UMLS:C0006142 - FACTA Search

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Query: UMLS:C0006142 (breast cancer)
160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although selective estrogen receptor modulators (SERMs) are useful in the treatment and prevention of breast cancer, the SERM tamoxifen has been associated with an increased risk of endometrial cancer possibly due to metabolism to electrophilic quinoids. Another SERM, arzoxifene is currently in clinical trials for the treatment of breast cancer, and since it has similar structural characteristics to tamoxifen, it also has the potential to form quinoids. In the current study, the active form of arzoxifene in vivo, desmethylated arzoxifene (DMA), was synthesized and chemically or enzymatically oxidized to DMA diquinone methide. The half-life of DMA diquinone methide at physiological pH and temperature was approximately 15 s. Reaction of DMA diquinone methide with glutathione (GSH) gave four mono-GSH conjugates, two di-GSH conjugates, and one tri-GSH conjugate. In incubations of DMA with GSH and either rat or human liver microsomes, DMA o-quinone-GSH conjugates were detected in addition to DMA diquinone methide-GSH conjugates. A DMA diquinone methide-deoxyguanosine adduct was detected following the incubation of DMA diquinone methide with deoxynucleosides. In preliminary studies with a human breast cancer cell line, DMA induced dose-dependent DNA damage and was more effective at causing DNA damage than raloxifene. These results suggest that DMA can be metabolized to electrophilic/redox-active quinoids, which have the potential to cause toxicity in vivo. A new fluorinated derivative unable to form a diquinone methide, 4'-F-DMA, was synthesized. 4'-F-DMA showed similar estrogen receptor (ER) binding affinity as compared to DMA. The antiestrogenic activity as measured by inhibition of estradiol-mediated induction of alkaline phosphatase activity in Ishikawa cells showed 10-fold lower activity for 4'-F-DMA compared to DMA; however, the antiestrogenic activity was comparable to raloxifene. In microsomal incubations of 4'-F-DMA in the presence of GSH, no GSH adducts were detected. These data suggest that 4'-F-DMA might be a promising SERM with similar activity to DMA and raloxifene and less toxicity.
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PMID:Bioactivation of the selective estrogen receptor modulator desmethylated arzoxifene to quinoids: 4'-fluoro substitution prevents quinoid formation. 1572 Jan 20

Although approved for the treatment of hormone-dependent breast cancer as well as for the prevention of breast cancer in high-risk women, the selective estrogen receptor modulator (SERM) tamoxifen has been associated with an increased risk of endometrial cancer in women. With an understanding of the potential carcinogenic mechanisms of these compounds, SERMs could in principle be designed or selected for use that avoids these problems. Acolbifene (EM-652) is a fourth-generation SERM and the active form of the ester prodrug EM-800. As a pure antagonist of breast tumor development and growth, acolbifene does not stimulate endometrial tissue. However, acolbifene was found in this investigation to form two kinds of quinone methides, either through chemical or through enzymatic oxidation. One was a classical acolbifene quinone methide, which was formed by oxidation at the C-17 methyl group, and the other was a diquinone methide involving the oxidation of two phenol groups. The half-life of the classical quinone methide was determined to be 32 +/- 0.4 s at physiological pH and temperature. The quinone methides reacted with glutathione (GSH) to form five mono-GSH conjugates and five di-GSH conjugates. The majority of GSH conjugates resulted from reaction of the classical acolbifene quinone methide with GSH. Incubations of acolbifene with GSH and either tyrosinase or human and rat liver microsomes also produced acolbifene quinone methide-GSH conjugates. In addition to reaction with GSH, the classical acolbifene quinone methide was also shown to react with deoxynucleosides. One of the major deoxynucleoside adducts was identified as the deoxyadenosine adduct resulting from reaction of the classical acolbifene quinone methide with the exocyclic amino group of adenine. Acolbifene could also induce DNA damage in the S30 breast cancer cell line. These data imply that the classical electrophilic acolbifene quinone methide might contribute to the potential toxicity of acolbifene.
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PMID:Bioactivation of the selective estrogen receptor modulator acolbifene to quinone methides. 1572 Jan 21

