Disease relevance of Bestatin

• We observed significant therapeutic activity against preexisting experimental and spontaneous metastases when bestatin was administered at high doses per animal for 4 weeks [1].
• The aminopeptidase inhibitor Bestatin [2S,3R-(3-amino-2-hydroxy-4-phenylbutanoyl)-L-leucine] was tested for both in vitro and in vivo macrophage activation and antitumor activity in various experimental tumor systems including the metastasizing ESb lymphoma system [2].
• Cultures of resting macrophages were rendered nonspecifically tumoricidal for the two lymphoma sublines ESb and 721 (ESb-Cl 18.1), for the mastocytoma P815X, for LS lymphoma cells, and for proliferating lymphoblasts from DBA/2, C57BL/6J, and CBA mice by exposure to Bestatin at 50 micrograms/ml culture medium [2].
• Bestatin reversibly inhibits Aeromonas aminopeptidase (EC 3.4.11.10) in a process that is remarkable for its unusual degree of time dependence [3].
• Inhibition by bestatin of a mouse ascites tumor dipeptidase. Reversal by certain substrates [4].

Psychiatry related information on Bestatin

• As bestatin has no direct antibiotic effect on S. typhimurium, it must be concluded that the therapeutic effects of the drug on chronic infection must be solely contributed to elevation of the host's own defense mechanisms [5].
• The effect of the inhibition of aminopeptidase and enkephalinase A on the pain threshold of mice and rats was investigated, using bestatin and thiorphan as selective peptidase inhibitors [6].
• The present study assesses the ability of bestatin to reduce chronic alcohol consumption in the genetically selected high alcohol-consuming P rats [7].
• In addition, the novel finding of a carry-over inhibition of alcohol intake in the bestatin-free period adds further impetus to the recommendation that this drug, which has been safely used in humans, might be examined as a possible therapeutic agent for alcohol abuse [8].
• Potentiation of phencyclidine-induced stereotyped behaviors in rats by thiorphan and bestatin [9].

High impact information on Bestatin

• The combination of endothelial IL-8 and bestatin induce leukemic cells expressing high levels of CD13/aminopeptidase N to undergo apoptosis [10].
• Bestatin treatment increased the level of IL-8 mRNA in and the amount of IL-8 secreted by vascular endothelial cells [10].
• Furthermore, both enzyme inactivation and peptide modification could be prevented by preincubation of LTA4 hydrolase with the competitive inhibitor bestatin, which demonstrates that the henicosapeptide contains functional elements of the active site(s) [11].
• Leucine aminopeptidase: bestatin inhibition and a model for enzyme-catalyzed peptide hydrolysis [12].
• The mode of binding of bestatin to leucine aminopeptidase may be similar to that of a tetrahedral intermediate that is thought to form during peptide bond hydrolysis [12].

Chemical compound and disease context of Bestatin

• The binding of bestatin by both Aeromonas aminopeptidase and cytosolic leucine aminopeptidase (EC 3.4.11.1) is slow and tight, with Ki values (determined from rate constants) of 1.8 X 10(-8) and 5.8 X 10(-10) M, respectively [3].
• These data, and interactions with pepstatin-A, E-64, and bestatin, suggest that human immunodeficiency virus protease inhibitors do not target digestive-vacuole plasmepsins [13].
• The antitumor effect of bleomycin combined with bestatin against Ehrlich ascites carcinoma in mice [14].
• Biological response modifiers (BRM's): levamisole, BCG, bestatin did not improve these results in the doses used in the experiment [15].
• The present findings suggest that bestatin (Ubenimex) might also be useful in the treatment of alcohol abuse in humans [7].

Biological context of Bestatin

• K562/CD13 cells cocultured with vascular endothelial cells did not undergo apoptosis, but the addition of bestatin resulted in the induction of apoptosis in K562/CD13 cells (2.70-fold difference [95% CI = 1.77-fold to 3.63-fold], P<.001) [10].
• In the presence of bestatin (0.5 mg/ml), one-fourth of these products appeared to be dipeptides, tripeptides, or both: they were resistant to ninhydrin at acid pH (a treatment that decarboxylates only free amino acids) except after intensive acid hydrolysis, and they eluted from a Sephadex G-10 column with an apparent average size of 300 daltons [16].
• Hydrogen bonds involving active site residues Lys-262, Asp-273, Gly-360, and Leu-362 are responsible for stabilizing the backbone nitrogen and oxygen atoms of bestatin [12].
• The macrophage activation to lyse tumor cells was sharply dependent on the Bestatin dose and appeared about 24 hr after injection of the dipeptide [2].
• Hydrolysis of the amide bond of arginyl-p-nitroanilide was inhibited by bestatin with an IC50 of 2.6 +/- 1.2 microM [17].

