Another comment on Alex’ post on DCIS.

Estrogens play an essential role in the normal physiology of the breast as well as in mammary tumorigenesis. Their effects are mediated by two nuclear estrogen receptors, ERα and β, which regulate transcription of specific genes by interacting with multiprotein complexes, including histone deacetylases (HDACs). During the past few years, HDACs have raised great interest as therapeutic targets in the field of cancer therapy. In breast cancer, several experimental arguments suggest that HDACs are involved at multiple levels in mammary tumorigenesis: their expression is deregulated in breast tumors; they interfere with ER signaling in intricate ways, restoring hormone sensitivity in models of estrogen resistance, and they clinically represent new potential targets for HDACs inhibitors (HDIs) in combination with hormonal therapies (Linares et al, 2011). Diverse cellular functions including the regulation of inflammatory gene expression, DNA repair and cell proliferation are regulated by changes in the acetylation status of histones and non-histone proteins. Many human diseases, particularly cancer, have been associated with altered patterns of histone acetylation. Furthermore, abnormal expression and activation of histone acetyltransferases, which act as transcriptional co-activators, has been reported in inflammatory diseases. Histone deacetylase (HDAC) inhibitors have been developed clinically for malignancies due to their effects on apoptosis. More recently, in vitro and in vivo data indicates that HDAC inhibitors may be anti-inflammatory due to their effects on cell death acting through acetylation of non-histone proteins (Adcock et al, 2007). Thymoquinone, a component derived from the medial plant Nigella sativa, has been used for medical purposes for more than 2,000 years. Recent studies reported that thymoquinone exhibited inhibitory effects on cell proliferation of many cancer cell lines and hormone-refractory prostate cancer by suppressing androgen receptor and E2F-1. Thymoquinone effectively inhibited human umbilical vein endothelial cell migration, invasion, and tube formation. Thymoquinone inhibited cell proliferation and suppressed the activation of AKT and extracellular signal-regulated kinase. Thymoquinone blocked angiogenesis in vitro and in vivo, prevented tumor angiogenesis in a xenograft human prostate cancer (PC3) model in mouse, and inhibited human prostate tumor growth at low dosage with almost no chemotoxic side effects. Endothelial cells were more sensitive to thymoquinone-induced cell apoptosis, cell proliferation, and migration inhibition compared with PC3 cancer cells. Thymoquinone inhibited vascular endothelial growth factor–induced extracellular signal-regulated kinase activation but showed no inhibitory effects on vascular endothelial growth factor receptor 2 activation Yi et al, 2008). Thymoquinone (TQ) suppressed tumor necrosis factor-induced NF-κB activation in a dose- and time-dependent manner and inhibited NF-kB activation induced by various carcinogens and inflammatory stimuli. The suppression of NF-kB activation correlated with sequential inhibition of the activation of IkBα kinase, IkBα phosphorylation, IkBα degradation, p65 phosphorylation, p65 nuclear translocation, and the NF-kB-dependent reporter gene expression. TQ specifically suppressed the direct binding of nuclear p65 and recombinant p65 to the DNA (Sethi et al, 2008). N. Sativa alone or in combination with oxidative stress was found to be effective (in vitro) in influencing the survival of MCF-7 breast cancer cells, unveiling promising opportunities in the field of cancer chemoprevention and/or treatment (Farah, 2005).

Adcock IM. HDAC inhibitors as anti-inflammatory agents. Br J Pharmacol. 2007 April; 150(7): 829–831. doi: 10.1038/sj.bjp.0707166.

Farah IO. Assessment of Cellular Responses to Oxidative Stress using MCF-7 Breast Cancer Cells, Black Seed (N. Sativa L.) Extracts and H2O2. Int. J. Environ. Res. Public Health 2005, 2(3) Pp.411-9

Linares A, Dalenc F, Balaguer P, et al. Manipulating Protein Acetylation in Breast Cancer: A Promising Approach in Combination with Hormonal Therapies? Journal of Biomedicine and Biotechnology. Volume 2011 (2011), Article ID 856985, 15 pages. doi:10.1155/2011/856985

Sethi G, Ahn KS and Aggarwal BB (2008) Targeting nuclear factor-{kappa}b activation pathway by thymoquinone: role in suppression of antiapoptotic gene products and enhancement of apoptosis. Mol Cancer Res 6, 1059-1070.

Yi T-f, Cho S-G, Yi Z-f, Pang X-f et al. Thymoquinone inhibits tumor angiogenesis and tumor growth through suppressing AKT and extracellular signal-regulated kinase signaling pathways. Mol Cancer Ther July 2008 7 1789. doi: 10.1158/1535-7163.MCT-08-0124

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