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)

Specific fatty acids such as linoleic acid (LA), gamma-linolenic acid (GLA), dihomo gamma linolenic acid (DGLA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) showed cytotoxicity towards human cervical (HeLa) cells in vitro. Cyclo-oxygenase inhibitor, indomethacin; lipoxygenase inhibitor, nordihydroguiaretic acid (NDGA); anti-oxidant, vitamin E; and calmodulin antagonists, trifluoperazine (TFP) and chlorpromazine (CPZ) blocked the cytotoxic action of these fatty acids. GLA-induced free radical generation and lipid peroxidation were also inhibited by indomethacin, NDGA, vitamin E, TFP and CPZ. Both indomethacin and NDGA also showed significant anti-oxidant property. These results suggest that fatty acid-induced cytotoxic action against HeLa cells is a free radical dependent process and that it can be modulated by calmodulin antagonists. These results are in contrast to those observed by us earlier with human breast cancer cells where in it was found that the tumoricidal action of fatty acids can be blocked by anti-oxidants but not by cyclo-oxygenase (CO) and lipoxygenase (LO) inhibitors. From these results it can be suggested that though free radicals are the mediators of the tumoricidal action of fatty acids, the mechanism of their production may be different in different types of tumor cells.
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PMID:Cytotoxic action of cis-unsaturated fatty acids on human cervical carcinoma (HeLa) cells: relationship to free radicals and lipid peroxidation and its modulation by calmodulin antagonists. 131 18

The growth-inhibitory effects of ketoconazole, an antifungal agent which inhibits arachidonic acid lipoxygenases and cytochrome P-450 enzymes, were tested in human colon and breast cancer cell lines. In the serum independent HT29-S-B6 colon cell clone, ketoconazole reduced cell proliferation and [3H]thymidine incorporation in a dose-dependent fashion, with a 50% inhibitory concentration of approximately 2.5 microM. Flow cytometry showed an accumulation of cells in the G0-G1 phase of the cell cycle and a concomitant decrease of the percentage of cells in S phase. Ketoconazole also inhibited [3H]thymidine incorporation in the hormone-independent breast cancer cells MDA-MB-231 and Evsa-T, with respective 50% inhibitory concentration of approximately 13 and 2 microM. The mechanism of action of ketoconazole is unknown. However, another lipoxygenase inhibitor, BW755C, inhibited only weakly [3H]-thymidine incorporation and accumulated the cells in S and G2. Conversely, clotrimazole and SKF525A, inhibitors of cytochrome P-450 enzymes, had effects similar to those of ketoconazole on HT29-S-B6 cells whereas metronidazole and secnidazole, other azole derivatives which do not inhibit cytochrome P-450 enzymes, had no effect. The results suggest that cytochrome P-450 enzyme(s) activity(ies) could be implicated in the antiproliferative effects of ketoconazole.
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PMID:Effects of ketoconazole on the proliferation and cell cycle of human cancer cell lines. 145 71

Dietary lipids may influence breast cancer progression and prognosis. The MDA-MB-231 human breast cancer cell line was used to examine the direct effects of the various classes of free fatty acids (FAs) on growth in serum-free medium and the involvement of eicosanoid biosynthesis. Linoleic acid, an omega 6 FA, stimulated MDA-MB-231 cell growth with an optimal effect at a concentration of 0.75 microgram/ml, whereas oleic acid, an omega 9 FA, produced growth stimulation at 0.25 microgram/ml but was inhibitory at higher concentrations. Docosahexaenoic acid exhibited a dose-related inhibition of cell growth at concentrations ranging from 0.5 to 2.5 micrograms/ml; eicosapentaenoic acid, also an omega 3 FA, was less effective. Similar inhibitory effects occurred with saturated FAs. Indomethacin, which at high concentrations is an inhibitor of both the cyclooxygenase- and lipoxygenase-catalyzed pathways of eicosanoid synthesis, suppressed cell growth stimulation by an otherwise optimal dose of linoleic acid when present at 40 micrograms/ml. Experiments with piroxicam, nordihydroguaiaretic acid, and esculetin, other inhibitors of eicosanoid biosynthesis with varying selectivity for enzymes of the prostaglandin and leukotriene pathways, indicated that MDA-MB-231 cell growth was dependent on leukotriene rather than prostaglandin production.
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PMID:Effects of fatty acids and inhibitors of eicosanoid synthesis on the growth of a human breast cancer cell line in culture. 222 49

