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)

We compared tumor necrosis factor (TNF) metabolism by wild-type MCF-7 (WT) cells, by 40-fold doxorubicin resistant (40F) breast cancer cells and by PC3 and LNCaP prostate cancer cell lines. MCF-7 WT and LNCaP cell lines were sensitive to TNF cytotoxicity and both lines produced two major intracellular TNF degradation products of 15 kDa and 5.5 kDa. The MCF-7 40F and the PC3 cell lines were resistant to TNF and produced multiple TNF degradation products with molecular weights lower than 15 kDa. Both the breast and prostate lines showed TNF receptor crosslinking patterns consistent with a molecular weight of 55 kDa. The breast and LNCaP lines expressed TNF receptors with an apparent dissociation constant (Kd) of 0.4 to 0.6 nM, while the TNF resistant line had a Kd of 2 nM. Similar receptor numbers per cell were found for all cell types (4,000 to 8,000/cell), and comparable levels of TNF internalization were noted. TNF-conditioned medium from the TNF-sensitive cell types was cytotoxic toward both the TNF-sensitive and TNF-resistant lines, and the toxicity was significantly blocked by an anti-TNF monoclonal antibody. Hydrophobic interaction column HPLC fractionation of the TNF-degradation products produced by MCF-7 WT and LNCaP cells revealed that the trimeric, monomeric, and 5.5 kDa fractions possessed the greatest in vitro antitumor activity. These findings suggest that a TNF degradation product, produced selectively by TNF-sensitive cells, may contribute to the antitumor action of TNF.
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PMID:Selective formation of tumor necrosis factor-alpha (TNF) degradation products contributes to TNF mediated cytotoxicity. 131 75

The trypanocidal drug, suramin, has been shown to possess antitumour activity, both in vitro and in vivo. Its mechanism of action, however, remains unclear although an effect on signal transduction has been proposed. We therefore studied the in vitro effect of suramin on protein kinase C (PKC), on adenylate cyclase and on the intracellular calcium concentrations [Ca2+]i in human cancer cell lines. Ca(2+)- and phospholipid-dependent PKC was isolated from a normal rat spleen, and compared with that of the human cancer cell lines MCF-7 (breast cancer) and PC3 (prostate cancer). PKC was inhibited by 50% at 55, 40 and 27 microM suramin in the three PKC sources, respectively, while 300 microM of suramin gave 97, 95 and 99% inhibition. With 50 nM staurosporine, a known PKC inhibitor, we observed 80, 99 and 96% inhibition in these three different sources of PKC. Six day exposure of these cell lines to suramin, causing 50% growth inhibition, decreased the Ca(2+)- and phospholipid-dependent PKC activity in MCF-7 cells to 52% of the control and in PC3 cells to 48% at equitoxic concentrations (45 and 150 microM suramin, respectively). These concentrations of suramin slightly increased (approximately 2-fold) the adenylate cyclase activity in MCF-7 cells, but not in PC3 cells. In MCF-7 and PC3 cells, we measured the [Ca2+]i using Fura-2 fluorescence and observed a decrease in MCF-7 cells from 126 to 99 nM when the cells were exposed for 6 days to 45 microM suramin. In PC3 cells, [C2+]i decreased from 131 to 117 nM after exposure to 150 microM suramin. In conclusion, suramin inhibited the Ca(2+)- and phospholipid-dependent PKC activity in both cell lines in a dose-dependent manner. Only in the more sensitive MCF-7 cell line was a significant effect of suramin on intracellular Ca2+ and adenylate cyclase observed, indicating that one of the mechanisms of action of suramin could be mediated by perturbations of intracellular signalling pathways.
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PMID:Effect of suramin on adenylate cyclase and protein kinase C. 791 97

Cathepsin D, a lysosomal aspartic proteinase, is secreted in the form of enzymatically inactive precursor in some cancer cells. This precursor, called procathepsin D, was found to exhibit growth factor activity toward breast cancer cell lines and this activity was later shown to be mediated by its activation peptide. In the present investigation we have used human procathepsin D and a synthetic 44 amino acid peptide corresponding to the activation peptide of procathepsin D to test its growth factor activity for human prostate cancer-derived cell lines PC3, DU145 and LNCaP. We have tested the level of proliferation of these cell lines depending on the presence of either procathepsin or activation peptide in the medium. In parallel, we have also measured the time dependency of this growth and established the optimal dose of activation peptide. These findings represent the first experimental data showing the direct effects of procathepsin D on prostate cancer cells.
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PMID:Effect of procathepsin D and its activation peptide on prostate cancer cells. 971 35