We demonstrated recently that phenethyl isothiocyanate (PEITC), a potent anticarcinogen present in cruciferous vegetables, inhibited P-glycoprotein (P-gp) and multidrug resistance protein 1 (MRP1) and that MRP1 can transport PEITC and/or its metabolites. In this study, we have examined whether PEITC is transported by P-gp and MRP2, two transporters with high expression in human intestine, liver and kidney. Using (14)C-PEITC, no significant difference was observed for the intracellular accumulation of PEITC in human breast cancer MCF-7/sensitive (control) and MCF-7/ADR (P-gp overexpressing) cells at PEITC concentrations of 1, 10 and 50 microM. Moreover, the presence of verapamil or PSC833, two P-gp inhibitors, had no significant effect on the intracellular accumulation of PEITC in P-gp overexpressing MCF-7/ADR and MDA435/LCC6MDR1 cells, indicating that PEITC may not be a substrate for P-gp. In contrast, (14)C-PEITC intracellular accumulation in the kidney epithelial MDCK II/MRP2 cells (transfected with human MRP2) was significantly lower than in the wild-type MDCK II/wt cells at PEITC concentrations of 1, 5, 10 and 50 microM. The presence of MK571, an MRP inhibitor, significantly enhanced (14)C-PEITC accumulation in MDCK II/MRP2 but not MDCK II/wt cells. Furthermore, depletion of intracellular glutathione (GSH) following treatment with buthionine sulphoximine, an inhibitor of GSH biosynthesis, significantly increased (14)C-PEITC intracellular accumulation in a concentration-dependent manner. Transcellular transport studies also demonstrated that depletion of intracellular GSH reduced the mean ratio of basal-to-apical transport to apical-to-basal transport of PEITC in MDCK II/MRP2, but not MDCK II/wt cell monolayers. These results indicate that GSH plays an important role in the MRP2-mediated transport of PEITC. The findings provide new information concerning the interactions between PEITC and membrane transporters and suggest the possibility of PEITC interactions with xenobiotics that are MRP2 substrates.
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PMID:Transport of dietary phenethyl isothiocyanate is mediated by multidrug resistance protein 2 but not P-glycoprotein. 1600 50

The cytotoxic effects of Triphala (TPL), an Indian Ayurvedic formulation with known anti-cancer properties, has been investigated on two human breast cancer cell lines differing in their p53 status. In vitro studies showed that MCF 7 with wild type p53 was more sensitive to TPL than T 47 D, which is p53 negative. TPL induced loss of cell viability was determined by MTT assay. After 72h incubation, the IC 50 values for MCF 7 was found to be approximately 8microg/ml and that for T 47 D was approximately 26microg/ml. Moreover, TPL inhibited the clonogenic growth of MCF 7 cells, which was significantly recovered by pifithrin-alpha, the p53 inhibitor. However, pifithrin-alpha, did not modify TPL induced cytotoxicity in T 47 D cells. Exogenous addition of antioxidants, glutathione (GSH) and N-Acetyl-Cysteine (NAC) inhibited the anti-proliferative ability of TPL in both MCF 7 and T47 D. Annexin-V and propidium iodide double staining of cells treated with TPL for 2h revealed that TPL induced significant apoptosis in both the cell lines in a dose dependant manner but magnitude of apoptosis was significantly higher in MCF 7 than in T 47-D cells. TPL was also found to induce dose and time dependent increase in intracellular reactive oxygen species in both the cell lines. Present results have demonstrated that MCF 7 and T 47 D cells exhibited differential sensitivity to TPL, which seems to be dependant on their p53 status. Inhibition of anti-proliferative ability of TPL by antioxidants suggests a role for TPL induced ROS in the induction of apoptosis. It is concluded that p53 status of cancer cells formed an important factor in predicting the response of cancer cells to prooxidant drugs.
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PMID:Cytotoxic response of breast cancer cell lines, MCF 7 and T 47 D to triphala and its modification by antioxidants. 1613 98

