Disease relevance of 2-(2-diethylaminoethoxy)-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-one

• Consistent with a late endocytic protein trafficking defect, the hydrophobic amine U18666A retained NPC1 in abnormally tubulated, cholesterol-poor, Tangier disease late endosomes, rather than cholesterol-laden lysosomes, as in wild type fibroblasts [1].
• Direct perturbation of lens membrane structure may contribute to cataracts caused by U18666A, an oxidosqualene cyclase inhibitor [2].
• To evaluate whether DHCR24 acts as an antiapoptotic factor in melanoma metastases, the cytotoxic effect of chemotherapeutic agents was tested in DHCR24 transfectants and in the presence of a DHCR24 inhibitor, U18666A [3].
• The hypocholesterolemic agent 3 beta-(2-diethylaminoethoxy)androst-5-en-17-one . HCl (U18666A) is known to induce experimental epilepsy [4].
• Cellular mechanism of U18666A-mediated apoptosis in cultured murine cortical neurons: Bridging Niemann-Pick disease type C and Alzheimer's disease [5].

High impact information on 2-(2-diethylaminoethoxy)-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-one

• NPC1 levels in cultured fibroblasts were unchanged by incubation with low density lipoproteins or oxysterols but were increased 2- to 3-fold by the drugs progesterone and U-18666A, which block cholesterol transport out of lysosomes, and by the lysosomotropic agent NH4Cl [6].
• U18666A induced the formation of late endosome-lysosome hybrid organelles, with GFP-ATP7B localized with NPC1 in these structures [7].
• U18666A, which induces the NPC phenotype, was used to modulate the intracellular vesicle traffic [7].
• In cultured cells, BACE and PLSCR1 were colocalized in the Golgi area and in endosomal compartments, whereas they were co-redistributed in late endosome-derived multivesicular bodies when treated with U18666A, suggesting that both proteins share a common trafficking pathway in cells [8].
• C(2)-ceramide abrogated the effect of U18666A on SRE-mediated gene transcription, suggesting cholesterol-independent regulation of SREBP [9].

Chemical compound and disease context of 2-(2-diethylaminoethoxy)-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-one

• When NO-catalyzed degradation of HS was depressed in mouse neuroblastoma cell line (N2a) by using 3-beta[2(diethylamino) ethoxy]androst-5-en-17-one (U18666A), both ascorbate and dehydroascorbic acid restored formation of anMan-positive products that colocalized with Rab7 [10].
• Lenses from rats treated with U18666A at a level known to produce cataracts were of smaller size and accumulated total sterol at about one-half the rate of untreated controls [11].
• However, additions of 10 and 25microM pravastatin with 0.5microg/ml U18666A significantly attenuated toxicity [12].

Biological context of 2-(2-diethylaminoethoxy)-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-one

• LDL binding, internalization, and lysosomal hydrolysis of LDL-cholesteryl esters are not affected by the presence of U18666A [13].
• By selecting for cell growth in the presence of U18666A, we have identified a CHO cell line, designated U18R, that is resistant to U18666A-inhibition of LDL-derived cholesterol trafficking [14].
• However, the mechanisms involved in U18666A-mediated apoptosis remain unknown [15].
• Chronic exposure to U18666A is associated with oxidative stress in cultured murine cortical neurons [16].
• The microarray approach was used in conjunction with proteomics techniques to identify specific proteins which may serve as signature biomarkers during U18666A treatment [15].

Anatomical context of 2-(2-diethylaminoethoxy)-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-one

• Importantly, the FC-induced decrease in ABCA1 function and protein was almost entirely prevented in macrophages that had partial deficiency of npc1 or were exposed to nanomolar concentrations of U18666A, both of which lead to defective cholesterol trafficking to the endoplasmic reticulum, but leave trafficking to the plasma membrane largely intact [17].
• This translocation/recruitment correlates with an increased membrane binding affinity of GST-annexin 6 to late endosomes of U18666A-treated cells in vitro [18].
• In addition, U18666A impedes the ability of LDL-derived cholesterol to support the growth of CHO cells [13].
• When cells are treated with U18666A, a drug that mimics the Niemann-Pick type C syndrome, both proteins accumulate in late endosomes and fail to reach Weibel-Palade bodies efficiently, suggesting that P-selectin, like CD63/lamp3, cycles via late endosomes [19].
• A hydrophobic amine, U18666A, causes cholesterol accumulation in LBPA+ late endosomes in osteoclasts [20].

Associations of 2-(2-diethylaminoethoxy)-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-one with other chemical compounds

• Addition of an intracellular cholesterol transport inhibitor, either progesterone or U18666A, together with CP-113,818 blocked the toxic effect of CP-113,818 [21].
• Exposure of C-6 glial cells to nanomolar quantities of U18666A caused a marked inhibition of total sterol synthesis from [14C]acetate or [3H]mevalonate within minutes [22].
• Treatment of rat intestinal epithelial cell cultures with the oxidosqualene cyclase inhibitor, 3 beta-[2-(diethylamino)-ethoxy]androst-5-en-17-one (U18666A), resulted in an accumulation of squalene 2,3:22,23-dioxide (SDO) [23].
• It showed a characteristic pattern of inhibition on exposure to trans-2-[4-(1,2-diphenylbuten-1-yl)phenoxy]-N,N-dimethylethylamine (tamoxifen; IC(50)=11.2 microM) and 3beta-[2-(diethylamino)ethoxy]androst-5-en-17-one (U18666A; IC(50)=4.2 microM), two well known potent inhibitors of SI [24].
• In view of this finding and the fact that U18666A and other OSC inhibitors are highly lipophilic cationic tertiary amines, we tested the hypothesis that the cataractogenic effect of U18666A is related to direct perturbation of lens membrane structure and function [2].

Gene context of 2-(2-diethylaminoethoxy)-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-one

• Addition of progesterone or U18666A to CHO cells elevated ABCA2 expression [25].
• Agents that specifically blocked sphingomyelinase-mediated delivery of cholesterol to acyl-CoA:cholesterol acyltransferase (U18666A) or promoted cholesterol efflux to the medium (cyclodextrin) did not inhibit OSBP dephosphorylation [26].
• Accumulation of tyrosinase in the endolysosomal compartment is induced by U18666A [27].
• Specific targeting of cathepsin K and the vacuolar H+-ATPase at the ruffled border is blocked by U18666A [20].
• In this model organism, the drug U18666A was shown to stimulate intra-endosomal budding, while an inhibitor of PI 3-kinase activity was found to have no effect on this process [28].

Analytical, diagnostic and therapeutic context of 2-(2-diethylaminoethoxy)-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-one

• The effects of U18666A on ruffled border formation were observed by electron microscopy [20].
• In U18666A-treated animals, 91% of rats developed EEG spike-waves (SWs) [29].
• Proteolytic modifications of specific water soluble lens crystallins during U18666A cataract formation in young rats were identified by two dimensional gel electrophoresis and contrasted with those produced by incubating control lens homogenates with calcium [30].

References