The aromatic fatty acid phenylacetate (PA) and its analogs have come under intense investigation due to their ability to cause the growth arrest of a variety of neoplasia, including human breast cancer. We have determined that PA and its halide derivative 4-chlorophenylacetate (4-CPA) showed marked antiproliferative activity on 3 of 6 human breast cancer cell lines tested. Interestingly, the 3 cell lines that were growth inhibited by PA and 4-CPA were estrogen receptor (ER) positive (T47-D, MCF-7 and ZR-75-1) whereas those that were little affected by these compounds were ER-negative (MDA-MB-157, MDA-MB-231 and SK-Br-3). Dose response studies indicated that 4-CPA inhibited the growth of the sensitive (ER؉) cell lines with a potency 3-4 times that of PA. These findings suggest that there is "crosstalk" between the PA and estrogen signaling pathways such that PA can directly inhibit estrogen-dependent events. This hypothesis was directly tested in vitro using ER؉ MCF-7 cells that were stably transfected with a luciferase reporter construct driven by the full length ( Key words: phenylacetate; breast cancer; estrogen; receptorBreast cancer is 1 of the most prevalent types of cancer observed in women, developing in approximately 1 of 9 women sometime during their lifetime. The etiology of this malignancy is known to involve a complex interplay of genetic, environmental, and hormonal factors that influence the physiological status of the host. 1,2 With regards to the latter factor, there is considerable data that implicate the involvement of steroid hormones, especially estrogen, in the development and progression of breast cancer. This fact has lead to the use of antiestrogens in the therapeutic intervention of this disease. To date, the clinical use of antiestrogens has been limited to compounds that inhibit estrogen signaling at the level of the estrogen receptor (ER) by competing with the ligand (i.e., estrogen) for receptor binding. 3 Although shown to be extremely useful, the clinical results are often unpredictable due to the complex functional activity of ERs liganded with different antiestrogen compounds or the ability of the receptors to undergo changes (mutations or otherwise) that can alter their functional characteristics or response to estrogen antagonists. 4 Thus, there is a need to develop therapeutic compounds that can inhibit the estrogen signaling pathway by mechanisms that may not depend upon competitive ligand binding to the ER.Aromatic fatty acids, of which phenylacetate (PA) is a prototype, constitute a new class of low toxicity drugs with demonstrated antitumor activity in experimental models and in humans. PA is a natural metabolite of phenylalanine that was originally described as a plant growth hormone. 5 Normally found in micromolar concentrations in human plasma, PA has a long clinical history as treatment for conditions associated with hyperammonemia such as in children with urea cycle disorders. 6,7 This clinical experience has indicated that millimolar blood serum levels can be achiev...
Saccharomyces cerevisiae, along with other eukaryotes, is resistant to tetracyclines. We found that deletion of SOD1 (encoding Cu/Zn superoxide dismutase) rendered S. cerevisiae hypersensitive to oxytetracycline (OTC): a sod1⌬ mutant exhibited a >95% reduction in colony-forming ability at an OTC concentration of 20 g ml ؊1 , whereas concentrations of up to 1,000 g ml ؊1 had no effect on the growth of the wild type. OTC resistance was restored in the sod1⌬ mutant by complementation with wild-type SOD1. The effect of OTC appeared to be cytotoxic and was not evident in a ctt1⌬ (cytosolic catalase) mutant or in the presence of tetracycline. SOD1 transcription was not induced by OTC, suggesting that constitutive SOD1 expression is sufficient for wild-type OTC resistance. OTC uptake levels in wild-type and sod1⌬ strains were similar. However, lipid peroxidation and protein oxidation were both enhanced during exposure of the sod1⌬ mutant, but not the wild type, to OTC. We propose that Sod1p protects S. cerevisiae against a mode of OTC action that is dependent on oxidative damage.Reactive oxygen species (ROS) are generated during normal cellular respiratory metabolism, but their damaging effects are generally suppressed by antioxidant defenses. Protective enzymes operating in the budding yeast Saccharomyces cerevisiae are well characterized (30); these include superoxide dismutases (SODs) and catalases, which specifically protect against O 2 ⅐ Ϫ and H 2 O 2 , respectively. S. cerevisiae mutants lacking the principal cellular SOD (Cu/Zn SOD; encoded by SOD1) display certain aerobic growth defects, e.g., reduced growth rate, and methionine and lysine auxotrophies (4). Moreover, sod1⌬ strains are hypersensitive to several types of stress, including oxidative stress (16), metal toxicity (6, 36), prolonged stationary incubation (24), and freeze-thaw stress (28). Such evidence has underscored the central role of ROS in mediating various stresses. However, there is presently no evidence to suggest that antioxidant defenses play a role in the insensitivity of eukaryotes, such as S. cerevisiae, to the action of prokaryotespecific antibiotics.The tetracyclines (e.g., tetracycline, doxycycline, and oxytetracycline [OTC]) are classic broad-spectrum bacteriostatic antibiotics. They are commonly thought to act by inhibiting protein synthesis, through inhibition of binding by aminoacyltRNA to the ribosomal A site (22). Although binding of the tetracyclines to eukaryotic ribosomes occurs in vitro, the in vivo insensitivity of eukaryotes to these antibiotics is usually considered a reflection of the inaccessibility of tetracyclines to the eukaryotic intracellular environment (19); genes conferring OTC resistance to prokaryotes generally encode OTC export proteins (18, 32). The generality of fungal tetracycline resistance is exemplified by the use of OTC in fungiselective growth media (Difco manual, Difco, Detroit, Mich.) and the opportunistic yeast infections that commonly arise following tetracycline administration to humans (22).Inhib...
