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Journal of Leukocyte Biology Mar 2005Dendritic cells (DC) play a crucial role in initiating immune responses to tumors. DC can efficiently present antigens from apoptotic tumor cells, but apoptotic cells...
Dendritic cells (DC) play a crucial role in initiating immune responses to tumors. DC can efficiently present antigens from apoptotic tumor cells, but apoptotic cells are thought to lack the inflammatory signals required to induce DC maturation. Here, we show that apoptosis of 67NR mouse carcinoma cells via the Fas (CD95) pathway or induced by the anticancer drug bortezomib (PS-341) but not by ultraviolet irradiation is associated with the production of maturation signals for DC. These data have important implications for the effects of chemotherapy on antitumor immunity in solid and hematologic malignancies.
Topics: Animals; Antineoplastic Agents; Apoptosis; Boronic Acids; Bortezomib; Cell Line, Tumor; Dendritic Cells; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Pyrazines; Signal Transduction; Tamoxifen; fas Receptor
PubMed: 15569694
DOI: 10.1189/jlb.0804478 -
The Journal of Clinical Investigation Oct 1994Tamoxifen is an antiestrogen frequently used in the treatment of breast cancer and is currently being assessed as a prophylactic for those at high risk of developing...
Tamoxifen is an antiestrogen frequently used in the treatment of breast cancer and is currently being assessed as a prophylactic for those at high risk of developing tumors. We have found that tamoxifen and its derivatives are high-affinity blockers of specific chloride channels. This blockade appears to be independent of the interaction of tamoxifen with the estrogen receptor and therefore reflects an alternative cellular target. One of the clinical side effects of tamoxifen is impaired vision and cataract. Chloride channels in the lens of the eye were shown to be essential for maintaining normal lens hydration and transmittance. These channels were blocked by tamoxifen and, in organ culture, tamoxifen led to lens opacity associated with cataracts at clinically relevant concentrations. These data suggest a molecular mechanism by which tamoxifen can cause cataract formation and have implications for the clinical use of tamoxifen and related antiestrogens.
Topics: 3T3 Cells; ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Cataract; Cattle; Chloride Channels; Estrogen Antagonists; Lens, Crystalline; Mice; Organ Culture Techniques; Patch-Clamp Techniques; Tamoxifen; Tumor Cells, Cultured
PubMed: 7929848
DOI: 10.1172/JCI117514 -
Gene Therapy Nov 2011Standard methods for producing high-capacity adenoviral vectors (HC-Ads) are based on co-infection with a helper adenovirus (HV). To avoid HV encapsidation, its...
Standard methods for producing high-capacity adenoviral vectors (HC-Ads) are based on co-infection with a helper adenovirus (HV). To avoid HV encapsidation, its packaging signal (Ψ) is flanked by recognition sequences for recombinases expressed in the producing cells. However, accumulation of HV and low yield of HC-Ad are frequently observed, due in part to insufficient recombinase expression. We describe here a novel HV (AdTetCre) in which Ψ is flanked by loxP sites that can be excised by a chimeric MerCreMer recombinase encoded in the same viral genome. Efficient modulation of cleavage was obtained by simultaneous control of MerCreMer expression using a tet-on inducible system, and translocation to the nucleus by 4-hydroxytamoxifen (TAM). Encapsidation of AdTetCre was strongly inhibited by TAM plus doxycicline. Using AdTetCre and 293Cre4 cells for the production of HC-Ads, we found that cellular and virus-encoded recombinases cooperate to minimize HV contamination. The method was highly reproducible and allowed the routine production of different HC-Ads in a medium-scale laboratory setting in adherent cells, with titers >10¹⁰ infectious units and <0.1% HV contamination. The residual HVs lacked Ψ and were highly attenuated. We conclude that self-inactivating HVs based on virally encoded recombinases are promising tools for the production of HC-Ads.
