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)

All alpha-interferons (IFNalpha) bind the IFNAR1 receptor subunit with low affinity. Increasing the binding affinity was shown to specifically increase the antiproliferative potency of IFNalpha2. Here, we constructed a phage display library by randomizing three positions on IFNalpha2 previously shown to confer weak binding to IFNAR1. The tightest binding variant selected, comprised of mutations H57Y, E58N, and Q61S (YNS), was shown to bind IFNAR1 60-fold tighter compared with wild-type IFNalpha2, and 3-fold tighter compared with IFNbeta. Binding of YNS to IFNAR2 was comparable with wild-type IFNalpha2. The YNS mutant conferred a 150-fold higher antiproliferative potency in WISH cells compared with wild-type IFNalpha2, whereas its antiviral activity was increased by only 3.5-fold. The high antiproliferative activity was related to an induction of apoptosis, as demonstrated by annexin V binding assays, and to specific gene induction, particularly TRAIL. To determine the potency of the YNS mutant in a xenograft cancer model, we injected it twice a week to nude mice carrying transplanted MDA231 human breast cancer cells. After 5 weeks, no tumors remained in mice treated with YNS, whereas most mice treated with wild-type IFNalpha2 showed visible tumors. Histological analysis of these tumors showed a significant anti-angiogenic effect of YNS, compared with wild-type IFNalpha2. This work demonstrates the application of detailed biophysical understanding in the process of protein engineering, yielding an interferon variant with highly increased biological potency.
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PMID:An interferon alpha2 mutant optimized by phage display for IFNAR1 binding confers specifically enhanced antitumor activities. 1731 65

The effects and mechanisms of exogenous phosphatase and tensin homolog deleted from chromosome ten (PTEN) gene on phosphatase activity-dependent apoptosis of breast cancer cell line MDA468 were investigated. PTEN gene packaged with lipofectin was transferred into breast cancer cell line MDA468 and parental MDA468 cells served as controls. RT-PCR and Western blot were done to detect the expression of target genes. The expression of phosphospecific protein kinase B (PKB/Akt) and focal adhesion kinase (FAK) protein stimulated by epidermal growth factor (EGF) was also detected. Apoptosis was determined by flow cytometry with a double-staining method using FITC-conjugated annexin V and PI. MDA468 cells transfected with PTEN gene could express PTEN mRNA and protein. PTEN decreased the phosphorylation level of AKT protein and down-regulated FAK protein expression in MDA468 stimulated by EGF. The apoptosis rate was 21.68%. PTEN induced breast cancer apoptosis phosphatase activity-dependently. The mechanism is possibly related with phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB)/AKT signaling pathway. Those results may provide new clues on the gene therapy in breast cancer.
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PMID:Exogenous PTEN gene induces apoptosis in breast carcinoma cell line MDA468. 1739 12

Guggulsterone is a plant polyphenol traditionally used to treat obesity, diabetes, hyperlipidemia, atherosclerosis, and osteoarthritis, possibly through an anti-inflammatory mechanism. Whether this steroid has any role in cancer is not known. In this study, we found that guggulsterone inhibits the proliferation of wide variety of human tumor cell types including leukemia, head and neck carcinoma, multiple myeloma, lung carcinoma, melanoma, breast carcinoma, and ovarian carcinoma. Guggulsterone also inhibited the proliferation of drug-resistant cancer cells (e.g., gleevac-resistant leukemia, dexamethasone-resistant multiple myeloma, and doxorubicin-resistant breast cancer cells). Guggulsterone suppressed the proliferation of cells through inhibition of DNA synthesis, producing cell cycle arrest in S-phase, and this arrest correlated with a decrease in the levels of cyclin D1 and cdc2 and a concomitant increase in the levels of cyclin-dependent kinase inhibitor p21 and p27. Guggulsterone-induced apoptosis as indicated by increase in the number of Annexin V- and TUNEL-positive cells, through the downregulation of anti-apoptototic products. The apoptosis induced by guggulsterone was also indicated by the activation of caspase-8, bid cleavage, cytochrome c release, caspase-9 activation, caspase-3 activation, and PARP cleavage. The apoptotic effects of guggulsterone were preceded by activation of JNK and downregulation of Akt activity. JNK was needed for guggulsterone-induced apoptosis, inasmuch as inhibition of JNK by pharmacological inhibitors or by genetic deletion of MKK4 (activator of JNK) abolished the activity. Overall, our results indicate that guggulsterone can inhibit cell proliferation and induce apoptosis through the activation of JNK, suppression of Akt, and downregulation of antiapoptotic protein expression.
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PMID:Guggulsterone inhibits tumor cell proliferation, induces S-phase arrest, and promotes apoptosis through activation of c-Jun N-terminal kinase, suppression of Akt pathway, and downregulation of antiapoptotic gene products. 1747 22