Isothiocyanates (ITCs) are non-nutrient constituents abundant in cruciferous vegetables and are effective in blocking carcinogenesis in a variety of tissues. ITCs permeate into cells rapidly and accumulate in cells primarily as glutathione (GSH) conjugates. We have demonstrated recently that certain ITCs are inhibitors of ABCG2 (breast cancer resistance protein, BCRP), an ATP-binding cassette transporter that plays an important role in drug absorption and disposition as well as in the development of multidrug resistance in cancer cells. The purpose of this study was to investigate the mechanisms of interactions between ITCs and BCRP and elucidate the transport of phenethyl isothiocyanate (PEITC) by BCRP. Inside-out membrane vesicles were prepared from human breast cancer BCRP-overexpressing MCF-7/MX100 and the parental MCF-7/sensitive cells. The ATPase study using 100 muM ITCs showed that ITCs are potential inhibitors of BCRP ATPase activity. The transport of (14)C-PEITC into BCRP-overexpressing MCF-7/MX100 cell vesicles was ATP-dependent and inhibited by fumitremorgin C (FTC), a specific inhibitor of BCRP, indicating that PEITC is a substrate for BCRP. In the control MCF-7/sensitive cell vesicles, no ATP-dependent and FTC-inhibited transport of (14)C-PEITC was observed. Taken together, the results of this investigation provided evidence that ITCs are potential inhibitors of BCRP ATPase and PEITC, in its unchanged form, is transported by BCRP. These data may be important in elucidating the interaction of ITCs and cellular transporters and in understanding the potential food-drug interaction.
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PMID:Membrane transport of dietary phenethyl isothiocyanate by ABCG2 (breast cancer resistance protein). 1619 94

Breast cancer is one of the most common cancers in women of developed and developing countries. The optimum management of which requires a multidisciplinary approach including the use of certain biochemical and molecular markers. The effect of propolis along with paclitaxel on 7,12 dimethyl benz(a)anthracene (DMBA) induced experimental breast cancer was investigated in female Sprague Dawley rats. Female Sprague Dawley rats were divided into five groups of six animals each. Group I served as normal control animal. Group II animals received DMBA (20 mg in 0.5 ml sunflower oil and 0.5 ml of saline) i.p. to develop mammary tumor by the end of 90 days. Group III were breast cancer animals treated with 33 mg paclitaxel/kg body weight (bw) weekly once for 4 weeks. Group IV were breast cancer-bearing animals treated with 50 mg propolis/kg bw for 30 days. Group V were breast cancer-bearing animals treated with both paclitaxel and propolis as mentioned above. Administration of paclitaxel and propolis effectively suppressed breast cancer, which is revealed by the decrease in the extent of lipid peroxidation (LPO) with concomitant increase in the activities of enzymic antioxidants (superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)) and non-enzymic antioxidants (reduced glutathione (GSH), Vitamin C and Vitamin E) levels when compared to breast cancer-bearing animals treated with either paclitaxel or propolis alone. From our results, we conclude that propolis is a potent antioxidant and, when given in combination with paclitaxel, offers maximum protection against DMBA induced mammary carcinogenesis.
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PMID:Therapeutic effect of paclitaxel and propolis on lipid peroxidation and antioxidant system in 7,12 dimethyl benz(a)anthracene-induced breast cancer in female Sprague Dawley rats. 1637 27

