title: Anticancer activity of Celastrol in combination with ErbB2-targeted therapeutics for treatment of ErbB2-overexpressing breast cancers.
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 HSP90 inhibitors is synergistic with Trastuzumab, suggesting that pharmacological agents that can inhibit HSP90 as well as signaling pathways activated by ErbB2 could be useful against ErbB2-overexpressing breast cancers. The triterpene natural product Celastrol inhibits HSP90 and several pathways relevant to ErbB2-dependent oncogenesis including the NFκB 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 HSP90 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.
authors.affiliation: Department of Medicine, Evanston Northwestern Healthcare Research Institute, Northwestern University, Evanston, IL, USA.
authors.forename: Srikumar M
authors.initials: SM
authors.lastname: Raja
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Clubb
authors.forename: Cesar
authors.initials: C
authors.lastname: Ortega-Cava
authors.forename: Stetson H
authors.initials: SH
authors.lastname: Williams
authors.forename: Tameka A
authors.initials: TA
authors.lastname: Bailey
authors.forename: Lei
authors.initials: L
authors.lastname: Duan
authors.forename: Xiangshan
authors.initials: X
authors.lastname: Zhao
authors.forename: Alagarasamy L
authors.initials: AL
authors.lastname: Reddi
authors.forename: Abijah M
authors.initials: AM
authors.lastname: Nyong
authors.forename: Amarnath
authors.initials: A
authors.lastname: Natarajan
authors.forename: Vimla
authors.initials: V
authors.lastname: Band
authors.forename: Hamid
authors.initials: H
authors.lastname: Band
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D020128:Inhibitory Concentration 50; D000077341:Lapatinib; D051379:Mice; D016513:Mice, SCID; D053978:Pentacyclic Triterpenes; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000627:therapeutic use; D015398:Signal Transduction; D000068878:Trastuzumab; D014315:Triterpenes / Q000008:administration & dosage*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D000077341:Lapatinib; D053978:Pentacyclic Triterpenes; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D014315:Triterpenes; C050414:celastrol