Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The antimetastatic activity of adriamycin in combination with proteinase inhibitors was investigated in mice bearing the metastatic tumors L1210 leukemia, Lewis lung carcinoma or M5076 sarcoma. Leupeptin, a cathepsin B inhibitor, when administered as a single agent was devoid of antimetastatic activity but some therapeutic activity was noted in mice with Lewis lung carcinoma when the agent was administered in combination with adriamycin. Pepstatin A, a cathepsin D inhibitor, had no effect as a single agent in mice with L1210 leukemia but displayed some antimetastatic activity in mice with Lewis lung carcinoma. In mice with M5076 sarcoma the combination of pepstatin A and adriamycin resulted in antimetastatic activity significantly greater than that observed with each agent alone. These results suggest that combinations of proteinase inhibitors with antitumor drugs such as adriamycin, might result in more effective antimetastatic treatment.
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PMID:Antimetastatic activity of adriamycin in combinations with proteinase inhibitors in mice. 233 38

The cellular levels of cathepsin B-like cysteine proteinases have been determined in a panel of transplantable mouse leukemias possessing a different potential to metastatize to the liver after i.p. implantation. The higher enzymatic activity observed in L1210 leukemic cells matches their higher capacity for hepatic infiltration. No significant difference is observed for TLX5 lymphoma and P388 leukemia, in spite of their different liver invasiveness, and their enzymatic levels do not significantly differ from that of the non-invasive Ehrlich ascitic carcinoma. The in vivo administration of the antimetastatic drugs ICRF159 and DM-COOK, or of the cytotoxic drugs cyclophosphamide, cisplatin, CCNU and GANU, does not cause a pattern of enzyme inhibition matching the tumor metastatic potential and the increase in life-span of the treated tumor bearing mice, indicating that the inhibition of cathepsin B-like cysteine proteinase is not involved in either their cytotoxic or their antimetastatic action.
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PMID:Activity and inhibition by cytotoxic and antimetastatic drugs of cathepsin B-like cysteine proteinase in transplantable leukemias in mice. 330 99

Three distinct lysosomal protease activities have been identified in the human leukemia cell line, K562. These include cathepsin D, the classic protease of the mature red blood cell, as well as two proteases, cathepsins B and H, which have been associated with development and differentiation in a variety of tissues. Each of these three lysosomal proteases was expressed in a specific fashion during hemoglobin induction in K562 cells. Both cathepsin B and cathepsin D activities could be induced by growth of K562 cells in medium containing either hemin or heat-treated serum or by increasing the concentrations of untreated serum in the medium. Cathepsin H activity in the same cells remained unchanged. This is the first report of inducible protease activities in K562 cells. Our identification of specific well-characterized protease activities that change differentially during K562 induction provides a framework for additional studies on the role of proteases in hematopoietic differentiation.
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PMID:Expression and induction of cathepsins B and D in K562 cells. 333 32

A lysosomal pathway, characterized by partial rupture of lysosomal membranes and cathepsin B activation, is activated during camptothecin (CPT)-induced apoptosis in U937 and Namalwa cancer cells. These lysosomal events occur simultaneously with mitochondrial permeabilization and caspase activation. In U937 cells, blocking mitochondrial permeability transition pore with cyclosporin A and bongkrekic acid reduces mitochondrial and lysosomal rupture, suggesting that lysosomal rupture may be dependent, in part, on mitochondrial disruption. Overexpressing bcl-xL, an antiapoptotic protein known to preserve mitochondrial functions, also impedes lysosomal and mitochondrial disruption in both cell lines, indicating signaling between the two organelles. In addition, no evidence was obtained of bcl-2-like proteins targeting lysosomes. Caspase activities, including caspase-2L, are required for lysosomal and mitochondrial disruption, and lysosomal cathepsin B slightly participates in apoptosis propagation after CPT, although not essential for apoptosis activation. Our study provides evidence for the participation of a lysosomal pathway during DNA damage-induced cell death. Our data suggest that caspase activation and mitochondrial disruption represent cell-context-specific mechanisms by which DNA damage leads to lysosomal rupture, and that lysosomal cathepsins could slightly participate in apoptosis propagation after CPT.
Leukemia 2005 May
PMID:Caspase- and mitochondrial dysfunction-dependent mechanisms of lysosomal leakage and cathepsin B activation in DNA damage-induced apoptosis. 1575 29