Assays of leukocyte adherence inhibition (LAI) and transmembrane potential (delta psi) change were used to examine the responses of T-cells from control subjects and breast cancer patients when incubated with extracts of breast cancer and other tissues. Of T-cells from 25 patients with breast cancer, 21 exhibited delta psi changes or inhibition of adherence to glass when they were incubated with extracts of autologous but not allogeneic breast cancer; extracts of autologous normal breast tissue did not induce delta psi changes or LAI in T-cells from patients with breast cancer. Supernatants were collected after incubating 1 X 10(7) T-cells from patients with breast cancer or from control subjects with extracts of the autologous cancer. When the supernatants were added to either peripheral blood leukocytes or mononuclear cells from normal donors, neither delta psi changes nor LAI were detected. To still determine whether the nonadherence was mediated by chemoattractant lymphokines, the effect of inhibiting T-cell arachidonic acid metabolism was examined. The lipoxygenase pathway antagonist, 5,8,11,14-eicosatetraynoic acid, or a leukotriene antagonist, FPL 55712, inhibited T-cell LAI, but a cyclooxygenase pathway antagonist, indomethacin, did not. Moreover, authentic leukotriene B4 induced delta psi changes and LAI in T-cells. The results indicated that T-cells from patients with breast cancer recognized and bound a tumor-specific antigen in the autologous neoplastic breast tissue that transduced a transmembrane signal to trigger a series of biochemical changes, releasing lipoxygenase products of arachidonate. The lipoxygenase products, which may be important in the inflammatory response to cancer, induced a loss of T-cell adherence to glass.
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PMID:Requirement for autologous cancer extracts and lipoxygenation of arachidonic acid for human T-cell responses in leukocyte adherence inhibition and transmembrane potential change assays. 642 56

We investigated the in vitro effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), with or without the addition of linoleic acid (LA), on cell growth and prostaglandin E (PGE) and leukotriene B (LTB) secretion by a human breast cancer cell line (MDA-MB-231). With or without the addition of LA, EPA and DHA suppressed cell growth and thymidine incorporation and reduced the secretion of PGE and LTB. In a univariate analysis, cell growth was significantly associated with both LTB and PGE concentrations when cells were treated with DHA or EPA, independent of the addition of LA. However, multivariate regression analysis showed that cell growth was more closely associated with the PGE concentration rather than the LTB concentration. These data suggest that both EPA and DHA suppress cell proliferation in the MDA-MB-231 cell line by inhibition of the cyclooxygenase rather than the lipoxygenase pathways. However, the exact mechanism underlying the antitumor activity of EPA and DHA remains unclear.
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PMID:Effects of eicosapentaenoic and docosahexaenoic acid on cell growth and prostaglandin E and leukotriene B production by a human breast cancer cell line (MDA-MB-231). 747 31

Polyunsaturated fatty acids influence several steps involved in metastasis formation in animal tumor models. During the process of metastasis from the primary site, tumor cells adhere to the endothelium and underlying basement membrane before extravasation and secondary growth. The purpose of this study was to determine the effect of unsaturated fatty acids on adhesion of human breast cancer cell lines to components of the basement membrane. Cells were cultured in low-serum medium for five days with or without added unsaturated fatty acids. Adhesion assays were conducted by incubating cells with basement membrane substrates coated on 96-well plates, washing to remove nonadherent cells, and staining adherent cells with crystal violet. Linoleic acid (LA) and eicosapentaenoic acid increased adhesion of the metastatic cell line MDA-MB-231 to Matrigel and type IV collagen, while eicosapentaenoic acid decreased adhesion of the less metastatic cell line SK-BR-3 to these two basement membrane substrates. Oleic acid increased adhesion of MDA-MB-231 cells to Matrigel and fibronectin. Nordihydroguaiaretic acid and high concentrations of indomethacin, each of which inhibits the lipoxygenase pathway of arachidonate metabolism, were effective in reversing the stimulatory effect of LA on MDA-MB-231 cell adhesion. A protein kinase C inhibitor likewise suppressed the increase in adhesion observed when MDA-MB-231 cells were incubated in media with added LA. Unsaturated fatty acids modified the adhesive properties of human breast cancer cell lines in vitro, and LA appeared to increase human breast cancer cell adhesion to extracellular matrix components by activating lipoxygenase and/or protein kinase C pathways.
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PMID:Unsaturated fatty acid effects on human breast cancer cell adhesion. 749 Dec 98