We have investigated the effects of the low-toxic retinoid, all-trans retinoyl b-glucuronide (RAG) alone and in combination with the phenylacetate (PA) derivative 4-chloro-phenylacetate (4-CPA) on the human neuroblastoma cell line, LA-N-5. In vitro studies demonstrated that RAG and 4-CPA treatments alone showed differentiation-inducing activity on LA-N-5 cells, with 4-CPA found to be about three-fold more potent than the PA parent compound in inducing morphologic differentiation and growth inhibition. As previously reported for retinoic acid (RA) and PA, RAG and 4-CPA were significantly more effective in their antiproliferative effects on the cells than either agent alone. Pharmacologic studies of 4-CPA in mice demonstrated that blood plasma levels reached peak concentrations 4 h after bolus administration of the compound and showed slow clearance characteristics with an apparent half-life of 4 -8 h. As opposed to PA, 4-CPA was found to be essentially odourless and readily consumed in drinking water, giving rise to steadystate blood plasma levels of 4-CPA in the near mM range. Continuous consumption of 4-CPA in this manner for up to 5 months demonstrated no apparent adverse effects on the mice. Long-term RAG-and/or 4-CPA-treatment of nude mice injected with LA-N-5 cells demonstrated that both compounds alone exhibit potent antitumour activity. Together, RAG plus 4-CPA was the most effective treatment for inhibiting established tumour growth. In contrast, 4-CPA alone was equally as effective as the combination for preventing tumour development. The potent in vivo antitumour effects of 4-CPA could not be accounted for by the known ability of PA compounds to induce expression of the RA nuclear receptor beta (RARb) suppressor gene. Taken together, these findings demonstrate the possibility that RAG and/or 4-CPA may serve as effective, less-toxic alternatives to 13-cis RA, which is presently being utilised for nb therapy.
Green Coffee Extract (GCE), an extract of Coffea arabica bean is a popular health supplement employed for anti-obesity and anti-diabetic effects. Here a hydroalcoholic extract of Green Coffee (GCE) was evaluated for its potential as a cardioprotective agent against Doxorubicin (Dox) induced cardiac insult in a H9C2 rat cardiomyocyte in vitro model system. The GCE was tested in an MTT viability assay using 1 μM Dox with and without GCE pretreatment at 50, 100 and 250 μg mLG 1 concentrations. GCE was also tested for its free radical scavenging ability in a DPPH assay at 10 concentrations (500 μg mLG 1 maximum concentration). To understand the mechanism of action of cardioprotection, mitochondrial membrane potential (Δψm) was compared between Dox treated cells with and without GCE pretreatment, using the JC-1 dye. Finally, the activation of caspase-3/7 was quantitated. Findings from the above experiments demonstrated that GCE rescued H9C2 cardiomyocytes from Dox induced loss of cell viability in a dose-dependent manner. While Dox treatment caused a clear decrease in the JC-1 ratio from 2 to 1.6 due to loss of Δψm, pretreatment with GCE at 25, 50 and 100 μg mLG 1 restored the JC-1 ratio to 1.6, 1.9 and 2.0, respectively. Dox treatment potently induced caspase 3/7 activity by 5 fold and pre-treatment with GCE at 100 and 500 μg mLG 1 reduced this activation to 3.5 and 1.5 fold, respectively. This data clearly demonstrates that GCE is strongly cardioprotective against Dox induced cardiac insult and the mechanism of action is by blocking activation of intrinsic apoptotic pathway.
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