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

We investigated the growth inhibitory activity of bestatin, an inhibitor of aminopeptidase N (CD13), on six human leukemic cell lines. Proliferation of all the cell lines except KG1 was inhibited by bestatin. P39/TSU, HL60 and U937 were highly sensitive, with 50% growth inhibitory concentrations (IC50) close to the maximum serum concentration when bestatin was orally administered at 30 mg in clinical application. All cell lines except for K562 highly expressed CD13, but a clear correlation between the sensitivity to bestatin and expression of CD13 was not observed. Other aminopeptidase inhibitors such as amastatin A, arphamenine B and WM15 antibody showed no growth inhibitory effects. To confirm the growth inhibitory effects of bestatin, we quantitatively examined DNA fragmentation in five bestatin-sensitive cell lines. Bestatin dose-dependently induced DNA fragmentation in those cell lines. In case of U937, bestatin induced DNA fragmentation quantitatively and DNA ladder and enhanced caspase-3 activity. Furthermore, the growth inhibition by bestatin was reduced by the caspase inhibitor Z-Asp-CH2-DCB. These results suggested that bestatin exhibits direct antileukemic effects against human leukemic cell lines through the induction of apoptosis.
Leukemia 1999 May
PMID:Induction of apoptosis by bestatin (ubenimex) in human leukemic cell lines. 1037 77

We previously reported that the aminopeptidase inhibitor bestatin induced apoptosis in several human leukemia cell lines. The present study was performed to examine whether bestatin can also induce apoptosis in solid tumor cell lines. Bestatin alone exhibited neither direct growth inhibition nor induction of apoptosis in the tumor cell lines examined. However, it significantly augmented the growth-inhibitory effect and induction of apoptosis by agonistic anti-Fas antibody (CH11). The augmentation by bestatin was also observed with other death ligands including tumor necrosis factor-alpha (TNF-alpha) in EBC-1 cells, a cell line sensitive to these death ligands. However, the HeLa S3 cell line, which is insensitive to TNF-alpha, showed no growth inhibition even by combination treatment. Bestatin methyl ester, a more cell-permeable derivative of bestatin with similar inhibitory activity to cytosolic neutral aminopeptidase, potentiated cell growth inhibition of CH11 more efficiently than bestatin. Other cytosolic neutral aminopeptidase inhibitors such as actinonin and puromycin also augmented cell growth suppression by CH11, while an enantiomer of bestatin lacking aminopeptidase inhibitory action did not increase the growth-inhibitory effects of CH11. The combination of 10 microg/ml of bestatin with CH11 promoted processing of caspase 3 to the active form p17 and efflux of mitochondrial cytochrome c into the cytosol more quickly and more intensely than CH11 alone. Inhibition of aminopeptidase was not involved in dATP- and cytochrome c-dependent caspase 3-activation in a cell-free system. Bestatin significantly augmented activation of caspase 8, which is upstream of cytochrome c efflux in the apoptosis cascade. These results suggested that intracellular neutral aminopeptidase might play an important role in Fas- or TNF-alpha-induced solid tumor cell apoptosis.
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PMID:Augmentation of death ligand-induced apoptosis by aminopeptidase inhibitors in human solid tumor cell lines. 1174 33

All-trans retinoic acid (ATRA) induces the differentiation of acute promyelocytic leukemia (APL) cells into neutrophils. We found that bestatin, an inhibitor of CD13/aminopeptidase N, enhanced the sensitivity of APL NB4 cells to ATRA at concentrations of 0.1-1000ng/ml. A structurally different aminopeptidase N inhibitor, actinonin, also increased the effect of ATRA on differentiation, but an inactive stereoisomer of bestatin, (2R,3S)-AHPA-(R)-Leu, did not. Bestatin synergistically enhanced the cytostatic effect of ATRA on NB4 cells. Masking of the cell-surface CD13 by anti-CD13 antibody WM15 blocked the synergistic effect of bestatin and ATRA on differentiation. Thus bestatin, an immunomodulator clinically used for nonlymphocytic leukemia, synergistically increased the ATRA-induced differentiation of NB4 cells by inhibiting CD13/aminopeptidase N on the cell-surface.
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PMID:Enhancement of sensitivity by bestatin of acute promyelocytic leukemia NB4 cells to all-trans retinoic acid. 1244 82

