Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Excessive exposure to synthetic and endogenous estrogens has been associated with the development of cancer in several tissues including the breast. 4-Hydroxyequilenin (4-OHEN), a major catechol metabolite of equine estrogens present in Premarin, an estrogen replacement formulation, has been shown to induce apoptosis and DNA damage in human breast cancer cells. It also has the potential to be a tumor initiator or promoter and complete carcinogen. To further understand the effects and mechanisms of equine catechol estrogen metabolite 4-OHEN action in vitro, human non-tumorigenic mammary epithelial MCF 10A cell line was used to study the toxic effects of 4-OHEN. In this study, we observed that 4-OHEN caused dose-dependent increases in apoptosis and DNA damage as measured by the DAPI nuclear screening assay and the Comet assay, respectively. Interestingly, cells treated with 100 nM 4-OHEN biweekly for 4 weeks became resistant to cisplatin-induced apoptosis. The resistance to apoptosis of the 100 nM 4-OHEN-treated cells was through multiple regulatory mechanisms. Compared to the DMSO-treated cells, the 100 nM 4-OHEN-treated cells had higher GSH levels and total SOD activity, and a stronger GSH response after cisplatin treatment. Expression levels of several genes involved in cell growth, DNA repair, and apoptosis were either up- or down-regulated. These data indicate that long-term low-level equine estrogen metabolite exposure could induce DNA damage and initiate cells to become resistant to apoptosis.
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PMID:Altered apoptotic response in MCF 10A cells treated with the equine estrogen metabolite, 4-hydroxyequilenin. 1550 14

4-Anilinoquinazoline derivatives are widely investigated due to their potent epidermal growth factor receptor (EGFR) tyrosine kinase inhibitory activity. Two 4-anilinoquinazolines with Lavendustin A subunit (10a,b) were synthesized and examined for their EGFR tyrosine kinase inhibitory activity as well as their antiproliferative properties on variant human cancer cell lines. Both compounds maintained their EGFR tyrosine kinase inhibitory activity at the 10-7 M level and led to significant growth inhibition in certain leukemia, non-small cell lung cancer (NSCLC), ovarian cancer, renal cancer and breast cancer cell lines with GI50 values at the 10-6 M level. There could not be observed any notable difference between 10a and 10b regarding to their antiproliferative activity. Interestingly, we observed the high tendency of 10a and 10b to include certain solvents, e.g. water, DMF, DMSO, which may be due to the remarkable number of hydrogen accepting/donating groups in 10a and b. An X-ray analysis of 10a including water and DMF illustrates a possible hydrogen bond pattern and could serve as information for preferred receptor (e.g. EGFR tyrosine kinase) binding sites. Finally, we aimed for irreversible EGFR tyrosine kinase inhibitors. The p-quinone derivatives 11a and 11b, which contain a Michael acceptor position according to the irreversible inhibitor CI-1033, could be derived from the p-hydroquinone derivatives 10a or 10b, respectively, by oxidation. However, due to their instability 11a and 11b could not be obtained in a pure form.
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PMID:4-Anilinoquinazolines with Lavendustin A subunit as inhibitors of epidermal growth factor receptor tyrosine kinase: syntheses, chemical and pharmacological properties. 1557 62

Addition of antioxidants to chemotherapy is an unresolved problem in oncology. It is still an issue of debate, whether antioxidants may reduce rough cellular toxicity and thereby the systemic side effects of the chemotherapy, without sacrificing the anti-tumor efficacy. Gemcitabine is a rather new anti-cancer agent, which is quite potent against a range of drug resistant tumors, particularly breast cancer. Tumor-sensitivity towards gemcitabine can be increased with COX inhibitory anti-inflammatory agents and ribonucleotide reductase (RR) inhibitor flavopiridol. Acetaminophen and DMSO are two unique anti-inflammatory and anti- oxidant agents with unrelated structures, yet both capable to block RR and COX, simultaneously. Using plating efficacy and 3H- thymidine labeling, we monitored efficacy of acetaminophen and DMSO to modulate growth and gemcitabine sensitivity in FM3A breast tumor cells, which is highly used to study thymineless death induced by nucleotide-metabolism hemming drugs. Peculiarly, acetaminophen alone stimulated S-phase, which was not accompanied with enhanced plating, rather resulting in 40.3% growth inhibition at the 96 hour. DMSO alone significantly diminished both the plating and S-phase, which resulted in 71.7% growth inhibition at the 96 hour. Gemcitabine drastically reduced S-phase and plating until 72 hours, yet at 96 hours it lost its efficacy to suppress the S-phase with concomitant 2-fold rise in cell numbers in comparison to 72 hour time point. Both DMSO and acetaminophen brought S-phase to around zero percent in combination with gemcitabine until 48 hours, yet they both reduced early cytotoxicity of gemcitabine at the same time interval. However, at the 96 hour, they both strongly augmented gemcitabine efficacy to block S-phase and prevented the rise in plating. Acetaminophen and DMSO should be tested in animal models, whether they could augment efficacy and reduce the toxicity of gemcitabine.
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PMID:Acetaminophen and DMSO modulate growth and gemcitabine cytotoxicity in FM3A breast cancer cells in vitro. 1564 Sep 56