Topics: Adenoviridae; Doxycycline; Genetic Therapy; Genetic Vectors; Helper Viruses; Integrases; Tamoxifen
PubMed: 21525953
DOI: 10.1038/gt.2011.58 -
Archives of Biochemistry and Biophysics Aug 1992The model of the estrogen receptor as a dimer of identical, interacting subunits and data obtained by Sasson and Notides (1988, Mol. Endocrinol. 2, 307-312) were used to...
The model of the estrogen receptor as a dimer of identical, interacting subunits and data obtained by Sasson and Notides (1988, Mol. Endocrinol. 2, 307-312) were used to find the standard free energy changes that describe the binding of estradiol and 4-hydroxytamoxifen to the estrogen receptor. For the binding of estradiol or 4-hydroxytamoxifen to the estrogen receptor the data do not deviate systematically from the best fit to the model. The standard free energy change for binding of one molecule of estradiol at one site and one molecule of 4-hydroxytamoxifen at the second site of estrogen receptor indicates that 4-hydroxytamoxifen antagonizes the binding of estradiol to the estrogen receptor.
Topics: Binding, Competitive; Estradiol; Macromolecular Substances; Models, Biological; Protein Binding; Receptors, Estrogen; Tamoxifen; Thermodynamics
PubMed: 1632645
DOI: 10.1016/0003-9861(92)90614-3 -
Breast Cancer Research and Treatment May 2010In the present study, we evaluated the ability of 4-hydroxytamoxifen (OHT) and epidermal growth factor (EGF) to regulate homotypic adhesion in MCF7 breast cancer cells....
In the present study, we evaluated the ability of 4-hydroxytamoxifen (OHT) and epidermal growth factor (EGF) to regulate homotypic adhesion in MCF7 breast cancer cells. Our results demonstrate that OHT and EGF activate the E-cadherin promoter, increase E-cadherin mRNA and protein expression and enhance homotypic aggregation of MCF7 cells. Interestingly, an ERalpha and EGFR cross-talk is involved in the E-cadherin expression by OHT and EGF, as demonstrated by knocking down either receptor. On the basis of our findings, the well-established cross-talk between ERalpha and EGFR could be extended to the modulation of E-cadherin expression by OHT and EGF. Thus, the potential ability of tamoxifen to induce cell-cell aggregation may contribute to the biologic response of pharmacologic intervention in patients with breast cancer.
Topics: Antineoplastic Agents, Hormonal; Blotting, Western; Breast Neoplasms; Cadherins; Cell Adhesion; Cell Aggregation; Cell Line, Tumor; Epidermal Growth Factor; ErbB Receptors; Estrogen Receptor alpha; Female; Gene Expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Oligonucleotide Array Sequence Analysis; Receptor Cross-Talk; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Tamoxifen; Transcriptional Activation; Transfection
PubMed: 19593637
DOI: 10.1007/s10549-009-0456-4 -
Biological Chemistry Nov 1999The budding yeast Saccharomyces cerevisiae has been used extensively as a biological 'test tube' to study the regulation of the human estrogen receptor (ER) alpha....
The budding yeast Saccharomyces cerevisiae has been used extensively as a biological 'test tube' to study the regulation of the human estrogen receptor (ER) alpha. However, anti-estrogens, which are of great importance as therapeutic agents and research tools, fail to antagonize the activation by estrogen in yeast. Here, we have surveyed the antagonistic potential of five different anti-estrogens of diverse chemical nature. While they all act as agonists for wild-type ERalpha, we have established a novel yeast assay system for anti-estrogens, in which at least the commonly used anti-estrogen hydroxytamoxifen is a potent antagonist.