Conjugation of gonadotropin-releasing hormone (GnRH) analogues GnRH-III, MI-1544, and MI-1892 through lysyl side chains and a tetrapeptide spacer, Gly-Phe-Leu-Gly (X) to a copolymer, poly(N-vinylpyrrolidone-co-maleic acid) (P) caused increased antiproliferative activity toward MCF-7 and MDA-MB-231 breast, PC3 and LNCaP prostate, and Ishikawa endometrial cancer cell lines in culture and against tumor development by xenografts of the breast cancer cells in immunodeficient mice. MCF-7 cells treated with P-X-1544 and P-X-1892 displayed characteristic signs of apoptosis, including vacuoles in the cytoplasm, rounding up, apoptotic bodies, bleb formation, and DNA fragmentation. Conjugates, but not free peptides, inhibited cdc25 phosphatase and caused accumulation of Ishikawa and PC3 cells in the G2/M phase of the cell cycle after 24 h at lower doses and in the G1 and G2 phases after 48 h. Since P-X-peptides appear to be internalized, the increased cytotoxicity of the conjugates is attributed to protection of peptides from proteolysis, enhanced interaction of the peptides with the GnRH receptors, and/or internalization of P-X-peptide receptor complexes so that P can exert toxic effects inside, possibly by inhibiting enzymes involved in the cell cycle. The additional specificity of P-X-peptides compared with free peptides for direct antiproliferative effects on the cancer cells but not for interactions in the pituitary indicates the therapeutic potential of the conjugates.
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PMID:Gonadotropin-releasing hormone analogue conjugates with strong selective antitumor activity. 1005 47

Long acting somatostatin-14 (SST) analogs are used clinically to inhibit tumor growth and proliferation of various tumor types via binding to specific receptors (R). We have developed a 111In-/90Y-labeled SST analog, DOTA-(D)betaNal1-lanreotide (DOTALAN), for tumor diagnosis and therapy. 111In-/90Y-DOTALAN bound with high affinity (dissociation constant, Kd, 1-12 nM) to a number of primary human tumors (n = 31) such as intestinal adenocarcinoma (n = 17; 150-4000 fmol/mg protein) or breast cancer (n = 4; 250-9000 fmol/mg protein). 111In-/90Y-DOTALAN exhibited a similar high binding affinity (Kd, 1-15 nM) for the human breast cancer cell lines T47D and ZR75-1, the prostate cancer cell lines PC3 and DU145, the colonic adenocarcinoma cell line HT29, the pancreatic adenocarcinoma cell line PANC1, and the melanoma cell line 518A2. When expressed in COS7 cells, 111In-DOTALAN bound with high affinity to hsst2 (Kd, 4.3 nM), hsst3 (Kd, 5.1 nM), hsst4 (Kd, 3.8 nM), and hsst5 (Kd, 10 nM) and with lower affinity to hsst1 (Kd, approximately 200 nM). The rank order of displacement of [125I]Tyr11-SST binding to hsst1 was: SST (IC50, 0.5 nM) >> DOTALAN (IC50, 154 nM) > lanreotide (LAN) approximate to Tyr3-octreotide (TOCT) approximate to DOTA-Tyr3-octreotide (DOTATOCT) approximate to DOTA-vapreotide (DOTAVAP; IC50, >1000 nM); that to hsst2 was: DOTATOCT approximate to TOCT approximate to DOTALAN approximate to SST approximately LAN approximate to DOTAVAP (IC50, 1.4 nM); that to hsst3 was: SST (IC50, 1.2 nM) > DOTALAN = LAN (IC50, 15 nM) approximate to TOCT (IC50, 20 nM) approximate to DOTAVAP (IC50, 28 nM) > DOTATOCT (IC50, 73 nM); that to hsst4 was: SST (IC50, 1.8 nM) approximate to DOTALAN (IC50, 2.5 nM) > LAN (IC50, 22 nM) >> DOTATOCT approximate to DOTAVAP approximate to TOCT (IC50, >500 nM); and that to hsst5 was: DOTALAN (IC50, 0.45 nM) > SST (IC50, 0.9 nM) > TOCT (IC50, 1.5 nM) > DOTAVAP (IC50, 5.4 nM) >> LAN (IC50, 21 nM) > DOTATOCT (IC50 260 nM). In Sprague Dawley rats (n = 10), 90Y-DOTALAN was rapidly cleared from the circulation and concentrated in hsst-positive tissues such as pancreas or pituitary. Taken together, our results indicate that 111In-/90Y-DOTALAN binds to a broad range of primary human tumors and tumor cell lines, probably via binding to hsst2-5. We conclude that this radiolabeled peptide can be used for hsst-mediated diagnosis (111In-DOTALAN) as well as systemic radiotherapy (90Y-DOTALAN) of human tumors.
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PMID:DOTA-lanreotide: a novel somatostatin analog for tumor diagnosis and therapy. 1053 42

