Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0276241 (MCF)
 28,353 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The analogs of tiapamil are highly active modifiers of P-glycoprotein-mediated multidrug resistance (MDR) in vitro. The activity of three analogs of tiapamil, Ro 11-2933, Ro 44-5911 and Ro 44-5912, was compared in K562/DXR and MCF-7/DXR cell lines, using flow cytometry for the determination of intracellular daunorubicin accumulation and MTT assays for the cytotoxic evaluation of the modulators combined or not with daunorubicin. Ro 44-5911 and Ro 44-5912 were not intrinsically more toxic than DL-verapamil and exhibited a significantly higher reversing effect. Ro 44-5912 was shown slightly more efficient than Ro 44-5911 for reversing daunorubicin cytotoxicity. Ro 11-2933 was found to be the most potent in modulating MDR but was not significantly more active than Ro 44-5912. These two compounds were able to achieve a near complete reversion (above 80%) at 5 mumol/I. However, the cytotoxicity of Ro 11-2933 was higher with an IC50 near 20 mumol/I in both K562 and MCF7 cell lines. Our results indicate that tiapamil derivatives are promising compounds for MDR modulation. Among them Ro 11-2933 and Ro 44-5912 seem to be particularly interesting for in vivo evaluations.
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PMID:Comparative in vitro evaluation of dithiane analogs of tiapamil, Ro 11-2933, Ro 44-5911 and Ro 44-5912 as multidrug resistance modulators. 882 12

The reversing effect of p-glycoprotein (Pgp) inhibitors on the multidrug resistance (MDR) phenotype is well established in a variety of MDR cell lines. The interactions of these inhibitors with individual MDR drugs in the respective parental lines, however, is less documented. This kind of information is not only essential for understanding of the outcome of clinical trials for MDR modulation in heterogeneous tumor populations but also important for evaluating of new Pgp blockers. Interaction of the Pgp inhibitor, thaliblastine (TBL), with several MDR drugs was therefore investigated in sensitive human breast cancer cell line (MCF-7) as well as adriamycin (AdR) selected MDR subline MCF/AdR. While the resistance to anthrapyrazole CI941 was completely overcome by simultaneous exposure to TBL (8 microM) in a 48 h exposure MTT assay compared with MCF-7 cells exposed to the same combination, only partial reversal was achieved in the case of AdR and etoposide (VP-16), but 240-fold hypersensitivity (or collateral sensitivity) was obtained in the MCF/AdR cells treated with taxol plus TBL, with IC50s of 0.10 +/- 0.03 microM and 24.6 +/- 5.0 microM in the resistant and sensitive cell lines, respectively. In the parental MCF-7 cells, on the other hand, no change of AdR cytotoxicity by simultaneous exposure to TBL was observed. There was an enhancement of CI941 cytotoxicity but an antagonism against taxol and VP-16 obtained upon addition of TBL to the treatment with the drugs in the MCF-7 parental cell line. Our results demonstrate that while TBL can overcome the resistance to each of the MDR drugs studied in MCF/AdR cells, albeit to a different extent varying from the partial reversal to the hypersensitivity, TBL co-exposure does not uniformly increase the cytotoxicity of these drugs in the parental MCF-7 cells.
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PMID:Differential interactions of Pgp inhibitor thaliblastine with adriamycin, etoposide, taxol and anthrapyrazole CI941 in sensitive and multidrug-resistant human MCF-7 breast cancer cells. 904 12