Topics: Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Estradiol; Estrogen Antagonists; Estrogen Receptor alpha; Humans; Indoles; Nafoxidine; Piperidines; Polyunsaturated Alkamides; Receptors, Estrogen; Saccharomyces cerevisiae; Sulfones; Tamoxifen; Two-Hybrid System Techniques
PubMed: 10614829
DOI: 10.1515/BC.1999.172 -
Pharmaceutical Research Feb 2010To determine the better liposomal formulation incorporating the active metabolite of tamoxifen, 4-hydroxy-tamoxifen (4HT) and the biological impact of 4HT-pH-gradient... (Comparative Study)
Comparative Study
PURPOSE
To determine the better liposomal formulation incorporating the active metabolite of tamoxifen, 4-hydroxy-tamoxifen (4HT) and the biological impact of 4HT-pH-gradient liposomes on response to in vivo treatment.
METHODS
Several pegylated liposomes were formulated by varying the composition of lipids, increasing external pH from 7.4 to 9.0 and doubling the lipid concentration. Dipalmitoylphosphatidylcholine / cholesterol / distearoylphosphoethanolamine poly(ethylene)glycol liposomes (DL-9 liposomes) were chosen for their physico-chemical properties. Toxicity and release kinetics were assessed in breast cancer MCF-7 as well as in multiple myeloma (MM) cells. In vivo antitumor activity and bio-distribution were measured in the RPMI8226 MM model.
RESULTS
Compared to conventional non-pH-gradient liposomes, 4HT-DL-9 liposomes resulted in concentration of up to 1 mM 4HT, greater stability, relative toxicity and slow 4HT release. Intravenous injections of 4HT-DL-9 liposomes at 4 mg/kg/week blocked MM tumor growth. Ki67 and CD34 labeling decreased in treated tumors, concomitantly with increase of activated caspase-3 supporting a cell proliferation arrest, a decrease of tumor vasculature and the induction of tumor cell death.
CONCLUSION
This antitumor effect was assumed to be the result of a modified biodistribution of 4HT once trapped in DL-9 liposomes. Such 4HT-containing pH-gradient Stealth nanocarriers could be helpful for MM treatment.
Topics: Animals; Cell Line, Tumor; Disease Models, Animal; Female; Humans; Liposomes; Mice; Mice, Nude; Multiple Myeloma; Proton-Motive Force; Tamoxifen; Xenograft Model Antitumor Assays
PubMed: 20033476
DOI: 10.1007/s11095-009-0023-z -
Environmental Pollution (Barking, Essex... May 2019Structural analogues of bisphenol A (BPA) have become widely used as alternatives in BPA-free products. Most toxicological investigations have focused on the estrogenic...
Structural analogues of bisphenol A (BPA) have become widely used as alternatives in BPA-free products. Most toxicological investigations have focused on the estrogenic activities of these analogues, which have been considered as potential environmental estrogens. However, recent studies revealed that certain BPA analogues could dramatically inhibit the proliferation of breast cancer cells, and exhibited strong anti-estrogenic effects compared with the antagonist 4-hydroxytamoxifen (OHT). Thus, we adopted computational models combining molecular dynamics simulations and binding free energy calculations to explore the underlying molecular basis of BPA analogues binding to estrogen receptor α (ERα). We also evaluated ligand-induced structural rearrangements of ERα at the atomic level. Conformational analyses showed that induced-fit H-bonding recognition by Thr347 was an important factor distinguishing antagonist from agonist BPA analogues. Moreover, antagonists of BPA analogues could indirectly induce the structural reposition of key helix 12 and produce an antagonistic conformation of ERα. Compared with OHT, the binding affinity of BPA analogues is stronger for antagonists than agonists. Taken together, we therefore propose computational indicators for screening of anti-estrogenic activities of BPA analogues, which may be beneficial for predicting the estrogenic or anti-estrogenic effects of BPA alternatives.
Topics: Benzhydryl Compounds; Estrogen Receptor Modulators; Estrogen Receptor alpha; Estrogens; Female; Humans; Ligands; Molecular Dynamics Simulation; Phenols; Protein Binding; Protein Conformation; Tamoxifen
PubMed: 30831350
DOI: 10.1016/j.envpol.2019.02.058 -
Biochemical and Biophysical Research... Dec 1998In this study we demonstrate that physiologic concentrations of genistein are sufficient to mediate agonism and to reverse the repressive effects of 4-hydroxytamoxifen...