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants, which are suspected carcinogens and may affect the reproductive system as potential endocrine disruptors. Therefore, we tested fluoranthene (FL) and benzo[a]pyrene (BaP) on human breast cancer cell line (MCF-7 cells) to determine possible toxic effects. The cells were incubated in the presence of medium, medium containing 0.1% dimethylsulfoxide (DMSO) as vehicle, or in the presence of FL (10, 50, and 100 microg/ml), BaP (10, 50, and 100 microg/ml), 17beta-estradiol (E2; 5 microg/ml and 500 ng/ml), or tamoxifen (Tx; 5 microg/ml and 500 ng/ml). After 24 h, FL (100 microg/ml), BaP (100 microg/ml), or Tx (5 microg/ml) killed significant numbers of cells. After 72 h, FL (50 and 100 microg/ml), BaP (100 microg/ml), E2 (5 microg/ml), or Tx (5 microg/ml and 500 ng/ml) decreased MCF-7 cell viability significantly as demonstrated by the MTT assay. Measurement of DNA synthesis was conducted using 3H-thymidine incorporation into MCF-7 cell DNA for 72 h. After 72 h, BaP (10, 50, and 100 microg/ml) and Tx (5 microg/ml and 500 ng/ml) significantly decreased DNA synthesis in MCF-7 cells. FL did not significantly alter 3H-thymidine incorporation into the cells. While higher concentration of E2 (5 microg/ml) decreased 3H-thymidine incorporation, the lower concentration of E2 (500 ng/ml) increased cell proliferation. Apoptotic response was tested by in situ fluorescence staining of cells incubated for 72 h in media containing 0.1% DMSO, or vehicle containing FL (10 microg/ml), BaP (10 microg/ml), E2 (500 ng/ml), or Tx (500 ng/ml). Microscopic examination demonstrated presence of apoptosis with BaP (10 microg/ml) and Tx (500 ng/ml), but not with FL (10 microg/ml) and E2 (500 ng/ml). The cell cycle analysis using flow cytometry demonstrated that E2 (500 ng/ml) did not significantly change the progression of MCF-7 cells after 72 h of incubation. However, FL (10 microg/ml) only suppressed G2/M phase. Tx (500 ng/ml) blocked G0/G1, S, and G2/M phases, and BaP (10 microg/ml) suppressed the G0/G1 phase. These data suggest that BaP on MCF-7 cells is growth inhibitory and apoptotic, whereas the toxic effects of FL are not exerted through apoptosis.
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PMID:Differential effects of fluoranthene and benzo[a]pyrene in MCF-7 cells. 1588 64

Soy isoflavones have been reported to be natural chemopreventive in several types of human cancer. Daidzein and genistein are two main components of soy isoflavones. In our previous study, they were shown to be anti-proliferative and induce cell cycle arrest at S phase of SHZ-88 rat breast cancer cells. We hypothesized that soy isoflavones might exert its anticancer effect by activating cAMP/PKA pathway. The present study was designed to analyze the effect of soy isoflavones on the cAMP/PKA pathway in SHZ-88 cells. Daidzein and genistein were dissolved in DMSO. Cells were treated with 50 mug/ml daidzein and 15 mug/ml genistein, respectively, and with only equal DMSO in the culture medium as control. The cellular cAMP content was tested by radioimmunoassay (RIA). The activity of adenylate cyclase (AC), phosphodiesterase (PDE) and PKA were measured by RIA and (gamma-(32)P) ATP incorporation. Reverse transcript-polymerase chain reaction (RT-PCR) was used to analyze the expression of cAMP response element binding protein (CREB) mRNA of the cells. The results showed that the concentration of cAMP in the cells treated with 50 mug/ml daidzein and 15 mug/ml genistein was significantly increased by 9.5%and 11.0%, respectively, 5 min later (P<0.05), then increased by 31.0%and 40.3%, respectively, 10 min later (P<0.01), compared with that of the control group cells. The activity of AC was not affected during the course of experiment, but that of PDE was decreased to 71.8%and 71.6%, respectively, in the control group 5 min later (P<0.05). The PKA activity was increased to 125.8%and 122.3%, respectively, in the control group 20 min after the cells were treated with daidzein and genistein (P<0.05), and kept at high level till 40 min after treatment. CREB mRNA of the cells treated with daidzein and genistein was increased by 31.6%and 51.1%, respectively, 3 h later (P<0.05), then began to decrease 6 h after treatment. The current study suggests that soy isoflavones activate the cAMP/PKA pathway in SHZ-88 rat breast cancer cells by inhibiting the activity of phosphodiesterase.
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PMID:[Effect of soy isoflavones on cAMP/PKA pathway in breast cancer cells of the rat.]. 1609 2