Inositol hexaphosphate (InsP6 or IP6) is an active ingredient of high fiber diet that has anti-cancer action in both in vitro and in vivo models. Recently we have demonstrated that InsP6 significantly inhibits DMBA-induced rat mammary cancer in vivo. To test the hypothesis that InsP6 mediates its function via inhibition of cell proliferation irrespective of hormonal dependence, its effect on growth inhibition and differentiation were studied in two human mammary carcinoma cell lines with different estrogen receptor status. Cell growth was measured by MTT incorporation assay, DNA synthesis by 3H-Tdr uptake and differentiation marker lactalbumin by immunocytochemistry. Dose-dependent growth inhibition was observed in both estrogen receptor-positive (MCF-7) and receptor-negative cells (MDA-MB-231). Statistically significant growth inhibition (p < 0.05) was observed starting at 1 mM InsP6 as early as after the first day of treatment and continued up to 6 days for both the cell lines. DNA synthesis in both the cell lines was suppressed by InsP6 occurring as early as 3 h after the beginning of treatment and continued up to 48 h; significant inhibition (p < 0.05) started at 1 mM InsP6 after 6 h of treatment. Compared to untreated cells, a 5-fold (p < 0.05) and 22-fold (p < 0.01) increase in expression of lactalbumin, associated with luminal cell differentiation was identified by immunocytochemistry after 48 h of treatment with 1 and 5 mM InsP6. Our data show that the inhibition of DNA synthesis and cell growth and induction of differentiation of human mammary cancer cell lines by InsP6 is independent of the estrogen receptor status of the cells. Taken together with results from in vivo studies, InsP6 may be an important candidate for the prevention and treatment of human breast cancer.
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PMID:Novel anti-cancer functions of IP6: growth inhibition and differentiation of human mammary cancer cell lines in vitro. 904 2

The pathogenesis of tumor-induced osteolysis (TIO) following breast cancer metastases in bone remains unclear. We postulated that osteoblasts could be target cells for the secretory products of breast cancer cells. We previously showed that serum-free conditioned medium (CM) of the breast cancer cell line MCF-7 inhibits DNA synthesis by 75% of control values in osteoblast-like cells SaOS-2 and that this effect is only in a minor part due to transforming growth factor beta secretion. To establish the specificity of our observations and to look for other biologically active factors, we have tested the effects of medium conditioned by several cancer and noncancer cell lines (breast, colon, placenta, or fibrosarcoma) on the proliferation of osteoblast-like cells (SaOS-2, MG-63), normal human osteoblasts, human fibrosarcoma cells, and normal human fibroblasts. Culture medium (1:2) of the breast cancer cell lines MCF-7, T-47D, MDA-MB-231, and SK-BR-3 inhibited by 25-50% the proliferation of osteoblast-like cells SaOS-2, MG-63, and normal osteoblasts as evaluated by the MTT survival test or [3H]thymidine incorporation. MCF-7 cells completely inhibited the proliferation of normal human osteoblasts in coculture. This inhibitory effect was reversible and not due to cytotoxicity. Moreover, the cyclic adenosine monophosphate (cAMP) response to parathyroid hormone (PTH) of osteoblast-like cells SaOS-2 was also increased by 100-240% by the same CM. Such activities were, however, not detected in medium from the breast noncancer cell line HBL-100 or in the medium conditioned by non-breast cancer cell lines (COLO 320DM, HT-29, JAR, or HT-1080). Medium from the breast cancer cells had no effect on normal human fibroblasts or fibrosarcoma cells (HT-1080), suggesting the specificity of their action on human osteoblasts. After partial purification by ultrafiltration and size-exclusion chromatography, we found that medium of T-47D cells contained at least three nonprostanoid factors of low molecular weights (apparent MW of 700, 1500, and 4000 D) which affected human osteoblast-like cells. These factors were heat stable and could be peptides without disulfide bonds. In summary, our data show that human breast cancer cells release soluble factors that inhibit osteoblast proliferation and increase their cAMP response to PTH, indicating that osteoblasts could be important target cells for breast cancer cells and could be involved in the process of TIO.
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PMID:Secretory products of breast cancer cells specifically affect human osteoblastic cells: partial characterization of active factors. 910 66

