Action of ubenimex on aminopeptidase activities in spleen cells and peritoneal macrophages from mice.

Kuramochi, Hlroshi; Motegi, Akiko; Iwabuchi, Mlnoru; Takahashi, K.; Horinishi, Hiroo; Umezawa, Hamao

doi:10.7164/antibiotics.40.1605

Cited by 18 publications

(12 citation statements)

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“…Bestatin was also found to inhibit aminopeptidase activities which are associated with the outer membrane of most mammalian cells, including spleen cells, macrophages and tumor cells [11,40,41]. The aminopeptidase activity was shown to increase in proportion to the activation and differentiation of macrophages in vivo [42,43].…”

Section: Discussionmentioning

confidence: 99%

“…Aminopeptidase activities were assayed by measuring fl-naphthylamine (fl-NA) liberated from amino acid-/3-NA (L-Leu-fl-NA or L-Arg-fl-NA; Sigma Chemical Co.) after incubation [11]. A Hank's balanced salt solution (HBSS) containing 0.2mM amino acid-~6-NA and tumor cells (2 × 104) in a total volume of 1.0 ml was incubated for 2 h at 37°C.…”

Section: Other Enzyme Activitiesmentioning

confidence: 99%

“…Ubenimex (hereafter referred to as bestatin) is a dipeptide discovered in the culture supernatant of inhibitor for aminopeptidase B and leucine amino peptidase [11][12][13]. The immunomodulatory properties of bestatin have been examined in preclinical and clinical studies [14][15][16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of tumor invasion and extracellular matrix degradation by ubenimex (bestatin)

et al. 1992

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We have investigated the effect of the immunomodulator ubenimex (hereafter referred to as bestatin) on the enzymatic degradation of the extracellular matrix by human renal cell carcinoma SN12M cells during the invasive process. The invasion of SN12M cells into reconstituted basement membrane (Matrigel) was inhibited by the presence of bestatin in a concentration-dependent manner. However, bestatin did not have any effect on tumor cell adhesion and migration to the extracellular matrices which may be involved in tumor cell invasion. Bestatin inhibited the degradation of type IV collagen by tumor cells, but not by tumor-conditioned medium (TCM), in a concentration-dependent manner. We also found that bestatin inhibited hydrolysing activities towards substrates of aminopeptidases in SN12M cells. Since bestatin was found to inhibit aminopeptidase activity, the inhibition of tumor invasion by bestatin is likely to be associated with its action as an enzyme inhibitor. Bestatin only slightly inhibited tumor cell plasmin activity, which can lead to the conversion of the latent collagenase to the active form, but this slight effect was not significant. The zymography of TCM from SN12M cells showed that the treatment of tumor cells with bestatin resulted in the disappearance of the 68 kDa type IV collagenase-enzyme level (active form) and slight reduction of the 72 kDa type IV collagenase-enzyme level (latent form). These results indicated that bestatin may inhibit tumor cell invasion through a mechanism involving its inhibitory action on aminopeptidases in tumor cells, suggesting that the aminopeptidase may partly be associated with the conversion of a latent form of type IV procollagenase to an active form or the secretion of the collagenases from tumor cells.

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Section: Discussionmentioning

confidence: 99%

Section: Other Enzyme Activitiesmentioning

confidence: 99%

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Inhibition of tumor invasion and extracellular matrix degradation by ubenimex (bestatin)

et al. 1992

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“…This metabolite is a potent inhibitor of leucine aminopeptidase and aminopeptidase B of mammalian cells [18,29,30] and immune cells both in vitro [17,19,22,36] and in vivo [15]. Aminopeptidase activity has been associated with macrophage activation and differentiation [21,37], the inflammatory process [20,23,28] and was shown in a cell-free system to correlate *This research was sponsored by the National Cancer Institute, DHHS, under contract no.…”

Section: Introductionmentioning

confidence: 99%

Chemoimmunotherapy with cyclophosphamide and bestatin in experimental metastasis in mice

Abe

Schneider²,

Black

et al. 1989

Cancer Immunol Immunother

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Bestatin has significant therapeutic activity (even following oral administration) for the treatment of metastatic disease, an activity which is limited by tumor burden. Therefore, the therapeutic potential of bestatin was examined in combination with chemotherapy to determine if there is additive activity for heavy tumor burdens. Bestatin significantly increased therapeutic activity and decreased the myelotoxicity of cyclophosphamide following a single injection of cyclophosphamide or split daily doses. In immune function studies, in tumor-bearing animals, bestatin increased the number of colony-forming units (granulocyte-macrophage) (CFU) and alveolar macrophage tumoricidal activity. However, when bestatin was combined with cyclophosphamide, which depressed bone marrow and macrophage activity, it did not show apparent augmentation of macrophage and NK cell activity, but did significantly increase bone marrow CFU activity. Thus, in combined chemoimmunotherapy, bestatin appears to enhance therapeutic activity by accelerating the recovery of hematopoiesis. We suggest, therefore, that a combination chemotherapy protocol, with oral bestatin, may facilitate myelorestoration following aggressive chemotherapy. The majority of biological response modifiers require parental administration; thus, the identification of an orally active, synthetic immunoaugmenting agent with a defined receptor is of particular interest.