In this study we demonstrate that physiologic concentrations of genistein are sufficient to mediate agonism and to reverse the repressive effects of 4-hydroxytamoxifen on estrogen receptor (ER alpha)-responsive reporter genes. We also show that overexpression of the steroid receptor coactivator (SRC-1) potentiates transactivation by genistein-activated ER alpha and that coexpression of CBP (the cAMP response element binding protein coactivator) synergistically increases this signal. Exogenous expression of a nuclear receptor corepressor (NCoR) was, however, unable to alter genistein-mediated transactivation. In in vitro binding assays, we show that genistein, but not 4-hydroxytamoxifen, induces a direct interaction between radiolabeled ER alpha and a GST-SRC-1 fusion protein. More importantly, coincubation with genistein and 4-hydroxytamoxifen or genistein treatment following preincubation of the ER with 4-hydroxytamoxifen also resulted in a strong physical interaction with SRC-1. These findings imply that genistein-induced shifts in the coregulator status of ER alpha may be involved in transcriptional regulation and suggest that tamoxifen-mediated antagonism at ER-dependent genes is sensitive to attenuation by low levels of genistein.
Topics: Drug Synergism; Estradiol; Estrogen Antagonists; Estrogen Receptor alpha; Gene Expression Regulation; Genistein; Glutathione Transferase; HeLa Cells; Histone Acetyltransferases; Humans; Nuclear Receptor Coactivator 1; Receptors, Estrogen; Recombinant Fusion Proteins; Tamoxifen; Transcription Factors; Transcriptional Activation; Transfection
PubMed: 9875216
DOI: 10.1006/bbrc.1998.9751 -
The Science of the Total Environment Mar 2016Tamoxifen and its metabolite 4-hydroxy-tamoxifen (4OHTam) are two potent molecules that have anticancer properties on breast cancers. Their medical use is expected to...
Tamoxifen and its metabolite 4-hydroxy-tamoxifen (4OHTam) are two potent molecules that have anticancer properties on breast cancers. Their medical use is expected to increase with the increasing global cancer rate. After consumption, patients excrete tamoxifen and the 4OHTam metabolite into wastewaters, and tamoxifen has been already detected in wastewaters and natural waters. The concentrations of 4OHTam in waters have never been reported. A single study reported 4OHTam effects on the microcrustacean Daphnia pulex. The effects of tamoxifen and 4OHTam over more than two generations are unknown in aquatic invertebrates. The main goal of this study was to assess the long-term sensitivity of the microcrustacean D. pulex over four generations, based on size, reproduction, viability and the intrinsic rate of natural increase (r). Additional experiments were carried out to observe whether the effects of tamoxifen and 4OHTam were reversible in the next generation after descendants were withdrawn from chemical stress (i.e., recovery experiment), and whether the lowest test concentration of each chemical induced toxic effects when both concentrations were combined (i.e., mixture experiments). Our results showed that tamoxifen and 4OHTam induced the adverse effects at environmentally relevant concentrations. Tamoxifen and 4OHTam impaired size, viability, reproduction and the r in four generations of treated D. pulex, but these effects were not clearly magnified over generations. Tamoxifen was more potent than 4OHTam on D. pulex. When used in a mixture, the combination of tamoxifen and 4OHTam induced effects in offspring, whereas no effects were observed when these chemicals were tested individually. In the recovery experiment, the reproduction and size were reduced in offspring withdrawn from chemical exposures. Our results suggested that tamoxifen and its metabolite may be a relevant pharmaceutical to consider in risk assessment.
Topics: Animals; Antineoplastic Agents; Daphnia; Humans; Tamoxifen; Water Pollutants, Chemical
PubMed: 26745289
DOI: 10.1016/j.scitotenv.2015.11.155