We have reviewed the literature concerning the role of fatty acids and eicosanoid synthesis inhibitors in breast carcinoma. The omega-6 polyunsaturated fatty acids (PUFAs), primarily linoleic acid, promote breast cancer tumorigenesis and tumor cell proliferation directly and indirectly via increased synthesis of cyclooxygenase- and lipoxygenase-catalyzed products. The omega-3 PUFAs, primarily docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), suppress breast carcinoma tumorigenesis and tumor cell proliferation, although the effect of DHA may be partly ascribed to increased amounts of EPA derived from DHA. Both cyclooxygenase and lipoxygenase inhibitors suppress tumorigenesis and/or tumor proliferation, with the latter being more active. Thus, arachidonic acid-derived eicosanoids play an important role in breast cancer, and the balance of the various eicosanoids may be a critical determinant of cell proliferation. However, the exact mechanism by which fatty acids and eicosanoid synthesis inhibitors exert stimulatory and inhibitory effects on breast carcinoma is still not well understood.
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PMID:The role of fatty acids and eicosanoid synthesis inhibitors in breast carcinoma. 777 37

We investigated the effects of cyclooxygenase and lipoxygenase inhibitors on a human breast cancer cell line (MDA-MB-231) in culture. Indomethacin (INDO), piroxicam, esculetin, and nordihydroguaiaretic acid (NDGA) significantly suppressed cell growth, although piroxicam caused significant suppression only at high concentrations. Esculetin and NDGA caused significantly reduced secretion of leukotriene B (LTB), while INDO and piroxicam caused significantly reduced secretion of prostaglandin E (PGE). Consequently, cell growth was significantly correlated with the LTB concentration when the cells were treated with esculetin or NDGA, whereas it was significantly correlated with the PGE concentration when they were treated with INDO or piroxicam. Therefore, MDA-MB-231 cell growth in vitro was independently associated with both the PG and LTB concentrations.
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PMID:Effects of eicosanoid synthesis inhibitors on the in vitro growth and prostaglandin E and leukotriene B secretion of a human breast cancer cell line. 785 76

We investigated the effects of piroxicam, esculetin, prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) on a human breast cancer cell line (MDA-MB-231). Both piroxicam and esculetin suppressed cell growth and thymidine incorporation, though esculetin was more active in inhibiting cell growth in the presence of linoleic acid (LA). Esculetin reduced the secretion of LTB independent of LA. Piroxicam reduced the secretion of PGE in the absence of LA but only at higher concentrations in the presence of LA. When the relationship between cell growth and PGE and LTB concentration was evaluated by multivariate regression analysis, cell growth was associated with the PGE and LTB concentration when the cells were treated with esculetin alone or with esculetin and LA. Cell growth was associated only with the PGE concentration when they were treated with piroxicam alone or with piroxicam and LA. Therefore, it appears that the growth of MDA-MB-231 cells in vitro is affected by both lipoxygenase and cyclooxygenase products, though lipoxygenase inhibition is more active than cyclooxygenase inhibition on suppression of cell growth in the presence of LA.
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PMID:Effects of piroxicam and esculetin on the MDA-MB-231 human breast cancer cell line. 859 70

Diets rich in linoleic acid (LA) stimulate the metastasis of MDA-MB-435 human breast cancer cells from the mammary fat pads of nude mice. This omega-6 fatty acid is metabolized to various cyclo-oxygenase and lipoxygenase products, several of which have been previously associated with tumor cell invasion and metastasis. We now report that MDA-MB-435 cells secreted increased levels of prostaglandin E2 (PGE2), and 12-hydroxyeicosatetraenoic acid (12-HETE) and 15-HETE when cultured in the presence of 2.7 microM (0.75 micrograms/ml) LA; 5-HETE secretion was unchanged. The 12-lipoxygenase inhibitor esculetin (20 microM) completely blocked the LA-stimulated 12-HETE secretion. Linoleic acid also increased MDA-MB-435 cell invasion in an in vitro assay; this stimulation was abolished by 20 microM esculetin, but was unaffected by piroxicam, a selective cyclooxygenase inhibitor. The effect of LA on invasion was replicated by 0.1 microM 12-HETE, but not by 5-HETE or PGE2; 15-HETE was stimulatory only at a concentration of 1.0 microM. Zymographic and Northern blot analyses showed that these events are accompanied by the induction of 92 kDa isoform type IV collagenase (metalloproteinase-9) enzymic activity and mRNA expression by exogenous LA and 12-HETE, and their suppression by the 12-lipoxygenase inhibitor. These results suggest that the effects of dietary LA on breast cancer cell metastasis in the nude mouse model are due, at least in part, to enhanced 12-HETE biosynthesis, with an associated increase in proteolytic enzyme activity and tumor cell invasiveness.
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PMID:Eicosanoids as mediators of linoleic acid-stimulated invasion and type IV collagenase production by a metastatic human breast cancer cell line. 860 28


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