Transferrin, an abundant bone marrow constituent, has been shown to be a potent mitogen in vitro in the prostate cancer cell line PC3. T4 (L-thyroxine) and T3 (3',3,5-tri-iodo-L-thyronine) are regulators of cell metabolism. In this study, the effects of nonphysiological concentrations (about two orders of magnitude higher) of T4, T3, T2 (3,5-di-iodo-L-thyronine), RT3 (reverse T3, 3',5', 3-tri-iodo-L-thyronine) and transferrin (about three orders of magnitude lower) were tested on the prostate cancer cell lines PC3, DU145 and LNCaP, and the breast cancer cell line MCF-7. In PC3 cells, increased proliferation by transferrin could be reversed by the addition of T3 or T4. T4 decreased proliferation in all cell lines tested, while transferrin increased proliferation in PC3 cells only. T3 decreased proliferation in PC3, LNCaP and MCF-7 cells but had no effect on DU145 cells. T4 and T3 gave two-state behavior in LNCaP cells. These results were combined to determine the essential iodines which produced the observed proliferative effects. Cell lines responded differently to T4, T3, T2, RT3 and transferrin suggesting a specific interaction among the compounds tested and the different cell lines. Finally, regulation of gene expression was demonstrated using DU145 cells. Upregulation of c-fos mRNA was observed in cultures at early time-points in the presence of T4, transferrin or both. Decreased expression was observed at later time-points with no expression at 4 h. An explanation for these results may be a change in thyroid hormone receptor/ligand affinity. Thus, the interactions between thyroid hormones and cancer cells may be different from those between thyroid hormones and normal cells.
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PMID:Altered response to thyroid hormones by prostate and breast cancer cells. 1066 23

During our work on the mechanism of hormone resistance of prostatic carcinomas, a novel gene that we called PAR (prostate androgen regulated) was isolated from an androgen resistant subline (LNCaP-OM) using a modified representational difference analysis. The complete sequence of the gene cDNA has 1029 nucleotides with a continuous reading frame of 438 bases encoding for 146 amino acids. Its deduced amino acid sequence has motifs for myristoylation and phosphorylation by protein kinase C. The PAR gene was overexpressed in all prostatic carcinoma cell lines studied (LNCaP, DU145, PC3 and LNCaP-OM) compared to the normal prostatic tissue. Furthermore, its expression was higher in androgen resistant prostate cancer lines DU145, PC3 and LNCaP-OM, in comparison to androgen sensitive LNCaP cells. The expression of this gene was down regulated by androgens in androgen sensitive prostate cells, but not in the hormone resistant cell lines. The PAR mRNA was detected in all 29 normal human tissues studied and overexpressed in most (67%) of their malignant counterparts. The PAR expression was higher in MCF7 and T47D breast cancer cell lines, as well as in all primary breast tumors studied compared to their normal tissue counterparts. The biological function of this gene is still unknown, but its ubiquitous expression in normal tissues and its overexpression in some malignancies suggest the PAR involvement in certain basic cellular processes and possibly, in malignant transformation.
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PMID:PAR, a novel androgen regulated gene, ubiquitously expressed in normal and malignant cells. 1076 45

Two distinct benzodiazepine binding sites have been identified, (i) a central site restricted to brain and (ii) a ubiquitously expressed mitochondrial binding site, the so-called peripheral-type benzodiazepine receptor (PBR). In this paper, we show that a benzazepine referred to as BBL22 (2-amino 9-chloro-7-(2-fluorophenyl)-5H-pyrimidol[5,4-d][2]benzazepine), which is classified as a PBR ligand based on structure, induces arrest in G(2)/M phase of the cell cycle in human tumor cell lines of both epithelial and hematopoietic cellular origin. After G(2)/M arrest, several tumor types, notably prostate and certain breast cancer lines exhibited significant apoptosis. Ideally, cancer therapies should selectively target tumor cells while sparing normal cell counterparts. BBL22 exhibited such selectivity, as it did not affect the growth and survival of nonmalignant breast and prostate epithelial lines. Moreover, BBL22 demonstrated structural requirements for this selective antitumor activity as 11 structurally related PBR ligands, including high-affinity ligands Ro5-4864 and PK11195, failed to induce tumor cell growth arrest or apoptosis. The in vivo antitumor activity of BBL22 was examined in a human xenograft model of androgen-independent prostate cancer where BBL22 significantly reduced the growth of PC3 prostate tumors without eliciting overt toxicity. Identification of BBL22 represents a tumor selective therapeutic strategy for a variety of human tumors.
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PMID:Tumor selective G2/M cell cycle arrest and apoptosis of epithelial and hematological malignancies by BBL22, a benzazepine. 1086 Oct 14

