Drug discovery today. Disease mechanisms最新文献

Asthma, a chronic airway inflammatory disease is typically associated with high levels of exhaled nitric oxide (NO). Over the past decades, extensive research has revealed that NO participates in several metabolic pathways that contribute to animal models of asthma and human asthma. In asthmatic airway, high levels of NO lead to greater formation of reactive nitrogen species (RNS), which modify proteins adversely affecting functional activities. By contrast, high levels of NO are associated with lower than normal levels of S-nitrosothiols, which serve a bronchodilator function in the airway. Detailed mechanistic studies have enabled the development of compounds that target NO metabolic pathways, and provide opportunities for novel asthma therapy. This review discusses the role of NO in asthma with the primary focus on therapeutic opportunities developed in recent years.

Our studies indicate that expression of antioxidative stress enzymes is upregulated by Selective Estrogen Receptor Modulators (SERMs) in breast epithelial cell lines, providing protection against the genotoxic effects of estrogens and against estrogen-induced mammary tumorigenesis. This upregulation of antioxidative stress enzymes requires Estrogen Receptor beta (ERβ) and human homolog of Xenopus gene which Prevents Mitotic Catastrophe (hPMC2). Further studies indicate that hPMC2 has a functional exonuclease domain that is required for upregulation of antioxidative stress enzymes by SERMs and repair of estrogen-induced abasic sites.

Breast cancer risk has been associated with long-term estrogen exposure including traditional hormone therapy (HT, formally hormone replacement therapy). To avoid traditional HT and associated risks, women have been turning to botanical supplements such as black cohosh, red clover, licorice, hops, dong gui, and ginger to relieve menopausal symptoms despite a lack of efficacy evidence. The mechanisms of estrogen carcinogenesis involve both hormonal and chemical pathways. Botanical supplements could protect women from estrogen carcinogenesis by modulating key enzymatic steps [aromatase, CYP1B1, CYP1A1, catechol-O-methyltransferase (COMT), NAD(P)H quinone oxidoreductase 1 (NQO1)] and reactive oxygen species (ROS) scavenging in estradiol metabolism leading to estrogen carcinogenesis. This review summarizes the influence of popular botanical supplements used for women's health on these key steps in the estrogen chemical carcinogenesis pathway, and suggests that botanical supplements may have added chemopreventive benefits by modulating estrogen metabolism.

Understanding the molecular changes that drive an acquired antiestrogen resistance phenotype is of major clinical relevance. Previous methodologies for addressing this question have taken a single gene/pathway approach and the resulting gains have been limited in terms of their clinical impact. Recent systems biology approaches allow for the integration of data from high throughput ‘-omics’ technologies. We highlight recent advances in the field of antiestrogen resistance with a focus on transcriptomics, proteomics and methylomics.

Metabolism of estrogens via the catechol estrogen pathway is characterized by a balanced set of activating and protective enzymes (homeostasis). Disruption of homeostasis, with excessive production of catechol estrogen quinones, can lead to reaction of these quinones with DNA to form depurinating estrogen-DNA adducts. Some of the mutations generated by these events can lead to initiation of breast cancer. A wealth of evidence, from studies of metabolism, mutagenicity, cell transformation and carcinogenicity, demonstrates that estrogens are genotoxic. Women at high risk for breast cancer, or diagnosed with the disease, have relatively high levels of depurinating estrogen-DNA adducts compared to normal-risk women. The dietary supplements N-acetylcysteine and resveratrol can inhibit formation of catechol estrogen quinones and their reaction with DNA to form estrogen-DNA adducts, thereby preventing initiation of breast cancer.

Majority of breast cancers are diagnosed in post-menopausal women. Hormone replacement therapy has been indicated as one of the major causes of increasing breast cancer risk in these women. Several epidemiological studies have attempted to discover the association between hormone replacement therapy and breast cancer. Because of the nature of data collection and study design it has been difficult to assess the real effect of hormone replacement therapy on breast cancer risk. Several hormones are biphasic in nature and one needs to take into account that the dose, duration and mode of administration of hormones could have a significant impact on increasing or decreasing the risk of breast cancer. This review will attempt to provide a broad summary of the evidence to date on the breast cancer risk associated with dose, duration and mode of administration of hormone replacement therapies.

The androgen receptor (AR) is a proven clinical target in prostate cancer. Recent research indicates that it is an emerging hormonal target in breast cancer as well, with potential clinical benefit in both estrogen receptor (ER) positive and negative tumors. Compared to the ER, AR contains unique functional domains with relevance to its altered role in human breast cancer. The majority of ER-positive tumors express AR, and a significant percentage of ER-negative tumors might benefit from combined targeting of AR and the ErbB2/HER2 oncogene. Signaling downstream of AR might also affect many clinically important pathways which are also emerging clinical targets in breast cancer. AR expression might also play a role during tumor progression to metastatic disease. The role of AR as a new important biomarker in breast cancer will be reviewed herein.

Catechol estrogens are carcinogenic, probably because of their estrogenicity and potential for further oxidative metabolism to reactive quinones. Estrogenic quinones cause oxidative DNA damage as well as form mutagenic depurinating adenine and guanine adducts. O-Methylation by catechol-O-methyltransferase (COMT) blocks their estrogenicity and prevents their oxidation to quinones. A single gene encodes both membrane bound (MB) and soluble (S) forms of COMT. The COMT gene contains 34 single nucleotide polymorphisms (SNPs). The valine108 (S-COMT)/158 (MB-COMT) SNP encodes a low activity form of COMT and has been widely studied as a putative risk factor for breast cancer, with inconsistent results. Investigations of two other SNPs in the promoter of MB-COMT that may affect its expression have also provided mixed results. Future studies on the role of COMT in breast cancer should incorporate measurement of biomarkers that reflect COMT activity and its protective effects.

The loss of epithelial expression markers by neoplastic breast cancer cells in the primary tumor is believed to play a pivotal role during breast cancer metastasis. This phenomenon is the hallmark of the epithelial mesenchymal transition (EMT) process. Gene expression microarrays were performed to investigate key functional elements on an in vitro metastasis model derived from human breast epithelial cells (MCF10F) treated with 17 beta estradiol. We identified groups of SLUG associated genes modulated during EMT.