Genistein is of great interest for its implications as an anticancer compound. We compared the effects of daily subcutaneous injections of 1mg/kg BW of genistein and vehicle (2% DMSO in peanut oil) for 20 weeks on N-nitroso-N-methylurea (NMU)-induced tumorigenesis in adult female rats. Genistein significantly increased tumor cross-sectional area and tumor multiplicity but not the tumor incidence and latency period when compared with the vehicle treated group. The serum E(2) levels of genistein treated group were significantly higher than those of the vehicle treated group at 1 and 2 months after treatment which is the time when most of the rats developed tumors. There were no significant differences in the length of the estrous cycle, food consumption and weights of body, livers, uteri and ovaries between the two groups. Our data shows that supplementation of genistein at a dosage comparable to the isoflavone consumption in humans did not affect the reproductive system but resulted in enhancement of NMU-induced tumorigenesis in adult female rats. Thus, the supplementation of soy isoflavone in premenopausal women may potentially potentiate the risk of breast cancer.
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PMID:Genistein enhances N-nitrosomethylurea-induced rat mammary tumorigenesis. 1633 62

A series of mononuclear and dinuclear alkylamine derivatives of [meso-1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II) (m-4F-PtL-R1 and (m-4F-PtL)2-R2; R(1) = alkylamine, R(2) = alkyldiamine, L = DMSO or Cl) as well as the DAB(PA)(4) polyimine dendrimer complex ((m-4F-PtDMSO)4DAB(PA)4; DAB(PA)4 = N,N,N',N'-tetrakis(3-aminopropyl)butane-1,4-diamine) were synthesized and tested for cytotoxicity, intracellular distribution, and DNA and protein binding. All compounds strongly bound to human serum albumin by hydrophobic and electrostatic interactions. These inactivation reactions hindered the uptake into tumor cells and prevented strong cytotoxic effects. If serum-free medium was used, a high accumulation grade in MCF-7 breast cancer cells and a high DNA binding was observed. As most efficient compound (m-4F-PtDMSO)4DAB(PA)4 was identified. It showed a 20-fold higher cellular uptake and an approximately 700-fold higher DNA binding than cisplatin.
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PMID:Mono- and polynuclear [alkylamine]platinum(II) complexes of [1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II): synthesis and investigations on cytotoxicity, cellular distribution, and DNA and protein binding. 1645 Oct 82

The alpha-amino acid ester prodrugs of the antitumor agent camptothecin and a more potent, lipophilic silatecan analogue, DB-67, have been shown by NMR spectroscopy and quantitative kinetic analyses to undergo quantitative conversion to their pharmacologically active lactones via a nonenzymatic mechanism that at pH 7.4 is favored over direct hydrolysis. The alternate pathway involves the reversible intramolecular nucleophilic amine attack at the camptothecin E-ring carbonyl to generate a lactam (I) followed by a second intramolecular reaction to produce a bicyclic hemiortho ester (I'). The intermediates were isolated and shown to exist in an apparent equilibrium dominated by the hemiortho ester in DMSO using NMR spectroscopy. The conversion of prodrugs of camptothecin or DB-67 containing either alpha-NH(2) or alpha-NHCH(3) and their corresponding hemiortho esters were monitored versus time in aqueous buffer (pH 3.0 and 7.4) at 37 degrees C, and the kinetic data were fit to a model based on the proposed mechanism. The results indicated that while the prodrugs are relatively stable at pH 3, facile lactone release occurs from both the prodrugs and their corresponding hemiortho ester intermediates under physiological conditions (pH 7.4). The glycinate esters and their hemiortho esters were found to be more cytotoxic than the N-methylglycinates or their corresponding hemiortho ester intermediates in vitro using a human breast cancer cell line (MDA-MB-435S), consistent with their more rapid conversion to active lactone. The pH dependence of the nonenzymatic pathway for conversion of these alpha-amino acid ester prodrugs suggests that they may be useful for tumor-targeting via liposomes, as they can be stabilized in an acidic environment in the core of liposomes and readily convert to the active lactone following their intratumoral release.
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PMID:Kinetics and mechanisms of activation of alpha-amino acid ester prodrugs of camptothecins. 1682 94