Metastatic spinal cancer is characterized by the maintenance of normal disc structure until the vertebral body is severely destroyed by cancer cells. Anatomic features of the discs have been thought to be the main factor which confer the discs their resistance to metastatic cancer. However, little is known about the biochemical mechanism to prevent or attenuate the local infiltration of cancer cells into the discs. The purpose of this study was to investigate whether Fas ligand (FasL) produced by disc cells can kill Fas-bearing breast cancer cells by Fas and FasL interaction. Two human breast cancer cells (MCF-7 and MDA-MB-231) were obtained and cultured (1 x 10(6) cells/well), and the expression of Fas was investigated by western blot analysis. Annulus fibrosus cells were isolated and cultured, and the presence of FasL was quantified in the supernatants of three different numbers of annulus fibrosus cells (1x, 2x, and 4 x 10(6) cells/well) by ELISA assay. The MCF-7 and MDA-MB-231 cancer cells were cultured with supernatants of annulus fibrosus cells for 48 h. As controls, MCF-7 and MDA-MB-231 cancer cells were also cultured by themselves for 48 h. Finally, we determined and quantified the apoptosis rates of MCF-7 and MDA-MB-231 cancer cells by Annexin V-FITC and PI and TUNEL at 48 h, respectively. The expression of Fas was identified in MCF-7 and MDA-MB-231 cancer cells. The mean concentrations of FasL in supernatants of annulus fibrosus cells (1x, 2x, and 4 x 10(6) cells/well) were 10.8, 29.6, and 56.4 pg/mL, respectively. After treatment with the supernatant of three different numbers of annulus fibrosus cells, the mean apoptosis rate of MCF-7 cancer cells was increased (2.8%, P < 0.01; 6.7%, P < 0.001; 31.0%, P < 0.001) in a dose-dependent manner of FasL compared to that of control (1.1%). The mean apoptosis rate of MDA-MB-231 cancer cells was also increased (5.7%, P < 0.01; 11.1%, P < 0.001; 25.3%, P < 0.001) in a dose-dependent manner of FasL compared to that of control (2.1%). TUNEL also demonstrated direct evidence of apoptosis of MCF-7 and MDA-MB-231 cancer cells. Our results demonstrate that Fas-bearing cancer cells undergo apoptosis by FasL produced by disc cells, which may be considered as a potential biochemical explanation for the disc's resistance to metastatic cancer.
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PMID:A biochemical mechanism for resistance of intervertebral discs to metastatic cancer: Fas ligand produced by disc cells induces apoptotic cell death of cancer cells. 1768 74

The tropical ginger compound, 1'-acetoxychavicol acetate (ACA) possesses cancer chemopreventive properties in several models but its effects on breast cancer have not been fully evaluated. In this study, the effects of ACA on human breast carcinoma-derived MCF-7 and MDA-MB-231 cell viability were assessed using trypan blue exclusion analysis. ACA significantly decreased cell viability in a time- and dose-dependent manner, with effective concentrations 10-50 microM. Apoptosis was confirmed by morphological examination of cells through light microscopy, 4,6-diamidino-2-phenylindole dihydrochloride staining, and annexin V/Alexa Fluor 488 staining visualized using flow cytometry. ACA also increased protein expression of the activated form of caspase-3 in MDA-MB-231 cells. Addition of antioxidants N-acetylcysteine, ascorbic acid, or trolox prevented the loss of viability caused by ACA using trypan blue uptake as a marker. These results suggest ACA may have potential anticancer effects against breast carcinoma cells by inducing apoptosis.
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PMID:Pro-apoptotic effects of 1'-acetoxychavicol acetate in human breast carcinoma cells. 1776 64

