From sound to waves to territories.

This paper explores the debate around environmental humanities through the lens of sound and recent examples of sound art. Taking the emergence of ecocriticism as a point of departure, it discusses sound as a conceptual interface in our technologically mediated relationship with the environment. The notion of "shared sonic spaces" is employed to address the shift that is occurring from a "poetic of authenticity" to a "poetic of responsibility" at the intersection of culture, technology and ecology

Selective Regulation of Aromatase Expression for Drug Discovery

Aromatase is a particularly attractive drug target in the treatment of hormone-responsive breast cancer, and aromatase activity in breast cancer patients is greater in or near the tumor tissue compared with the normal breast tissue. Complex regulation of aromatase expression in human tissues involves alternative promoter sites that provide tissue-specific control. Previous studies in our laboratories suggested a strong association between aromatase (CYP19) gene expression and the expression of cyclooxygenase (COX) genes. Additionally, COX selective inhibitors can suppress CYP19 gene expression and decrease aromatase activity. Our current hypothesis is that pharmacological regulation of aromatase can act locally to decrease the biosynthesis of estrogen and may provide additional therapy options for patients with hormone-dependent breast cancer. Two pharmacological approaches are being developed, one approach utilizing small molecule drug design and the second approach involving mRNA silencing technology. The small molecule drug design approach focuses on the synthesis and biological evaluation of a novel series of sulfonanilide analogs derived from COX-2 selective inhibitors. Combinatorial chemistry approaches were used to generate diversely substituted novel sulfonanilides. The compounds suppress aromatase enzyme activity in SK-BR-3 breast cancer cells in a dose and time dependent manner, and structure activity analysis does not find a correlation between aromatase suppression and COX inhibition. Real-time PCR analysis demonstrates that the sulfonanilide analogs decrease aromatase gene transcription in breast cells. Furthermore, the sulfonanilide compounds selectively decrease aromatase gene expression in several breast cancer cells, without exhibiting cytotoxic or apoptotic effects at low micromole concentrations. A ligand-based pharmacophore model for selective aromatase modulation (SAM) by the novel sulfonanilides identified an aromatic ring, two hydrogen bond acceptors, and a hydrophobic function as four key chemical features. In the second approach, short interfering RNAs (siRNA) were designed targeting human aromatase mRNA. Treatment of breast cancer cells with siRNAs targeting aromatase (siAROMs) completely masked the aromatase enzyme activity and resulted in suppression of CYP19 mRNA. Thus, these results suggest that the novel sulfonanilides and the siRNAs targeting aromatase expression may be valuable tools for selective regulation of aromatase in breast cancer

Synthesis and Characterization of Azole Isoflavone Inhibitors of Aromatase

The synthesis and biological evaluation of a series of 2-azole and 2-thioazole isoflavones as potential aromatase inhibitors are described. Differences in inhibitory activity of triazole and imidazole inhibitors are rationalized with density functional theory to expose a key difference in the electronic structure of these molecules. In addition, difference binding spectra of inhibitors to immunoaffinity-purified aromatase produces classical Type II spectra consistent with coordination of the nitrogen lone pair electrons to the aromatase P450 heme

Synthesis and Characterization of Azole Isoflavone Inhibitors of Aromatase

The synthesis and biological evaluation of a series of 2-azole and 2-thioazole isoflavones as potential aromatase inhibitors are described. Differences in inhibitory activity of triazole and imidazole inhibitors are rationalized with density functional theory to expose a key difference in the electronic structure of these molecules. In addition, difference binding spectra of inhibitors to immunoaffinity-purified aromatase produces classical Type II spectra consistent with coordination of the nitrogen lone pair electrons to the aromatase P450 heme

Suppression of Aromatase in Human Breast Cells by A Cyclooxygenase-2 Inhibitor and Its Analog Involves Multiple Mechanisms Independent of Cyclooxygenase-2 Inhibition

Previous studies have demonstrated that cyclooxygenase-2 (COX-2) inhibitor NS-398 decrease aromatase activity at the transcript level in breast cancer cells. However, N-Methyl NS-398, which does not have COX-2 inhibitory activity but has very similar structure to NS-398, decreases aromatase activity and transcription in MCF-7 and MDA-MB-231 breast cells to the same extent as NS-398. This suggests that NS-398 decrease aromatase expression in breast cancer cells via other mechanism(s). Further investigations find that both compounds only decrease aromatase activity stimulated by forskolin/phorbol ester at the transcript level in both breast cancer cell lines and in breast stromal cells from patients. They do not affect aromatase expression and activity stimulated by dexamethasone. Both compounds also suppress MCF-7 cell proliferation stimulated by testosterone. Aromatase inhibition studies using placental microsomes demonstrate that the compounds show only weak direct aromatase inhibition. These results suggest that NS-398 and its N-methyl analog suppress aromatase expression and activity with multiple mechanisms