The cell death mechanism of cytotoxicity induced by the Biphosphinic Palladacycle Complex (BPC) was studied using a K562 leukaemia cell line. The IC50 values obtained for K562 cells post-72 h of BPC were less than 5.0 microM by using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) and trypan blue assays. Using the Acridine Orange vital staining combining fluorescence microscopy it was observed that the complex triggers apoptosis in K562 cells, inducing DNA fragmentation, as analysed through electrophoresis. Lysosomal-membrane permeabilization was also observed in K562 cells post-5 h of BPC, which suggests intralysosomal accumulation by proton-trapping, since its pKa value ranged from 5.1 to 6.5. Caspase-3, and -6 activity induced by BPC in K562 cells was prevented by the cathepsin-B inhibitor [N-(L-3-trans-propylcarbamoyl-oxirane-2-carbonyl)-L-isoleucyl-L-proline] (CA074). These events occurred in the presence of endogenous bcl-2 and bax expression. Acute toxicological studies demonstrated that BPC produces no lesions for liver and kidney fourteen-days after drug administration (100 mg/kg--i.p.). White and red blood cells of BPC-treated mice presented normal morphological characteristics. Taken together, these data suggest a novel lysosomal pathway for BPC-induced apoptosis, in which lysosomes are the primary target and cathepsin B acts as death mediator.
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PMID:Biphosphinic palladacycle complex mediates lysosomal-membrane permeabilization and cell death in K562 leukaemia cells. 1683 19

Calpain is a cytosolic cysteine endopeptidase that has been implicated in a number of disorders including cancer. We have synthesized and studied the mu-calpain inhibitory activity and cytotoxicity of peptidyl aldehydes and peptidyl alpha-ketoamides with N-substituted D-proline or L-thiaproline residues at the P2-postion. The most potent and most selective members of the series were (R)-1-(4-nitrophenylsulfonyl)-N-((R,S)-1-oxo-3-phenylpropan-2-yl)pyrrolidine-2-carboxamide (1j) and (R)-1-(4-iodophenylsulfonyl)-N-((R,S)-1-oxo-3-phenylpropan-2-yl)pyrrolidine-2-carboxamide (1n). The compounds inhibited mu-calpain with Ki values of 0.02 microM and 0.03 microM, respectively, and displayed over 180-fold (1j) and 130-fold (1n) greater affinity for mu-calpain compared to cathepsin B. The cytotoxic effect of the compounds was evaluated in two leukemia cell lines (Daudi and Jurkat) and three solid tumor cell lines (DU-145, PC-3, and HeLa). Generally the compounds were modestly cytotoxic and displayed no correlation between the cytotoxic activity and mu-calpain inhibition.
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PMID:Synthesis, calpain inhibitory activity, and cytotoxicity of P2-substituted proline and thiaproline peptidyl aldehydes and peptidyl alpha-ketoamides. 1691 17

In recent years the use of the microarray technology has allowed the identification of numerous cancer-related genes and proteins. Today anticancer drug discovery is mainly target driven, which requires the characterization of molecular targets in existing cell lines or xenograft models. However, this analysis is time consuming and labor intensive. In order to ease this bottleneck, we have established tissue microarrays of 41 human tumor cell lines on glass slides. The purpose of our study was to (a) establish a simple and efficient method for cell line microarray construction, (b) apply the resulting array to the profiling of cathepsin B and transferrin receptor by immunohistochemistry and (c) verify the results in separate Western blot analyses. Ten to twenty million (1-2 x 10(7)) cells were harvested without trypsinization and fixed with Bouin's solution containing 8% formalin. Cell pellets 2-5 mm in diameter were embedded in paraffin. Microarrays were assembled using a tissue arrayer. Pellet biopsies 0.6 cm in diameter were taken and arrayed in duplicate in a new recipient paraffin block. About 60 slides can be obtained from one block. Citrate buffer was used for antigen retrieval. Expression of cathepsin B was granular and located in the cytoplasm. High cathepsin B levels were detected in 2 melanomas (MEXF 514L and MEXF 276L) and in the renal cell line RXF 486L. Twenty-five cell lines showed only minimal positivity. Nine cell lines of leukemia and lymphoma, breast, ovarian, prostate and renal cancer origin were positive for the transferrin receptor, while 32 cell lines were negative. Western blotting confirmed the results obtained by immunohistochemistry. Using these cell line microarrays, cell lines overexpressing a target of interest can be selected for in vitro evaluation of specific inhibitors.
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PMID:Microarrays of 41 human tumor cell lines for the characterization of new molecular targets: expression patterns of cathepsin B and the transferrin receptor. 1734 87

