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

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

AML, the second most common childhood leukemia is also one of the deadliest cancers. High mortality rate in AML is due to high incidence of relapse after complete remission with chemotherapy and inadequate prognostic assessment of patients. Moreover, there is dearth of therapeutic targets for treatment of this malignancy. Previous pilot study (n = 24) by our group revealed strong association between cathepsin B (CTSB) overexpression in peripheral blood mononuclear cells (PBMCs) and poor survival outcome in pediatric AML patients. To further explore the clinical utility and role of this protease in pediatric AML, we measured its enzymatic activity and mRNA expression in PBMCs as well as bone marrow mononuclear cells (BMMCs) of patients (n = 101) and PBMCs of healthy controls. Our results revealed elevated CTSB activity (P < 0.01) and overexpression of its mRNA (P < 0.01) in AML patients. Interestingly CTSB in BMMCs of patients emerged as an independent prognostic marker when compared with other known risk factors. Moreover, chemical inhibition of CTSB activity compromised survival, and induced apoptosis in an AML cell line THP-1. We further demonstrate the inhibition of CTSB activity by chemotherapeutic agent doxorubicin in these cells. Docking and simulation studies suggested the binding of doxorubicin to CTSB with higher affinity than its known specific inhibitor CA-074 Me, thereby indicating that cell death induced by this drug may at least partly be mediated by CTSB inhibition. CTSB, therefore, may serve as a prognostic marker and an attractive chemotherapeutic target in pediatric AML.
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PMID:Prognostic and therapeutic relevance of cathepsin B in pediatric acute myeloid leukemia. 3191 51