Synthesis, structure elucidation and anticancer activities of novel fused 1,2,4-triazine aryl derivatives containing the ethoxycarbonyl (6-10) and carbohydrazide formations (11-15) are presented. Molecular structures of the synthesized compounds were confirmed by IR, (1)H NMR, (13)C NMR, EI-MS spectra and elemental analyses. Antitumour activities in vitro for heterobicyclic hydrazides of the type 11-14 were evaluated by BrdU method for human LS180, SiHa and T47D carcinoma cells. Amongst them, hydrazide 14 has exhibited remarkable inhibitory effect against SiHa and LS180 tumour cells, and simultaneously was found to be non-toxic towards the human normal cell line-HSF cells. Furthermore, the pulse field gel electrophoresis experiment was performed for characterizing DNA-cleaving activity of heterobicycle 14. The DNA fragments of 2500, 2000 and 500 kilobase pairs (kbp) were commonly detected in the cancer cell lines (SiHa, LS180 and T47D) treated with compound 14. DNA fragmentation pattern, since three types of fragments induced by the tested hydrazide of the type 14 were detected, suggesting a way of interaction with DNA. It is worth pointing out, that DNA strand breaks were also produced in human breast cancer (T47D) cells, a cell line where the induction of DNA fragmentation is very difficult. Moreover, the statistically significant apoptotic activity in T47D human breast cancer cells for the tested heterobicycle 14 was proved using the annexin V-binding assay. The antiproliferative properties in vitro for compounds 6-14 were evaluated by MTT method for human leukaemic Jurkat cells. Significant viability decreases in Jurkat cells treated with different concentrations of compounds 10 and 11 were observed, suggesting that these derivatives have antiproliferative activities. Their acute toxicities were established. For these compounds the influence on the central nervous system of mice in behavioural tests was examined. Molecular structure for free base of the intermediate 4 was confirmed by (1)H-(1)H COSY, HMBC and HMQC correlations.
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PMID:Synthesis, structure elucidation and identification of antitumoural properties of novel fused 1,2,4-triazine aryl derivatives. 1786 55

Undecylprodigiosin (UP) is a bacterial bioactive metabolite produced by Streptomyces and Serratia. In this study, we explored the anticancer effect of UP. Human breast carcinoma cell lines BT-20, MCF-7, MDA-MB-231 and T47D and one nonmalignant human breast epithelial cell line, MCF-10A, were tested in this study. We found that UP exerted a potent cytotoxicity against all breast carcinoma cell lines in a dose- and time-dependent manner. In contrast, UP showed limited toxicity to MCF-10A cells, indicating UP's cytotoxic effect is selective for malignant cells. UP's cytotoxic effect was due to apoptosis, as confirmed by positive TUNEL signals, annexin V-binding, caspase 9 activation and PARP cleavage. Notably, UP-induced apoptosis was blocked by the pan-caspase inhibitor z-VAD.fmk, further indicating the involvement of caspase activity. Moreover, UP caused a marked decrease of the levels of antiapoptotic BCL-X(L), Survivin and XIAP while enhancing the levels of proapoptotic BIK, BIM, MCL-1S and NOXA, consequently favoring induction of apoptosis. Additionally, we found that cells with functional p53 (MCF-7, T47D) or mutant p53 (BT-20, MDA-MB-231) were both susceptible to UP's cytotoxicity. Importantly, UP was able to induce apoptosis in MCF-7 cells with p53 knockdown by RNA interference, confirming the dispensability of p53 in UP-induced apoptosis. Overall, our results establish that UP induces p53-independent apoptosis in breast carcinoma cells with no marked toxicity to nonmalignant cells, raising the possibility of its use as a new chemotherapeutic drug for breast cancer irrespective of p53 status.
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PMID:Undecylprodigiosin selectively induces apoptosis in human breast carcinoma cells independent of p53. 1788 Oct 28

