Disease relevance of X 4357 B

• Further, the perforin inhibitor concanamycin A blocks autologous monocyte killing by CD4+ lupus T cells, suggesting that the perforin is functional [1].
• Bafilomycin A1 and concanamycin A, present at the low concentrations of 5 x 10(-7) and 5 x 10(-9) M, respectively, prevented the entry of influenza virus into cells when added during the first minutes of infection [2].
• Moreover, modifying the ionic conditions of the culture medium (increasing the concentration of K(+) and decreasing the concentration of Na(+)), together with concanamycin A, also significantly interfered with poliovirus entry [3].
• Entry of Semliki forest virus into cells: effects of concanamycin A and nigericin on viral membrane fusion and infection [4].
• Here, we show that bafilomycins and concanamycin A, selective inhibitors of the vacuolar ATPase proton pump, are the most powerful known inhibitors of LF macrophage toxicity [5].

High impact information on X 4357 B

• In contrast use of the vacuolar H+/ATPase inhibitor, concanamycin A, stabilized total cellular free oligosaccharides and enabled us to demonstrate a translocation of partially trimmed oligosaccharides from the cytosol into a membrane-bound compartment [6].
• In addition, we detected autophagic bodies in the vacuoles of wild-type roots but not in those of atg4a4b-1 in the presence of concanamycin A, a V-ATPase inhibitor [7].
• Although sensitive to concanamycin A and ethyleneglycotetraacetic acid, which inhibit cytotoxicity by granule exocytosis, the CD4(+) cytotoxic T lymphocytes (CTLs) did not express perforin, suggesting a cytotoxic mechanism independent of perforin although involving exocytosis [8].
• Again, cyclosporin A, but not concanamycin A, strongly reduced activating receptor-mediated IFN-gamma production [9].
• Conversely, concanamycin A, an inhibitor of vacuolar type H(+)-adenosine triphosphatase (H(+)-ATPase) of granules, inhibited activating receptor-induced NK cell cytolysis, suggesting that activating receptor-mediated apoptosis and cytolysis can use different intracellular pathways [9].

Chemical compound and disease context of X 4357 B

• Combination of concanamycin A, a vacuolar proton-ATPase inhibitor, and valinomycin, an ionophore that promotes K(+) efflux from cells, powerfully prevented poliovirus infection [3].
• Inhibition of influenza virus entry into cells by concanamycin A or by nigericin takes place under acidic conditions [10].

Biological context of X 4357 B

• On the other hand, CTL activity was blocked by inhibitors of the granule exocytosis pathway such as ethylene-glyco-tetra-acetic acid or concanamycin A [11].
• We examined the function of the V-ATPase in cytosolic Ca(2+) homeostasis by comparing responses to a brief Ca(2+) challenge of a V-ATPase mutant (vma2Delta) and wild-type cells treated with the V-ATPase inhibitor concanamycin A [12].
• The accelerated apoptotic cell death induced by concanamycin A occurred in OCLs treated with interleukin-1 alpha or macrophage colony-stimulating factor as well, which are known to elongate the survival time of osteoclasts [13].
• We previously reported that concanamycin A, a specific inhibitor of vacuolar type H+-ATPases, induces DNA fragmentation in B cell hybridoma HS-72 cells [14].
• Inhibition of the pH-dependent translocation process by pretreating cultures with concanamycin A (Con A) prevents cleavage of SNAP-25 with IC50 values of approximately 25 nM [15].

Anatomical context of X 4357 B

• