Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Immunotoxins (ITs) containing plant or bacterial toxins have a dose-limiting toxicity of vascular leak syndrome (VLS) in humans. The active A chain of ricin toxin (RTA), other toxins, ribosome-inactivating proteins, and the VLS-inducing cytokine IL-2 contain the conserved sequence motif (x)D(y) where x = L, I, G, or V and y = V, L, or S. RTA-derived LDV-containing peptides attached to a monoclonal antibody, RFB4, induce endothelial cell (EC) damage in vitro and vascular leak in two animal models in vivo. We have now investigated the mechanism(s) by which this occurs and have found that (1) the exposed D75 in the LDV sequence in RTA and the C-terminal flanking threonine play critical roles in the ability of RFB4-conjugated RTA peptide to bind to and damage ECs and (2) the LDV sequence in RTA induces early manifestations of apoptosis in HUVECs by activating caspase-3. These data suggest that RTA-mediated inhibition of protein synthesis (due to its active site) and apoptosis (due to LDV) may be mediated by different portions of the RTA molecule. These results suggest that ITs prepared with RTA mutants containing alterations in LDVT may kill tumor cells in vivo in the absence of EC-mediated VLS.
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PMID:The effect of a monoclonal antibody coupled to ricin A chain-derived peptides on endothelial cells in vitro: insights into toxin-mediated vascular damage. 1089 93

This study was aimed at investigating and comparing the cytotoxicities of two structurally similar type I RIPs, namely trichosanthin (TCS) and free ricin A chain (RTA). A type II RIP, namely Ricinus communis agglutinin (RCA), was also included for comparison. The three RIPs were added separately to cultures of NIH 3T3 cells. The effective doses and time courses were analyzed using cell counts. Polyclonal antibodies against TCS and RTA were produced in rabbits and purified by a protein A-Sepharose CL-4B column. The mechanisms of cell death were determined by TUNEL, immunohistochemical staining, flow cytometry, and Western blotting. The effective doses for TCS, RTA and RCA were found to be 800, 50, and 50 nM, respectively. All three RIPs induced apoptosis. In all cases, activation of caspase-3 and caspase-8, but not caspase-9, was detected. Additionally, RTA caused in vivo tissue necrosis in rabbits after intradermal administration. Hence the mechanism of cell death due to RTA intoxication may vary depending on the experimental conditions, being necrosis in vivo and apoptosis in vitro. The present findings may shed light on the apoptotic pathway induced by RIPs. RTA may be useful for studying the shift in cell death.
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PMID:Different in vitro toxicities of structurally similar type I ribosome-inactivating proteins (RIPs). 2017 Jul 25

Primary effusion lymphoma (PEL) is a subtype of non-Hodgkin lymphoma associated with infection by Kaposi sarcoma-associated herpes virus (KSHV). PEL is an aggressive disease with extremely poor prognosis when treated with conventional chemotherapy. Narciclasine, a natural product present in Amaryllidaceae family of flowering plants including daffodils, belongs to a class of molecules termed 'isocarbostyril alkaloid'. We have found that narciclasine displays preferential cytotoxicity towards PEL at low nanomolar concentrations and is approximately 10 and 100-fold more potent than its structural analogs lycoricidine and lycorine, respectively. Narciclasine arrested cell-cycle progression at the G1 phase and induced apoptosis in PEL, which is accompanied by activation of caspase-3/7, cleavage of PARP and increase in the surface expression of Annexin-V. Although narciclasine treatment resulted in a marked decrease in the expression of MYC and its direct target genes,time-course experiments revealed that MYC is not a direct target of narciclasine. Narciclasine treatment neither induces the expression of KSHV-RTA/ORF50 nor the production of infectious KSHV virions in PEL. Finally, narciclasine provides dramatic survival advantages to mice in two distinct mouse xenograft models of PEL. In conclusion, our results suggest that narciclasine could be a promising agent for the treatment of PEL.
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PMID:Narciclasine, an isocarbostyril alkaloid, has preferential activity against primary effusion lymphoma. 3223 78