Anticancer activity of Celastrol in combination with ErbB2-targeted therapeutics for treatment of ErbB2-overexpressing breast cancers

Srikumar M. Raja, Robert J. Clubb, Cesar Ortega-Cava, Stetson H. Williams, Tameka A. Bailey, Lei Duan, Xiangshan Zhao, Alagarasamy L. Reddi, Abijah M. Nyong, Amarnath Natarajan, Vimla Band, Hamid Band

Research output: Contribution to journalArticle

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Abstract

The receptor tyrosine kinase ErbB2 is overexpressed in up to a third of breast cancers, allowing targeted therapy with ErbB2-directed humanized antibodies such as Trastuzumab. Concurrent targeting of ErbB2 stability with HSP 90 inhibitors is synergistic with Trastuzumab, suggesting that pharmacological agents that can inhibit HSP 90 as well as signaling pathways activated by ErbB2 could be useful against ErbB2-overexpressing breast cancers. The triterpene natural product Celastrol inhibits HSP 90 and several pathways relevant to ErbB2-dependent oncogenesis including the NF?B pathway and the proteasome, and has shown promising activity in other cancer models. Here, we demonstrate that Celastrol exhibits in vitro antitumor activity against a panel of human breast cancer cell lines with selectivity towards those overexpressing ErbB2. Celastrol strongly synergized with ErbB2-targeted therapeutics Trastuzumab and Lapatinib, producing higher cytotoxicity with substantially lower doses of Celastrol. Celastrol significantly retarded the rate of growth of ErbB2-overexpressing human breast cancer cells in a mouse xenograft model with only minor systemic toxicity. Mechanistically, Celastrol not only induced the expected ubiquitinylation and degradation of ErbB2 and other HSP 90 client proteins, but it also increased the levels of reactive oxygen species (ROS). Our studies show that the Michael Acceptor functionality in Celastrol is important for its ability to destabilize ErbB2 and exert its bioactivity against ErbB2-overexpressing breast cancer cells. These studies suggest the potential use of Michael acceptor-containing molecules as novel therapeutic modalities against ErbB2-driven breast cancer by targeting multiple biological attributes of the driver oncogene.

Original languageEnglish (US)
Pages (from-to)263-276
Number of pages14
JournalCancer Biology and Therapy
Volume11
Issue number2
DOIs
StatePublished - Jan 15 2011

Fingerprint

Breast Neoplasms
Therapeutics
Antibodies, Monoclonal, Humanized
Triterpenes
Receptor Protein-Tyrosine Kinases
Proteasome Endopeptidase Complex
tripterine
Biological Products
Oncogenes
Heterografts
Reactive Oxygen Species
Carcinogenesis
Pharmacology
Cell Line
Growth
Trastuzumab
Neoplasms
Proteins

Keywords

  • 17-AAG
  • Celastrol
  • Drug interaction
  • ErbB2
  • HSP90
  • Her2/Neu
  • Proteasome
  • ROS
  • Targeted therapy
  • Trastuzumab
  • Ubiquitin

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

Anticancer activity of Celastrol in combination with ErbB2-targeted therapeutics for treatment of ErbB2-overexpressing breast cancers. / Raja, Srikumar M.; Clubb, Robert J.; Ortega-Cava, Cesar; Williams, Stetson H.; Bailey, Tameka A.; Duan, Lei; Zhao, Xiangshan; Reddi, Alagarasamy L.; Nyong, Abijah M.; Natarajan, Amarnath; Band, Vimla; Band, Hamid.

In: Cancer Biology and Therapy, Vol. 11, No. 2, 15.01.2011, p. 263-276.

Research output: Contribution to journalArticle

Raja, Srikumar M. ; Clubb, Robert J. ; Ortega-Cava, Cesar ; Williams, Stetson H. ; Bailey, Tameka A. ; Duan, Lei ; Zhao, Xiangshan ; Reddi, Alagarasamy L. ; Nyong, Abijah M. ; Natarajan, Amarnath ; Band, Vimla ; Band, Hamid. / Anticancer activity of Celastrol in combination with ErbB2-targeted therapeutics for treatment of ErbB2-overexpressing breast cancers. In: Cancer Biology and Therapy. 2011 ; Vol. 11, No. 2. pp. 263-276.
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