Anatomical context of Bestatin

• Degradation of abnormal proteins in intact mouse reticulocytes: accumulation of intermediates in the presence of bestatin [16].
• Bestatin also had T-cell adjuvant activity when it was admixed with a suboptimal vaccine composed of irradiated tumor cells [1].
• Bestatin activates macrophages through a T-cell-independent process to lyse tumor target cells, inasmuch as macrophages from homozygous athymic nude (nu/nu) mice treated i.p. with the dipeptide were also stimulated and cytotoxic for tumor cells [2].
• We present evidence that the macrophage is the prominent host cell responsible for tumor cell destruction in animals treated with Bestatin and rule out the possibility that natural killer cells play a major role in the experiments described [2].
• Ability of the immunomodulating dipeptide bestatin to activate cytotoxic mononuclear phagocytes [2].

Associations of Bestatin with other chemical compounds

• Uptake was pH dependent and inhibited by several di/tripeptides and bestatin, but it remained unaffected by glycine and tetraglycine [18].
• NAALA dipeptidase activity was also sensitive to the aminopeptidase inhibitors bestatin and puromycin, although not to the selective aminopeptidase A inhibitor amastatin [19].
• EDTA or EGTA and bestatin separately inhibited the receptor down-regulation by 98%, indicating the involvement of metalloprotease(s), more specifically an aminopeptidase in the process [20].
• In the presence of bacitracin and bestatin, the amounts of glucagon-(19-29) obtained from glucagon increased continuously, 1 and 2% of glucagon being transformed after 10 and 30 min, respectively [21].
• In agreement with kinetic data, electrospray ionization mass spectrometry shows that bestatin inhibits the covalent modification of enzyme by LTA4 and that the extent of modification is proportional to the loss of enzymatic activity [22].

Gene context of Bestatin

• Among the herein described and evaluated compounds, the 2',3-dinitroflavone-8-acetic acid (19b) proved to be the most efficient and exhibited an IC(50) of 25 microM which is 2.5 times higher than that of bestatin (1), the natural known inhibitor of APN/CD13 [23].
• To further examine the role of LTB4 in oral carcinogenesis, two LTA4H inhibitors, bestatin and SA6541, were evaluated in a long-term chemoprevention experiment [24].
• The behavioural response to SP was significantly increased by 2.0 nmol of bestatin, an aminopeptidase inhibitor, but not by 1.0 nmol [25].
• Verapamil significantly increased the inhibitory activity of bestatin on K562 cells, indicating that the intracellular concentration of bestatin can be mediated also by P-glycoprotein [26].
• When phosphoramidon was injected together with bestatin and captopril which have no significant effect alone, SP- or NK A-induced behavioral response was significantly increased [25].

Analytical, diagnostic and therapeutic context of Bestatin

• When titrated with bestatin, 1 mol of cytosolic leucine aminopeptidase (containing 6 g atoms each of zinc and manganese) is rendered 80% inactive by 1 mol of inhibitor, thus suggesting that enzymatic activity depends on one active site/hexamer; titration of Aeromonas aminopeptidase by bestatin reveals a 1:1 stoichiometry [3].
• Third, microarray analysis using Arabidopsis whole-genome chip demonstrates that the gene expression profile of bestatin-treated plants is similar to that of JA-treated plants [27].
• Several aminopeptidase (Ap) activities were defined by (1) substrate specificity with leucine-enkephalin (leu-Ap) and alanine-nitroanilide (ala-Ap), (2) inhibitor studies with puromycin and bestatin, (3) enzyme activity histochemistry (zymography), (4) immunohistochemistry, and (5) gel electrophoresis [28].
• Crystallization and preliminary X-ray crystallographic studies of recombinant human leukotriene A4 hydrolase complexed with bestatin [29].
• In vivo, repeated oral administration of bestatin for 28 days suppressed the growth of HeLa-hPepT1 tumor specifically [30].

References