The human alpha class glutathione S-transferases (GSTs) consist of 5 genes, hGSTA1-hGSTA5, and 7 pseudogenes on chromosome 6p12.1-6p12.2. hGSTA1-hGSTA4 have been well characterized as proteins, but hGSTA5 has not been detected as a gene product. hGSTA1-1 (and to a lesser extent hGSTA2-2) catalyzes the GSH-dependent detoxification of carcinogenic metabolites of environmental pollutants and tobacco smoke (e.g., polycyclic aromatic hydrocarbon diolepoxides) and several alkylating chemotherapeutic agents and has peroxidase activity toward fatty acid hydroperoxides (FA-OOH) and phosphatidyl FA-OOH. hGSTA3-3 has high activity for the GSH-dependent Delta(5)-Delta(4) isomerization of steroids, and hGSTA4-4 has high activity for the GSH conjugation of 4-hydroxynonenal. hGSTA4 is expressed in many tissues; hGSTA1-1 and hGSTA2-2 are expressed at high levels in liver, intestine, kidney, adrenal gland, and testis; and hGSTA3 is expressed in steroidogenic tissues. Functional, allelic, single nucleotide polymorphisms occur in an SP1-binding element of hGSTA1 and in the coding regions of hGSTA2 and hGSTA3. The main effects of these polymorphisms are the low hepatic expression of hGSTA1 in individuals homozygous for hGSTA1*B and the low specific activity of the hGSTA2E-2E variant toward FA-OOH. These properties suggest that alpha class GSTs will be involved in susceptibility to diseases with an environmental component (such as cancer, asthma, and cardiovascular disease) and in response to chemotherapy. Although hGSTM1, hGSTT1, and hGSTP1 have been associated with such diseases (on the basis of genetic polymorphisms as indicators of expression), alpha class GSTs have been little studied in this respect. Nevertheless, hGSTA1*B has been associated with increased susceptibility to colorectal cancer and with increased efficacy of chemotherapy for breast cancer. Methods for identification and quantitation of human alpha class GST protein, mRNA, and genotype are reviewed, and the potential for GST-alpha in plasma to be used as a marker for hepatic expression and induction is discussed.
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PMID:Human alpha class glutathione S-transferases: genetic polymorphism, expression, and susceptibility to disease. 1639 77

Menopause is often accompanied by hot flashes and degenerative processes such as arteriosclerosis and atrophic changes of the skin that suggest an acceleration of aging triggered by estrogen lack. Therefore, hormone replacement therapy (HRT) has been considered the most suitable treatment for the above symptoms and processes. However, because of the possible serious side effects of HRT (especially the increased risk of thrombo-embolic accidents and breast cancer) there is a growing demand for alternative treatments of the symptoms and pathological processes associated with menopause. In agreement with the above, we review research that supports the concept that oxygen stress contributes to menopause and that some of its physiopathological effects may be prevented and/or treated improving the antioxidant defense of menopausic and postmenopausic women. Accordingly, a selection of micronutrients may be useful as a dietary supplement for protection against the decline of physiological functions caused by age-related oxygen stress. Since aging is accompanied by a progressive oxidation of the physiological sulfur pool, we emphasize the role of the vitamins B that help to maintain the GSH/GSSG ratio in its normal reduced state. Nutritional supplements should also include the key antioxidant vitamins C and E, as well as beta-carotene and the mineral micronutrients found in the oxygen radical-detoxifying enzymes glutathione peroxidase and superoxide dismutase. Moreover, the reviewed data suport the concept that other antioxidants such as lipoic acid and the precursors of glutathione thioproline (TP) and l-2-oxothiazolidine-4-carboxylic acid (OTC), as well as the soy isoflavones and the "coantioxidants" of an hydroalcoholic extract of Curcuma longa may help to prevent antioxidant deficiency with resulting protection of mitochondria against premature oxidative damage with loss of ATP synthesis and especialized cellular functions. Therefore, the administration under medical advice of synergistic combinations of some of the above mentioned antioxidants in the diet as well as topically (for skin protection) may have favorable effects on the health and quality of life of women, especially of those who cannot be treated with HR, suffer high levels of oxygen stress, and do not consume a healthy diet that includes five daily rations of fresh fruit and vegetables.
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PMID:Menopause: a review on the role of oxygen stress and favorable effects of dietary antioxidants. 1644 44

