Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently demonstrated that the cysteine proteinase inhibitor, E-64, sensitizes human Burkitt's lymphoma (Daudi) to the antitumor action of bleomycin (BLM) by blocking its metabolism. We now report that E-64 sensitizes the BLM resistant human lung carcinoma A-549 by a mechanism unrelated to the inhibition of BLM metabolism. Treatment of A-549 tumor-bearing nude mice with either BLM (10 mg/kg) or E-64 (40 mg/kg) every other day for 10 days did not inhibit tumor growth. However, a 30 min pretreatment with E-64 prior to BLM caused complete and sustained inhibition of tumor growth. In contrast to our results with Burkitt's lymphoma, E-64 did not inhibit BLM metabolism but rather enhanced the tumor accumulation of BLM; within 10 min of BLM administration, tumors from E-64 pretreated mice showed a 6-fold higher accumulation of BLM A2 compared to non-pretreated xenografts. Furthermore, the level of tumor-associated BLM A2 remained 2-fold higher in E-64 pretreated mice 20 and 30 min after BLM administration. In E-64 pretreated mice, the plasma level of BLM was increased by 2-fold. These results demonstrate that the cysteine proteinase inhibitor, E-64, sensitized human lung carcinoma A-549 to BLM and, contrary to the expected mechanism, this effect of E-64 was not related to the inhibition of BLM metabolism.
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PMID:In vivo sensitization of human lung carcinoma to bleomycin by the cysteine proteinase inhibitor E-64. 137 52

The cysteine proteases cathepsin B and cathepsin L are very likely involved in invasive processes of normal and malignant cells, they become relevant for a number of diseases and are possibly prognostic markers for the outcome of human lung cancer. Therefore, we have determined activities of these related enzymes in cells and in cell extracts of human lung carcinoma cell lines of different cathepsin composition by flow cytometry and by spectrophotometry, respectively. To this end we applied the synthetic dipeptidyl substrates benzoxycarbonyl-arginyl-arginine- and benzoxycarbonyl-phenyl-arginine- coupled to 4-methoxy-beta-naphthylamide, aminomethyl-coumarine or rhodamine R110. The apparent enzymatic activities were differentially defined by protease inhibitors, particularly E-64 and CA-074. Independent of the dipeptidyl-composition more than 99 per cent of the apparent activity was due to cathepsin B when 4-methoxy-beta-naphthylamide or aminomethylcoumarine were the leaving groups. The 4-methoxy-beta-naphthylamide precipitate used for detection of cell associated activities revealed a wide spectrum of excitation to fluorescence thwarting the application of other possible fluorescent tags. Therefore, its application is restricted to uniparametric fluorescence investigations. Both dipeptidylgroups coupled to rhodamine R110 were promiscuous: only 25 to 30% of the apparent activity were due to cathepsin B; the predominant activity came from cathepsin L, irrespective whether intracellular or activities of cellular extracts were analyzed. However, rhodamine R110-coupled substrates open the way for multiparametric fluorescent analysis of cathepsins B and L containing cells if appropriate inhibitors for specification of the enzymatic activities are additionally applied. In very contrast to 4-methoxy-beta-naphthylamide, which causes irreparable damage to the cells, the rhodamine substrates permit studies with living cells and live cell sorting.
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PMID:Quantification of intracellular cathepsin activities in human lung tumor cell lines by flow cytometry. 757 37

In this study we have examined, by means of isoelectric focusing (IEF) in native polyacrylamide gel and contact-print fluorescence zymography, whether human lung carcinomas and the lung parenchyma contain different pools of multiple charge forms of the cysteine proteinase cathepsin B. The isoelectric point (pI) patterns of cathepsin B from lung carcinoma and matched lung were similar, particularly with regard to 2 major intermediate acidic enzyme pI forms designated as I and II (pIapp of 5.10 and 4.93 in tumors, and 5.11 and 4.94 in lungs, respectively). The slightly acidic cathepsin B pI forms (pIapp 5.47-5.19) in squamous-cell lung carcinoma (SQCLC) were significantly more numerous than such enzyme pI forms in lungs. The numbers of the highly acidic cathepsin B pI forms (pIapp 4.82-4.33) were significantly higher in SQCLC and lung adenocarcinoma (ACL) than in matched lung. The activity distribution percentage in the set of highly acidic cathepsin B pI forms was significantly higher in SQCLC and ACL than in matched lung. We also observed that cathepsin B from SQCLC and matched lung was fully recoverable by IEF from inhibition by leupeptin. Using the cysteine-proteinase-specific inactivator E-64, we revealed by IEF that some cathepsin B isoforms (charge forms) from SQCLC were more resistant to inactivation by this compound than the corresponding enzyme isoforms from lungs. After IEF, the enzyme isoforms apparently lost their resistance to E-64. Our results indicate that the pool of multiple charge forms of cathepsin B in SQCLC and ACL is different from that in the lung, and also that there may be an increased level of loose complexes between cathepsin B and some proteins or polypeptides in SQCLC compared to the lung.
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PMID:Multiple forms of cathepsin B in human lung cancer. 770 33