Bestatin, a small molecular weight dipeptide, is a potent inhibitor of various aminopeptidases as well as LTA4 hydrolase. Various physiological functions of Bestatin have been identified, viz.: (1) an immunomodifier for enhancing the proliferation of normal human bone marrow granulocyte-macrophage progenitor cells to form CFU-GM colonies; Bestatin exerts a direct stimulating effect on lymphocytes via its fixation on the cell surface and an indirect effect on monocytes via aminopeptidase B inhibition of tuftsin catabolism; (2) an immunorestorator and curative or preventive agent for spontaneous tumor; Bestatin alone or its combination with chemicals can prolongate the disease-free interval and survival period in adult acute or chronic leukemia, therefore, it was primarily marketed in 1987 in Japan as an anticancer drug and servers as the only marketed inhibitor of Aminopeptidase N (APN/CD13) to cure leukemia to date; (3) a pan-hematopoietic stimulator and restorator; Bestatin promotes granulocytopoiesis and thrombocytopoiesis in vitro and restores them in myelo-hypoplastic men; (4) an inhibitor of several natural opioid peptides. Based on the knowledge that APN can cleave several bioactive neuropeptides such as Met-enkaphalins, Leu-enkaphalins, beta-Endorphin, and so on, the anti-aminopeptidase action of Bestatin also allows it to protect endopeptides against their catabolism, exhibiting analgesic activity. Although many scientific studies and great accomplishments have been achieved in this field, a large amount of problems are unsolved. This article reviews the promising results obtained for future development of the analgesic activity of Bestatin that can be of vital interest in a number of severe and chronic pain syndromes.
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PMID:The Analgesic Activity of Bestatin as a Potent APN Inhibitor. 2063 48

Bestatin has been known as an immunomodulating agent in anti-leukemia treatment. The mechanism by which Bestatin enhances all-trans retinoic acid (ATRA)-induced cell differentiation of acute promyelocytic leukemia (APL) cells is generally attributed to inhibition of cell surface CD13/aminopeptidase N activity. Bestatin also exerts its biological activities besides its ability to inhibit aminopeptidase N enzymatic activity. This article provides data to support an alternative mechanism regarding an important role of inhibition of p38 mitogen-activated protein kinase (MAPK) signal pathway in Bestatin's anti-leukemia effect. Bestatin enhanced ATRA-induced differentiation and inhibited ATRA-driven phosphorylation of p38 MAPK in ATRA-sensitive APL NB4 cells. In contrast, Bestatin could not reverse the differentiation block in ATRA-resistant APL MR2 cells, in which ATRA was unable to induce phosphorylation of p38 MAPK. Moreover, CD13 ligation with anti-CD13 antibody WM-15 resulted in phosphorylation of p38 MAPK, reduced the inhibition of Bestatin on the phosphorylation of p38 MAPK, and completely abolished the enhancement of Bestatin on ATRA-inducing differentiation in NB4 cells. This study shows that inhibition of p38 MAPK phosphorylation is critical for Bestatin to enhance ATRA-induced cell differentiation in ATRA-sensitive APL NB4 cells. Results suggested that pharmacological inhibition of the p38 MAPK pathway might enhance ATRA-dependent differentiation.
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PMID:Inhibition of p38 MAPK Phosphorylation Is Critical for Bestatin to Enhance ATRA-Induced Cell Differentiation in Acute Promyelocytic Leukemia NB4 Cells. 2414 Nov 98


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