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“…5) Bestatin is an inhibitor of APN and aminopeptidase B. [6][7][8] The immunomodulatory properties of bestatin have been examined in both preclinical and clinical studies. [9][10][11][12][13][14] The pharmacokinetics and biotransformation of bestatin have also been examined in detail.…”

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confidence: 99%

A Derivative of Aminopeptidase Inhibitor (BE15) Has a Dual Inhibitory Effect of Invasion and Motility on Tumor and Endothelial Cells

Saitoh

Koizumi

Minami

et al. 2006

Biological & Pharmaceutical Bulletin

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The metastatic process can be divided into several steps. First, tumor cells are released from the primary tumor and invade the surrounding tissues, enter the vascular or lymphatic circulation, and transit there. Next, the cells arrest in the capillary bed of a distant organ and extravasate from the circulation to organ parenchyma. Finally, tumor cells grow at apparently selective sites which are distant from the original site. Neovascularization toward and into a tumor is crucial for the delivery of nutrition and oxygen to that tumor, and also functions as the metastatic pathway to distant organs. The invasion by tumor cells and endothelial cells has a similar process involving cell adhesion, motility and the degradation of the extracellular matrix (ECM) and tissues.Aminopeptidase N (APN)/CD13 is a Zn (2ϩ)-dependent exopeptidase that is anchored to the plasma membrane by its N-terminal segment and acts as an ectoenzyme. 1) We have reported that APN plays an important role in tumor-cell invasion, degradation of the ECM by tumor cells and tumor metastasis and angiogenesis in vitro and in vivo.2-5) Functional studies using tumor invasion assays revealed that APN on the tumor cell surface cleaves certain ECM proteins, including type IV collagen and some components of Matrigel. 3,4) In addition, transfection of the APN gene into A375 human melanoma (A375) cells significantly enhanced the metastatic potential of tumor cells on their intravenous inoculation into nude mice. 5)Bestatin is an inhibitor of APN and aminopeptidase B. 6-8)The immunomodulatory properties of bestatin have been examined in both preclinical and clinical studies. [9][10][11][12][13][14] The pharmacokinetics and biotransformation of bestatin have also been examined in detail. 15,16) Bestatin has been shown to augment the humoral and cellular immune responses in experimental animals, [17][18][19][20] and can activate murine macrophages to become cytotoxic against tumor cells in vivo and in vitro, possibly through a T-dependent mechanism.10,20) Talmadge et al. 21) reported significant therapeutic potential of bestatin against pre-existing experimental and spontaneous metastases when it was orally administered at high doses per animal.We have shown that Bestatin inhibited tumor cell invasion 2-4) and the formation of capillary structure by HUVECs in vitro and angiogenesis induced by B16-BL6 in syngeneic mice. 22)We also found that the inhibition of tumor invasion and angiogenesis by bestatin is mainly mediated by inhibition of the degradation of the ECM and basement membrane (BM) by tumor and endothelial cells.In the present study, we investigated the effects of bestatin derivatives on the invasive activity and motility of tumor and endothelial cells in vitro and capillary formation of endothelial cells in vitro. MATERIALS AND METHODSCells and Cell Culture A375 cells were kindly provided by Dr. I. J. Fidler, M.D. Anderson Cancer Center, Houston, TX. A375 cells were maintained as monolayer cultures in RPMI Medium supplemented with 10% FCS and L-gluta...

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Action of ubenimex on aminopeptidase activities in spleen cells and peritoneal macrophages from mice.

Abstract: The action of ubenimex on aminopeptidase (APase) activity was studied in intact spleen cells and peritoneal macrophages from mice. Ubenimex strongly inhibited hydrolyzing activities against arginine-^-naphtylamide (Arg-NA), Lys-NA and Pro-NA in both cells.

Cited by 18 publications

References 18 publications

Inhibition of tumor invasion and extracellular matrix degradation by ubenimex (bestatin)

Inhibition of tumor invasion and extracellular matrix degradation by ubenimex (bestatin)

Chemoimmunotherapy with cyclophosphamide and bestatin in experimental metastasis in mice

A Derivative of Aminopeptidase Inhibitor (BE15) Has a Dual Inhibitory Effect of Invasion and Motility on Tumor and Endothelial Cells

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