The benzothiophene selective estrogen receptor modulators (SERMs), raloxifene and arzoxifene, in the clinic or clinical trials for treatment of breast cancer and postmenopausal symptoms, are highly susceptible to oxidative metabolism and formation of electrophilic metabolites. 4'F-DMA, fluoro-substituted desmethyl arzoxifene (DMA), showed attenuated oxidation to quinoids in incubation with rat hepatocytes as well as in rat and human liver microsomes. Incubations of 4'F-DMA with hepatocytes yielded only one glucuronide conjugate and no GSH conjugates, whereas DMA underwent greater metabolism giving two glucuronide conjugates, one sulfate conjugate, and two GSH conjugates. Phase I and phase II metabolism were further evaluated in human small intestine microsomes and in human intestinal Caco-2 cells. In comparison to DMA, 4'F-DMA formed significantly less glucuronide and sulfate conjugates. The formation of quinoids was further explored in hepatocytes in which DMA was observed to give concentration- and time-dependent depletion of GSH accompanied by damage to DNA, which showed inverse dependence on GSH; in contrast, GSH depletion and DNA damage were almost completely abrogated in incubations with 4'F-DMA. 4'F-DMA shows ligand binding affinity to estrogen receptor (ER)alpha and ERbeta with similarity to both raloxifene and to DMA. ER-mediated biological activity was measured with the ERE-luciferase reporter system in transfected MCF-7 cells and Ishikawa cells, and in MCF-7 cells, proliferation was measured. In all systems, 4'F-DMA exhibited anitestrogenic activity of comparable potency to raloxifene but did not manifest estrogenic properties, mirroring previous results on inhibition of estradiol-mediated induction of alkaline phosphatase activity in Ishikawa cells. These results suggest that 4'F-DMA might be an improved benzothiophene SERM with similar antiestrogenic activity to raloxifene but improved metabolic stability and attenuated toxicity, showing that simple chemical modification can abrogate oxidative bioactivation to potentially toxic metabolites without loss of activity.
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PMID:Chemical modification modulates estrogenic activity, oxidative reactivity, and metabolic stability in 4'F-DMA, a new benzothiophene selective estrogen receptor modulator. 1678 Mar 56

Previous studies established that oral glutamine (GLN) reduced tumor development in implantable and 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast cancer models. This finding was associated with a decrease in tumor glutathione (GSH) levels, while maintaining normal gut, blood, and breast GSH. Alterations in GSH levels contribute to the control of apoptotic and cell cycle-regulating signaling. The aim of this study was to examine the role of dietary GLN on activation of p53 and c-myc, which play critical roles in cancer development and sensitivity to radiation and chemotherapy. Mammary gland carcinomas were induced in rats by DMBA. The rats were gavaged daily with GLN or water (controls), starting 1 wk prior DMBA-application and throughout the duration of the experiment (11 wk after DMBA). Tumor DNA was examined for mutations in p53 exons 5 and 6. Protein and mRNA levels of p53, p21(WAF1/CIP1), PTEN, IGF-IR, mdm2, and c-myc in tumors of GLN-supplemented rats were compared with those of the control rats (received water). The sequencing of p53 showed that it was wild type. Increased phosphorylation of p53, as well as higher mRNA and protein levels of p21(WAF1/CIP1), PTEN, and mdm2, and lower levels of IGF-IR were detected in tumors of GLN-supplemented rats vs. controls. Both phosphorylated c-myc and c-myc mRNA levels were reduced by GLN. The up-regulation of tumor p53 signaling and down-regulation of c-myc, in addition to previously established inhibition of Akt signaling in DMBA-breast cancer model, suggest that dietary GLN could be a useful approach for increasing the effectiveness of cancer treatment.
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PMID:Modulation of p53 and c-myc in DMBA-induced mammary tumors by oral glutamine. 1689 71

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