The effects of berberine on the behavior of breast tumors have not yet been established. To determine whether this compound is useful in the treatment of breast cancer, we analyzed the impact of berberine on the human breast cancer cell lines MCF-7 and MDA-MB-231 cells. Berberine was added to proliferating MCF-7 and MDA-MB-231 cells in culture. Following treatment, changes in cell growth characteristics such as proliferation, cell cycle duration, and the degree of apoptosis were assayed. Following berberine treatment, a time-dependent reduction in proliferation was observed in both cell lines at differing concentrations: 20 microM for MCF-7 and 10 microM for MDA-MB-231 cells. Annexin V staining showed an increase in apoptosis in both cell lines of 31 % in MCF-7 and 12 % in MDA-MB-231 cells compared to their respective controls. In addition, 12 % of the MCF-7 cells were arrested at G0/G1, compared to 62 % of control cells. These results demonstrate that treatment with berberine inhibits growth in both MDA-MB-231 and MCF-7 cells. In addition, they show that this partly occurs through the induction of apoptosis in MDA-MB-231 cells, and through both cell cycle arrest and induction of apoptosis in MCF-7 cells. Thus, berberine may be a novel therapeutic drug for breast cancer.
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PMID:Berberine inhibits growth of the breast cancer cell lines MCF-7 and MDA-MB-231. 1820 57

We report a new series of Herceptin-platinum(II) binding complexes, Her-nLPt(II) (Her denotes Herceptin; L denotes diamino ligands and L=L1-L4; n=1, 5, or 10). Solution chemistry studies have shown that these complexes are stable under physiological conditions (pH 7.4 in PBS). The platinum(II) compound L1Pt(II)Cl(2) inhibits the growth of a panel of human cancer cell lines at sub-micromolar concentrations. Remarkable cancer-cell-specific cytotoxicity was observed with Her-nL1Pt(II) (n=1, 5, 10) toward Her2/neu-overexpressing cancer cells (SK-BR-3 and SK-OV-3) over normal fibroblast cells. Annexin V apoptosis assays in SK-BR-3 and low-Her2/neu-expressing MCF-7 breast cancer cells further confirmed the critical role of Herceptin with this cancer-cell-specific agent. It was also found that the L1Pt(II)Cl(2) complex is an efficient regulator of the apoptotic genes Bcl-2 in the treated SK-BR-3 cells. Also, enhanced regulatory effects were observed in Her-10L1Pt(II). Taken together, this study suggests a new approach for the development of mAb-platinum(II)-based targeting agents for the treatment of human cancers.
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PMID:Herceptin-platinum(II) binding complexes: novel cancer-cell-specific agents. 1836 39

Enzastaurin (LY317615.HCI), a protein kinase C (PKC)-beta inhibitor, has a radiosensitising effect on 4T1 murine breast cancer and human glioma cells; however, the exact mechanism of this action has not been evaluated. The present study investigated the effects of enzastaurin and gamma irradiation on PKC activity in MCF-7 human breast cancer cells in vitro and in vivo. Enzastaurin (5 microM) in combination with irradiation (2-8 Gy) produced a synergistic decline in MCF-7 clonogenic cell survival. Analysis of MCF-7 cells stained with Annexin V and 7-aminoactinomycin D showed a dose-dependent increase in apoptosis in response to enzastaurin (3, 5 and 7 microM) and irradiation (10 Gy) compared to irradiation alone. This pro-apoptotic effect was confirmed by increases in caspase-3 and -9 activity. In a MCF-7 xenograft model, irradiation with 25 Gy increased PKC-alpha activity by 2.5-fold compared to untreated controls, whereas PKC-epsilon and -betaII activity was increased by 1.8-fold. Radiation-induced activation of all three anti-apoptotic isoforms of PKC was reversed by pre-treatment with enzastaurin (75 mg/kg, twice daily for 3 days). We conclude that enzastaurin has a radiosensitising effect on MCF-7 human xenograft tumours through the reversal of anti-apoptotic activation of PKC isoforms.
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PMID:Enzastaurin renders MCF-7 breast cancer cells sensitive to radiation through reversal of radiation-induced activation of protein kinase C. 1844 27


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