In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 3559-3559
Abstract:
Celastrol, a novel triterpene natural product, has shown immense promise against various cancer models including prostate cancer, pancreatic cancer, leukemia, and melanoma. A unique property of Celastrol is its ability to affect multiple oncogenic cellular targets that include the proteasome, HSP90, I Kappa B Kinase and the cellular redox-balance system. Celastrol could therefore be viewed as a multifunctional pharmacophore simultaneously affecting multiple targets within oncogenically transformed cell. In this paper we explore the properties of this unique pharmacophore as therapeutic agent for treating ErbB2-overexpressing breast cancers. Celastrol not only induced ubiquitinylation and degradation of ErbB2 and other HSP90 client proteins; it also increased cellular ROS levels, and killed ErbB2-overexpressing cells with higher selectivity. Comparison of IC50 values amongst a panel of breast cancer cell lines indicated a strong correlation of basal ROS-levels to sensitivity to killing. ErbB2-overexpression led to increase in basal ROS and consequently ErbB2-high cells were more sensitive to Celastrol than ErbB2-low cells. Celastrol also strongly synergized with ErbB2-targeted therapeutics, Trastuzumab and Lapatinib, resulting in enhanced ErbB2-specific cellular cytotoxicity at substantially reduced doses of Celastrol. Pharmacogenomic expression analysis comparing 17-AAG and Celastrol confirmed several common signatures and revealed unique signatures. Celastrol, but not 17-AAG, could potently induce depletion of Aurora A Kinase at both the transcript as well as protein level, adding to the spectrum of targets, given the importance of Aurora Kinase as a target in development of anti-cancer therapeutics. In vivo xenograft experiments using ErbB2-overexpressing breast cancer model confirmed the potential of Celastrol as a therapeutic agent for the treatment of ErbB2-overexpressing breast cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3559.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM10-3559
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2010
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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