Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of chlorpromazine (CPZ) and mepacrine on hypoxic liver cell damage was studied using an isolated perfused cat liver preparation. High concentrations of CPZ (10(-4) M) significantly augmented the hypoxic leakage of the lysosomal enzyme, cathepsin D, and the cytoplasmic enzyme, lactate dehydrogenase (LDH) into the perfusate. The per cent free cathepsin D activity of hepatic tissue was significantly higher in the 10(-4) M CPZ treated groups (87%) than in the vehicle group (65%). CPZ at a concentration of 10(-6) M also possessed a detrimental effect on hypoxic liver integrity but to a lesser extent compared to 10(-4) M. In contrast, low concentrations of CPZ (10(-7) M) showed a protective effect during hypoxia (i.e., significantly lower perfusate cathepsin D activity and per cent free cathepsin D activity) compared to livers receiving only the vehicle. Mepacrine, another phospholipase A2 inhibitor, showed no significant effect on hypoxic liver damage at concentration of 10(-6) and 5 x 10(-5) M. CPZ has a biphasic action on liver integrity during hypoxia, low concentrations being protective and high concentrations are deleterious. Mepacrine had no significant effect in the hypoxic liver.
 ...
PMID:Biphasic actions of chlorpromazine and mepacrine on modulation of hepatic cell injury in the perfused cat liver. 722 15

Glioblastoma (GBM) is a high-grade central nervous system malignancy and despite aggressive treatment strategies, GBM patients have a median survival time of just 1 year. Chloroquine (CQ), an antimalarial lysosomotropic agent, has been identified as a potential adjuvant in the treatment regimen of GBMs. However, the mechanism of CQ-induced tumor cell death is poorly defined. We and others have shown that CQ-mediated cell death may be p53-dependent and at least in part due to the intrinsic apoptotic death pathway. Here, we investigated the effects of CQ on 5 established human GBM lines, differing in their p53 gene status. CQ was found to induce a concentration-dependent death in each of these cell lines. Although CQ treatment increased caspase-3-like enzymatic activity in all 5 cell lines, a broad-spectrum caspase inhibitor did not significantly attenuate death. Moreover, CQ caused an accumulation of autophagic vacuoles in all cell lines and was found to affect the levels and subcellular distribution of cathepsin D, suggesting that altered lysosomal function may also play a role in CQ-induced cell death. Thus, CQ can induce p53-independent death in gliomas that do not require caspase-mediated apoptosis. To potentially identify more potent chemotherapeutics, various CQ derivatives and lysosomotropic compounds were tested on the GBM cells. Quinacrine and mefloquine were found to be more potent than CQ in killing GBM cells in vitro and given their superior blood-brain barrier penetration compared with CQ may prove more efficacious as chemotherapeutic agents for GBM patients.
 ...
PMID:Chloroquine-induced autophagic vacuole accumulation and cell death in glioma cells is p53 independent. 2040 98