolamwini, J. K., Yu, X., Yan, C., & Chen, X. (2013). Inhibition of gastric tumor growth by a novel Hsp90 inhibitor. Biochemical Pharmacology, 85(9), 1246-1256. https://doi.org/10.1016/j.bcp.2013.02.003