The roles of cellular proteases in Moloney murine leukemia virus (MLV) infection were investigated using MLV particles pseudotyped with vesicular stomatitis virus (VSV) G glycoprotein as a control for effects on core MLV particles versus effects specific to Moloney MLV envelope protein (Env). The broad-spectrum inhibitors cathepsin inhibitor III and E-64d gave comparable dose-dependent inhibition of Moloney MLV Env and VSV G pseudotypes, suggesting that the decrease did not involve the envelope protein. Whereas, CA-074 Me gave a biphasic response that differentiated between Moloney MLV Env and VSV G at low concentrations, at which the drug is highly selective for cathepsin B, but was similar for both glycoproteins at higher concentrations, at which CA-074 Me inhibits other cathepsins. Moloney MLV infection was lower on cathepsin B knockout fibroblasts than wild-type cells, whereas VSV G infection was not reduced on the B-/- cells. Taken together, these results support the notion that cathepsin B acts at an envelope-dependent step while another cathepsin acts at an envelope-independent step, such as uncoating or viral-DNA synthesis. Virus binding was not affected by CA-074 Me, whereas syncytium induction was inhibited in a dose-dependent manner, consistent with cathepsin B involvement in membrane fusion. Western blot analysis revealed specific cathepsin B cleavage of SU in vitro, while TM and CA remained intact. Infection could be enhanced by preincubation of Moloney MLV with cathepsin B, consistent with SU cleavage potentiating infection. These data suggested that during infection of NIH 3T3 cells, endocytosis brings Moloney MLV to early lysosomes, where the virus encounters cellular proteases, including cathepsin B, that cleave SU.
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PMID:Host cell cathepsins potentiate Moloney murine leukemia virus infection. 1763 28

Organotellurium(IV) compounds have been reported to have multiple biological activities including cysteine protease-inhibitory activity, mainly cathepsin B. As cathepsin B is a highly predictive indicator for prognosis and diagnosis of cancer, a possible antitumor potential for these new compounds is expected. In this work, it was investigated the effectiveness of organotellurium(IV) RT-04 to produce lethal effects in the human promyelocytic leukaemia cell line HL60. Using the MTT tetrazolium reduction test, and trypan blue exclusion assay, the IC50 for the compound after 24 h incubation was 6.8 and 0.35 microM, respectively. Moreover, the compound was found to trigger apoptosis in HL60 cells, inducing DNA fragmentation and caspase-3, -6, and -9 activations. The apoptsosis-induced by RT-04 is probably related to the diminished Bcl-2 expression, observed by RT-PCR, in HL60-treated cells. In vivo studies demonstrated that the RT-04 treatment (2.76 mg/kg given for three consecutive days) produces no significant toxic effects for bone marrow and spleen CFU-GM. However, higher doses (5.0 and 10 mg/kg) produced a dose-dependent reduction in the number of CFU-GM of RT-04-treated mice. These results suggest that RT-04 is able to induce apoptosis in HL60 cells by Bcl-2 expression down-modulation. Further studies are necessary to better clarify the effects of this compound on bone marrow normal cells.
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PMID:Bcl-2 expression and apoptosis induction in human HL60 leukaemic cells treated with a novel organotellurium(IV) compound RT-04. 1849 15

The poor prognosis of pancreatic cancer and poor sensitivity to current therapeutics, associated with resistance to apoptosis, urge the search for new drugs. We previously described the induction of caspase-independent mithochondrial death in leukemia cells by Bobel-24 (AM-24) and derivatives. Here, we explored whether these compounds induce a similar cytotoxicity in human pancreatic carcinoma cell lines (NP18, NP9, NP31, and NP29). Bobel-24 or Bobel-16 induced cytotoxicity and DNA synthesis inhibition in all cell lines and apoptosis in all lines, except for NP9. Caspase and/or poly(ADP-ribose) polymerase-1 (PARP-1) activity inhibition experiments showed that cytotoxicity was mainly induced through apoptosis in NP18 and through a caspase-independent process in NP9. Moreover, in NP29 or NP31 cell lines, both caspase-dependent and caspase-independent cell death mechanisms coexisted. Cell death was associated with reactive oxygen species (ROS) production, mitochondrial depolarization, cytochrome c and apoptosis-inducing factor (AIF) release, AIF nuclear translocation, and lysosomal cathepsin release. Inhibition of ROS production, mitochondrial pore permeability, PARP-1, or phospholipase A2 partially prevented cell death. Moreover, cathepsin B inhibition or down-regulation by small interfering RNA partially blocked cell death. In conclusion, Bobel-24 and derivatives trigger caspase-independent lysosomal and mitochondrial death in all tested human pancreatic cancer lines, irrespective of their degree of apoptotic sensitivity, becoming the only active cytotoxic mechanism in the apoptosis-resistant NP9 line. This mechanism may overcome the resistance to apoptosis observed in pancreatic carcinoma when treated with current genotoxic drugs.
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PMID:Bobel-24 and derivatives induce caspase-independent death in pancreatic cancer regardless of apoptotic resistance. 1867 56


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