Recent studies have demonstrated that following estrogen ablation, estrogen responsive breast cancer cells undergo apoptosis. In addition, estrogen receptor (ER) expression has been strongly correlated with the expression of the bcl-2 gene product, p26Bcl-2 protein, which is known to inhibit apoptosis. In the present studies, we investigated whether estrogen affects the intracellular levels of p26Bcl-2 and thereby modulates taxol-induced apoptosis of estrogen responsive human breast cancer MCF-7 cells. Transfer of MCF-7 cells to a culture-medium without estrogens reduced their intracellular p26Bcl-2 levels by 50%. Inclusion of 0.1 microM estradiol in the medium produced approximately a four-fold increase in p26Bcl-2, but not p29Bcl-x1, or p21Bax levels; the expression of the c-myc and mdr-1 genes remained unchanged. Estradiol-induced four-fold increase in the ratio of the p26Bcl-2 to p21Bax levels caused a significant decline in the lethal, kilobase size DNA fragments of apoptosis, which had resulted when MCF-7 cells were cultured in a medium without estrogen. In addition, in MCF-7 cells, estradiol-induced increase in the intracellular p26Bcl-2 to p21Bax ratios was associated with a significant reduction in the large-sized DNA fragmentation induced by treatment with taxol. The increased ratios also protected MCF-7 cells against taxol-mediated cytotoxicity as assessed by the MTT assay. These results suggest that by modulating p26Bcl-2 levels, estrogens may affect the antitumor activity of taxol and potentially of other anti-breast cancer drugs against estrogen responsive human breast cancer cells.
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PMID:Estrogen increases intracellular p26Bcl-2 to p21Bax ratios and inhibits taxol-induced apoptosis of human breast cancer MCF-7 cells. 911 21

The potential of zalcitabine (ddC) to act as an ionizing radiation response modifier was tested on exponentially growing human cancer cells in vitro. Two human cell lines, WiDr (colon) and MCF-7 (breast) were exposed to ddC at 10 microM concentration for various lengths of time (18, 24, 48 and 72 h). On the WiDr cell line the dual effect of concentration and duration of exposure prior to irradiation was investigated. Experimental endpoints were clonogenicity and viability, as measured by colony formation assay (CFA) and MTT assay respectively. The impact on cell-cycle distribution prior to irradiation was assessed by flow cytometry using a double labeling technique (propidium iodide and bromodeoxyuridine pulse label). A significant reduction in surviving fraction and viability was observed for WiDr-cells irradiated after pre-exposure to 10 microM for 18, 48 and 72 h as compared to corresponding irradiated controls. At lower concentrations (1 and 5 microM), the radiosensitizing effect was only significant after a 72-h exposure (assessed by CFA). For MCF-7, ddC induced a significant modification of the dose response only with 24 and 48 h preincubation. However, the overall effect was less pronounced as compared to WiDr. Cell-cycle analysis showed accumulation in S-phase, 48 and 72 h after treatment with 10 microM ddC in the WiDr cells, with a progressive shift to late S-phase as shown by the biparametric analysis. The degree of radiosensitization is cell-line dependent with the most important sensitization observed on the most "radioresistant cell line", i.e., the cell line with the lowest alpha value and highest SF 2 (WiDr). For WiDr, radiosensitization by ddC depends on the duration of exposure and the concentration of the drug.
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PMID:Cell line specific radiosensitizing effect of zalcitabine (2',3'-dideoxycytidine). 914 Apr 38

We examined in vitro cytotoxic activity of imidazolyl-1,3,5-triazine derivatives using human breast cancer cell lines (MCF-7, R-27, T-47D and ZR-75-1) and murine leukemia cell line (P388). The percentage of viable cells was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazorium bromide (MTT) assay. Hexamethylmelamine (HMM), a 1,3,5-triazine derivative has previously been recognized as an antitumor agent effective against lung, ovarian and breast cancer, but failed to show a significant cytotoxic activity in the present study. In contrast, four imidazolyl-1,3,5-triazine derivatives, 2-(1-imidazolyl)-4,6-bis(morpholino)-1,3,5-triazine, 2-(1-imidazolyl)-4-morpholino-6-(3-thiazolidinyl)-1,3,5-triazine, 2-(4-cyano-4-phenylpiperidino)-4-(1-imidazolyl)-6-morpholino-1,3,5-triaz ine and 2-(1-imidazolyl)-4-(N-methyl-N-phenylamino)-6-morpholino-1,3,5-triazine showed cytotoxic activity for most cell lines, which was significantly greater than the activity of hydroxymethylpentamethylmelamine (HMPMM), a major metabolite of HMM.
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PMID:In vitro cytotoxicity of imidazolyl-1,3,5-triazine derivatives. 921 94