Cysteine proteinases, in particular cathepsins B and L, have been implicated in tumor invasion and are thought to be important mediators of metastasis. Using two clonal sublines of the Lewis lung carcinoma with distinct patterns of metastasis, we previously reported that H-59 carcinoma cells, which are highly invasive and preferentially metastatic to the liver, express high levels of cathepsin L and lower levels of cathepsin B whereas M-27 cells which are less invasive and only moderately metastatic to the lung express cathepsin B only. In the present study, the role of these enzymes in invasion and metastasis, in particular the involvement of cysteine proteinases in liver metastasis of H-59 cells was further investigated. Using a reconstituted basement membrane (Matrigel) invasion assay we found that the cysteine proteinase inhibitor, E-64, blocked the invasion of H-59 cells under conditions which did not affect cell viability. A more minor but significant inhibitory effect (up to 32%) was also seen with the propeptide of cathepsin B, implicating this enzyme in the invasion process. Furthermore, treatment of H-59 cells with E-64 inhibited experimental liver metastases formation by up to 90%. On the other hand, invasion of M-27 cells could not be blocked by cysteine proteinase inhibitors even under conditions which resulted in complete abrogation of intracellular enzymatic activity, as assessed using synthetic substrates. Together, these results confirm our previous conclusion that the two carcinoma sublines utilize distinct proteolytic mechanisms for invasion and identify the cysteine proteinases as key mediators of H-59 carcinoma invasion and metastasis.
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PMID:Inhibition of carcinoma cell invasion and liver metastases formation by the cysteine proteinase inhibitor E-64. 906 88

Cathepsin B and in particular cell-surface and secreted cathepsin B has been implicated in the invasive and metastatic phenotype of numerous types of cancer. We describe here a method to easily survey cancer cell lines for cathepsin B activity using the highly selective substrate Z-Arg-Arg-AMC. Intact human U87 glioma cells hydrolyze Z-Arg-Arg-AMC with a Km of 460 microM at pH 7.0 and 37 degrees C. This is nearly the same as the Km of 430 microM obtained with purified cathepsin B assayed under the same conditions. The pericellular (i.e. both cell-surface and released) cathepsin B activity was inhibited by the cysteine protease inhibitors E-64, leupeptin, Mu-Np2-HphVS-2Np, Mu-Leu-HpHVSPh and the cathepsin B selective inhibitor Mu-Tyr(3,5 I2)-HphVSPh with IC50 values similar to those observed for the inhibition of purified human liver cathepsin B. Other human cancer cell lines with measurable pericellular cathepsin B activity included HT-1080 fibrosarcoma, MiaPaCa pancreatic, PC-3 prostate and HCT-116 colon. Cathepsin B activity correlated with protein levels of cathepsin B as determined by immunoblot analysis. Pericellular cathepsin B activity was also detected in the rat cell lines MatLyLu prostate and Mat B III adenocarcinoma and in the murine lines B16a melanoma and Lewis lung carcinoma. The ability to determine pericellular cathepsin B activity will be useful in selecting appropriate cell lines for use in vivo when analyzing the effects of inhibiting cathepsin B activity on tumor growth and metastasis.
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PMID:Fluorescent microplate assay for cancer cell-associated cathepsin B. 1086 20

The receptor for the type 1 insulin-like growth factor (IGF-I) has been implicated in cellular transformation and the acquisition of an invasive/metastatic phenotype in various tumors. Following ligand binding, the IGF-I receptor is internalized, and the receptor.ligand complex dissociates as the ligand is degraded by endosomal proteinases. In the present study we show that the inhibition of endosomal IGF-I-degrading enzymes in human breast and murine lung carcinoma cells by the cysteine proteinase inhibitors, E-64 and CA074-methyl ester, profoundly altered receptor trafficking and signaling. In treated cells, intracellular ligand degradation was blocked, and although the receptor and two substrates, Shc and Insulin receptor substrate, were hyperphosphorylated on tyrosine, IGF-I-induced DNA synthesis, anchorage-independent growth, and matrix metalloproteinase synthesis were inhibited. The results suggest that ligand processing by endosomal proteinases is a key step in receptor signaling and function and a potential target for therapy.
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PMID:Inhibition of endosomal insulin-like growth factor-I processing by cysteine proteinase inhibitors blocks receptor-mediated functions. 1127 93

Several molecules extracted from natural products exhibit different biological activities, such as ion channel modulation, activation of signaling pathways, and anti-inflammatory or antitumor activity. In this study, we tested the antitumor ability of natural compounds extracted from the Raputia praetermissa plant. Among the compounds tested, an alkaloid, here called compound S4 (4-Deoxyraputindole C), showed antitumor effects against human tumor lineages. Compound S4 was the most active against Raji, a lymphoma lineage, promoting cell death with characteristics that including membrane permeabilization, dissipation of the mitochondrial potential, increased superoxide production, and lysosomal membrane permeabilization. The use of cell death inhibitors such as Z-VAD-FMK (caspase inhibitor), necrostatin-1 (receptor-interacting serine/threonine-protein kinase 1 inhibitor), E-64 (cysteine peptidases inhibitor), and N-acetyl- L-cysteine (antioxidant) did not decrease compound S4-dependent cell death. Additionally, we tested the effect of cellular activity on adherent human tumor cells. The highest reduction of cellular activity was observed in A549 cells, a lung carcinoma lineage. In this lineage, the effect on the reduction of the cellular activity was due to cell cycle arrest, without plasma membrane permeabilization, loss of the mitochondrial potential or lysosomal membrane permeabilization. Compound S4 was able to inhibit cathepsin B and L by a nonlinear competitive (negative co-operativity) and simple-linear competitive inhibitions, respectively. The potency of inhibition was higher against cathepsin L. Compound S4 promoted cell cycle arrest at G 0 and G 2 phase, and increase the expression of p16 and p21 proteins. In conclusion, compound S4 is an interesting molecule against cancer, promoting cell death in the human lymphoma lineage Raji and cell cycle arrest in the human lung carcinoma lineage A549.
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PMID:4-Deoxyraputindole C induces cell death and cell cycle arrest in tumor cell lines. 3052 30