Aromatase and COX in Breast Cancer: Enzyme Inhibitors and Beyond

Aromatase expression and enzyme activity in breast cancer patients is greater in or near the tumor tissue compared with the normal breast tissue. Complex regulation of aromatase expression in human tissues involves alternative promoter sites that provide tissue-specific control. Previous studies in our laboratories suggested a strong association between aromatase (CYP19) gene expression and the expression of cyclooxygenase (COX) genes. Additionally, nonsteroidal anti-inflammatory drugs (NSAIDs) and COX selective inhibitors can suppress CYP19 gene expression and decrease aromatase activity. Our current hypothesis is that pharmacological regulation of aromatase and/or cyclooxygenases can act locally to decrease the biosynthesis of estrogen and may provide additional therapy options for patients with hormone-dependent breast cancer. Two pharmacological approaches are being developed, one involving mRNA silencing by selective short interfering RNAs (siRNA) molecules and the second utilizing small molecule drug design. In the first approach, short interfering RNAs were designed against either human aromatase mRNA or human COX-2 mRNA. Treatment of breast cancer cells with siAROMs completely masked the aromatase enzyme activity. Treatment with COX-2 siRNAs decreased the expression of COX-2 mRNA; furthermore, the siCOX-2-mediated decrease also resulted in suppression of CYP19 mRNA. The small molecule drug design approach focuses on the synthesis and biological evaluation of a novel series of sulfonanilide analogs derived from the COX-2 selective inhibitors. The compounds suppress aromatase enzyme activity in SK-BR-3 breast cancer cells in a dose and time-dependent manner, and structure activity analysis does not find a correlation between aromatase suppression and COX inhibition. Real-time PCR analysis demonstrates that the sulfonanilide analogs decrease aromatase gene transcription in breast cells. Thus, these results suggest that the siRNAs and novel sulfonanilides targeting aromatase expression may be valuable tools for selective regulation of aromatase in breast cancer

4-Hydroxyphenylretinamide (4HPR) Derivatives Regulate Aromatase Activity and Expression in Breast Cancer Cells

Recent studies exhibit that 4-hydroxyphenylretinamide (4HPR) decreases aromatase activity in breast and placental cells. The effect of synthetic 4HPR analogs on aromatase and expression was examined in three breast cancer cell lines. Most derivatives did not decrease cellular aromatase activity. Two of the analogs even stimulated aromatase activity at the transcriptional level. Only one derivative significantly decreased aromatase in all three breast cancer cell lines and also suppressed CYP19 gene expression in one of the cell line. Placental microsomal aromatase assay rule out the possibility that this compound directly inhibits the aromatase enzyme. A non-genomic mechanism in suppression of cellular aromatase activity of this compound is proposed

Lead Optimization of 7-benzyloxy 2-(4′-pyridylmethyl)Thio Isoflavone Aromatase Inhibitors

Aromatase, the enzyme responsible for estrogen biosynthesis, is a particularly attractive target in the treatment of hormone-dependent breast cancer. The synthesis and biological evaluation of a series of 2-(4′-pyridylmethyl)thio, 7-alkyl- or aryl-substituted isoflavones as potential aromatase inhibitors are described. The isoflavone derivatives demonstrate IC50 values from 79 to 553 nM and compete with the endogenous substrate, androstenedione. Data supporting the ability of these analogs to suppress aromatase enzyme activity in the SK-BR-3 breast cancer cell line are also presented

Isolation and Characterization of Aromatase Inhibitors from Brassaiopsis Glomerulata (Araliaceae)

The hexane- and ethyl acetate-soluble extracts of the leaves of Brassaiopsis glomerulata (Blume) Regel (Araliaceae), collected in Indonesia, were found to inhibit aromatase, the rate-limiting enzyme in the production of estrogens from androgens, in both enzyme- and cell-based aromatase inhibition (AI) assays. Bioassay-guided fractionation led to the isolation of six known compounds of the steroid and triterpenoid classes (1–6) from the hexane extract, of which 6β-hydroxystimasta-4-en-3-one (5), was moderately active in the cell-based AI assay. Fractionation of the ethyl acetate extract afforded seven pure isolates (7–13) of the modified peptide, fatty acid, monoterpenoid, and benzenoid types, including six known compounds and the new natural product, N-benzoyl-l-phenylalanine methyl ester (9). The absolute stereochemistry of 9 and the other two peptides, 7 and 8, was determined by Marfey’s analysis. Linoleic acid (10) was found to be active in the enzyme-based AI assay, while 9 and (−)-dehydrololiolide (12) showed activity in the cell-based AI assay

Potential use of COX-2–aromatase inhibitor combinations in breast cancer

Cyclooxygenase-2 (COX-2) is overexpressed in several epithelial tumours, including breast cancer. Cyclooxygenase-2-positive tumours tend to be larger, higher grade, node-positive and HER-2/neu-positive. High COX-2 expression is associated with poor prognosis. Cyclooxygenase-2 inhibition reduces the incidence of tumours in animal models, inhibits the development of invasive cancer in colorectal cancer and reduces the frequency of polyps in familial adenomatous polyposis (FAP). These effects may be as a result of increased apoptosis, reduced angiogenesis and/or proliferation. Studies of COX-2 inhibitors in breast cancer are underway both alone and in combination with other agents. There is evidence to suggest that combining COX-2 inhibitors with aromatase inhibitors, growth factor receptor blockers, or chemo- or radiotherapy may be particularly effective. Preliminary results from combination therapy with celecoxib and exemestane in postmenopausal women with advanced breast cancer showed that the combination increased the time to recurrence. Up to 80% of ductal carcinomas in situ (DCISs) express COX-2, therefore COX-2 inhibition may be of particular use in this situation. Cyclooxygenase-2 expression correlates strongly with expression of HER-2/neu. As aromatase inhibitors appear particularly effective in patients with HER-2/neu-positive tumours, the combination of aromatase inhibitors and COX-2 inhibitors may be particularly useful in both DCIS and invasive cancer