We developed a group of synthetic analogs of GnRH and Somatostatin to inhibit the tumor growth of different kind. The GnRH analogs decreasing the gonadotroph and steroid hormone levels act on the hormone dependent tumors and influence their growth. One of the most effective antitumor analog was patented under the name FOLLIGEN which inhibited the breast cancer caused by DMBA in rats without any side-effects. Other inhibitory analogs of GnRH with long-lasting effect were effective in the treatment of breast, ovary and prostate tumors. Another analog [alpha-Asp(DEA)]6,Gln8-hGnRH showed a very low endocrine but high antitumor effect in both in vitro and in vivo experiments. Its tritium labeled derivative exhibited specific binding sites on human tumor cell lines. We synthesized the analogs of GnRH-III with effective selective antitumor activity which does not alter the ovarian cycle of rats but inhibits the colony-formation of human breast cancer cell lines and has a significant antiproliferative effect. We also synthesized conjugates of potent GnRH analogs with a branched chain polylysine backbone which induce a 33-35% decrease of cell numbers of MCF-7 and MDA-MB-231 human breast cancer cell lines and 45-50% inhibition of cell proliferation. Another conjugate decreased the tumor growth of MDA-MB-231 xenografts by 80% in a treatment of 9 weeks and even tumor free animals could be found among the ones treated. Using these radiolabeled peptide hormone analogs we found that human tumor cell lines and xenografts specifically bind the GnRH conjugates. We also synthesized a series of Somatostatin analogs which inhibit tyrosine kinases and the growth of several breast, prostate and colon tumor cell lines. One of our best analogs was a heptapeptide, TT-232, which strongly inhibited the tyrosine kinase activity and the cell-proliferation in different colon tumor cells. However, it did not inhibit the growth hormone release either in vitro or in vivo from rat pituitary cells. The TT-232 was found to be effective on 60 human tumor cell lines, it significantly inhibited the tumor growth on different animal tumor models, and induced apoptosis, as a result of which some animals became tumor free. The TT-232 inhibited the tumor growth of PC3 prostate xenografts with 60% and caused a 100% survival of mice 60 days after the transplantation. It is being preclinically tested at present. We have shown that the new GnRH analogs acting without any hormonal effect and the Somatostatin analogs with strong antitumor and tyrosine kinase inhibitory activity but no hormonal effect may represent a breakthrough in the research of the antitumor peptides, having direct effect on tumor cells.
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PMID:Peptides and antitumor activity. Development and investigation of some peptides with antitumor activity. 1086 57

Inhibitors of proteases are currently emerging as a potential anti-cancer modality. Nonselective protease inhibitors are cytotoxic to leukemia and cancer cell lines and we found that this cytotoxicity is correlated with their potency as inhibitors of the proteasome but not as inhibitors of calpain and cathepsin. Highly selective inhibitors of the proteasome were more cytotoxic and fast-acting than less selective inhibitors (PS341>>ALLN>>ALLM). Induction of wt p53 correlated with inhibition of the proteasome and antiproliferative effect in MCF7, a breast cancer cell line, which was resistant to apoptosis caused by proteasome inhibitors. In contrast, inhibitors of the proteasome induced apoptosis in four leukemia cell lines lacking wt p53. The order of sensitivity of leukemia cells was: Jurkat>HL60> or =U937>>K562. The highly selective proteasome inhibitor PS-341 induced cell death with an IC50 as low as 5 nM in apoptosis-prone leukemia cells. Cell death was preceded by p21WAF1/CIP1 accumulation, an alternative marker of proteasome inhibition, and by cleavage of PARP and Rb proteins and nuclear fragmentation. Inhibition of caspases abrogated PARP cleavage and nuclear fragmentation and delayed, but did not completely prevent cell death caused by PS-341. Reintroduction of wt p53 into p53-null PC3 prostate carcinoma cells did not increase their sensitivity to proteasome inhibitors. Likewise, comparison of parental and p21-deficient cells demonstrated that p21WAF1/CIP1 was dispensable for proteasome inhibitor-induced cytotoxicity. We conclude that accumulation of wt p53 and induction of apoptosis are independent markers of proteasome inhibition.
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PMID:Protease inhibitor-induced apoptosis: accumulation of wt p53, p21WAF1/CIP1, and induction of apoptosis are independent markers of proteasome inhibition. 1091 53


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