Avlimil, a dietary supplement advertised to ameliorate female sexual dysfunction, is a mixture of eleven herbal components, and some herbal constituents of Avlimil (including black cohosh, licorice, red raspberry, red clover and kudzu) contain phenolic compounds, which are suggested to have estrogenic, anti-estrogenic, or androgenic potential for relieving menopausal symptoms. We hypothesize that Avlimil could modulate the growth of estrogen receptor positive human breast cancer (MCF-7) cells in vitro and in vivo. A dimethylsulfoxide (DMSO) extract of Avlimil (0.001-100 microg Avlimil powder equivalents/mL media) was tested for its estrogenic and anti-estrogenic effects on the growth of MCF-7 cells in vitro. We observed that the DMSO extract of Avlimil at low concentrations (0.1-50 microg/mL media) dose-dependently increased MCF-7 cell proliferation in vitro, and Avlimil DMSO extract at 100 microg/mL inhibited the growth of MCF-7 cells in vitro. Avlimil and some constituents (black cohosh and licorice roots) of Avlimil were fractionated by using sequential solvent extraction (hexane, ethyl acetate, and methanol) and the activities of the fractions were monitored by effects on the growth of MCF-7 cells. Depending on dosage (0.1-100 microg/mL media) both stimulatory and inhibitory effects of the extracts on the growth of MCF-7 cells were observed. The effect of dietary Avlimil at dosages approximating human intake was evaluated using ovariectomized mice implanted with MCF-7 cells. Animals were fed diets containing 500 ppm or 1000 ppm Avlimil for 16 weeks. Dietary Avlimil at 500 ppm stimulated MCF-7 tumors, but Avlimil at 1000 ppm had no apparent effect on the growth of MCF-7 tumors. The observation of stimulated tumor growth in the absence of uterine wet weight gains suggest that estrogenic/anti-estrogenic effects of Avlimil we observed may be dosage- and target tissue-specific and that Avlimil may not be safe for women with estrogen-dependent breast cancer. The different biological effects of fractionated Avlimil components and the different concentration dependencies warrant further compound identification and dose-response studies, especially at recommended intake levels that could have estrogenic effects in women.
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PMID:A dietary supplement for female sexual dysfunction, Avlimil, stimulates the growth of estrogen-dependent breast tumors (MCF-7) implanted in ovariectomized athymic nude mice. 1791

Exemestane-resistant breast cancer cell lines (i.e., ExeR), derived from MCF-7 cells expressing a high level of aromatase (MCF-7aro), were generated in our laboratory. The epidermal growth factor (EGF)-like protein amphiregulin (AREG) was highly expressed in ExeR cells based on cDNA microarray analysis. The high levels of AREG mRNA in ExeR cell lines were confirmed by real-time reverse transcription-PCR. The high levels of AREG protein in ExeR cell lysates and culture media were confirmed by Western blot analysis and ELISA, respectively. Furthermore, our Western blot analysis showed that whereas no AREG was detected in the DMSO control, overnight treatment of parental MCF-7aro cells with 1 micromol/L exemestane strongly induced the expression of AREG. This induction was totally blocked by 100 nmol/L of pure antiestrogen ICI 182,780, implying estrogen receptor (ER) dependence of exemestane-induced AREG expression. MCF-7aro cells were not able to proliferate in hormone-free medium, but were able to proliferate in conditioned medium from ExeR cells, similar to the treatment of recombinant human AREG. Small interference RNA targeting AREG inhibited ExeR proliferation, confirming that AREG is truly functioning as a growth factor of ExeR cells. The specific inhibitors to ER (ICI 182,780), EGF receptor (EGFR; AG1478), and mitogen-activated protein kinase (MAPK; U0126) all showed dose-dependent suppression of the proliferation of ExeR cells, indicating the involvement of the ER, EGFR, and MAPK pathways. Based on these findings, we propose a possible mechanism that underlies exemestane resistance: exemestane induces AREG in an ER-dependent manner. AREG then activates the EGFR pathway and leads to the activation of the MAPK pathway that drives cell proliferation.
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PMID:The role of amphiregulin in exemestane-resistant breast cancer cells: evidence of an autocrine loop. 1838 32


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