Clinical chemotherapy of breast carcinomas must be considered insufficient, mainly due to the appearance of drug resistance. The multidrug resistance (MDR) phenotype, either intrinsically occurring or acquired, e.g., against a panel of different antineoplastic drugs, is discussed in relation to several MDR-associated genes such as the MDR-gene mdr1 encoding the P-glycoprotein (PGP), the MRP gene (multidrug resistance protein) encoding an MDR-related protein or the LRP gene encoding the lung resistance protein. Numerous experimental and clinical approaches aiming at reversing resistance require well-characterised in vitro and in vivo models. The aim of our work was to develop multidrug resistant sublines from human xenotransplanted breast carcinomas, in addition to the broadly used line MCF-7 and its multidrug resistant subline MCF-7/AdrR. MDR was induced in vitro with increasing concentrations of Adriablastin (ADR) for several weeks, resulting in a 3.5- to 35-fold increase in IC50 values using the MTT-test. Cell lines were cross-resistant toward another MDR-related drug, vincristine, but remained sensitive to non-MDR-related compounds such as cisplatin and methotrexate. The resistance toward Adriamycin and vincristine was confirmed in vivo by a lack of tumour growth inhibition in the nude mouse system. Gene expression data for the mdr1/PGP, MRP/MRP and LRP/LRP on both the mRNA (RT-PCR) and the protein levels (immunoflow cytometry) demonstrated that induction of mdr1 gene expression was responsible for the acquired MDR phenotype. Rhodamine efflux data, indicated by PGP overexpression, underlined the development of this MDR mechanism in the newly established breast carcinoma lines MT-1/ADR, MT-3/ADR and MaTu/ADR.
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PMID:Development and characterisation of novel human multidrug resistant mammary carcinoma lines in vitro and in vivo. 931 9

Invasiveness, the ability of certain tumour cells to migrate beyond their natural tissue boundaries, often leads to metastasis, and usually determines the fatal outcome of cancer. The need for anti-invasive agents has led us to search for possibly active compounds among alkaloids and polyphenolics. One hundred compounds were screened in an assay based on the confrontation of invasive human MCF-7/6 mammary carcinoma cells with fragments of normal embryonic chick heart in vitro. Anti-invasive activity was frequently found among chalcones having a prenyl group. Six compounds were found to inhibit invasion when added to the culture medium at concentrations as low as 1 microM. For at least three of them the anti-invasive effect could be associated with a cytotoxic effect on the MCF-7/6 cells, but not on the heart tissue. This selective cytotoxicity was substantiated by different methods, such as histology and growth assays (volume measurements, cell counts, MTT and sulforhodamine B assays). The anti-invasive effects of the compounds could neither be ascribed to induction of apoptosis nor to the promotion of cell-cell adhesion. Our data indicate that among the alkaloids and polyphenolics a number of molecules can inhibit growth and invasion of human mammary cancer cells via selective cytotoxicity.
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PMID:Anti-invasive activity of alkaloids and polyphenolics in vitro. 931 66

When epithelial cells reach confluency in vitro, a number of energy-requiring activities such as growth and motility are contact-inhibited. We investigated the possible role of the E-cadherin/catenin complex, which acts as an invasion suppressor, in contact inhibition. Three strategies for modulation of the complex were used. Firstly, the cell-cell adhesion and signal transduction functions of E-cadherin were neutralized immunologically in human MCF-7/6 mammary carcinoma cells possessing a complete complex. Secondly, the effect of E-cadherin transfection in E-cadherin negative cell lines was investigated. Thirdly, alpha-catenin deficient variants of the human HCT-8/S11 colon carcinoma cell line were compared with their parent cells. In confluent cultures functional downregulation of the E-cadherin/catenin complex did not alter cell growth nor saturation density. This was shown by cell number counts, protein staining assays, cell cycle analysis, proliferation markers (Ki67 and Proliferating Cell Nuclear Antigen) and apoptosis assays. However, confluent cells with a functionally deficient complex showed positional instability and enhanced succinate dehydrogenase-mediated mitochondrial 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyl) tetrazolium bromide (MTT) conversion, as compared to cells with an active complex. Our data indicate that contact inhibition of motility and of mitochondrial enzyme activity, but not of growth is regulated by the E-cadherin/catenin complex in epithelial cells.
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PMID:Functional downregulation of the E-cadherin/catenin complex leads to loss of contact inhibition of motility and of mitochondrial activity, but not of growth in confluent epithelial cell cultures. 943 30


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