Scriptaid effects on breast cancer cell lines.

Abstract

In breast cancer tumor expression of estrogen receptors (ERs) is important as a marker of prognosis and mostly as a predictor of response to endocrine therapy. In fact, the loss of α-ER expression leads to unresponsiveness to anti-hormone treatment. In a significant fraction of breast cancers, this loss of expression is a result of epigenetic mechanisms, such as DNA methylation and histone deacetylation, within the α-ER promoter. Previous studies have shown that pharmacologic inhibition of these mechanisms using the DNA methyltransferase inhibitor, 5-aza-2-deoxycytidine (AZA), and the histone deacetylase (HDAC) inhibitor, Trichostatin A (TSA), results in expression of functional α-ER mRNA and protein. Moreover, the activity of a novel HDAC inhibitor, Scriptaid, has been shown to induce inhibition of tumor growth in breast cancer and to cause re-expression of functional α-ER in α-ER negative breast cancer cells. We sought to better characterize the effects of Scriptaid on cell growth, apoptosis, and α-ER expression in α-ER-positive (MCF-7), α-ER-negative (MDA-MB-231), and α-ER-negative/Her-2 over-expressing (SKBr-3) human breast cancer cell lines. In all of these cell lines Scriptaid treatment resulted in significant growth inhibition and apoptosis, and RT-PCR confirmed an increase of α-ER mRNA transcript in MDA-MB-231 after 48 h of Scriptaid treatment. Furthermore, following treatment with Scriptaid, the formerly unresponsive MDA-MB-231 and SKBr-3 breast cancer cells became responsive to tamoxifen. These results show that the HDAC inhibitor Scriptaid is able to sensitize tamoxifen hormone-resistant breast cancer cells, and that Scriptaid or related HDAC inhibitors are candidates for further study in breast cancer.

• Authors: L Giacinti, C Giacinti, C Gabellini, E Rizzuto, M Lopez, A Giordano
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 227 Issue 10 Pg. 3426-33 (Oct 2012) ISSN: 1097-4652 [Electronic] United States
• PMID: 22213035 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Wiley Periodicals, Inc.

Chemical References

• ESR1 protein, human
• Estrogen Receptor alpha
• Histone Deacetylase Inhibitors
• Hydroxylamines
• NF-kappa B
• Quinolines
• RNA, Messenger
• scriptaid
• Tamoxifen
• ERBB2 protein, human
• Receptor, ErbB-2

Topics

• Apoptosis (drug effects, genetics)
• Breast Neoplasms (drug therapy, genetics, metabolism)
• Cell Cycle (drug effects, genetics)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Down-Regulation
• Estrogen Receptor alpha (genetics, metabolism)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Hydroxylamines (pharmacology)
• NF-kappa B (genetics, metabolism)
• Quinolines (pharmacology)
• RNA, Messenger (biosynthesis, genetics)
• Receptor, ErbB-2 (genetics, metabolism)
• Tamoxifen (pharmacology)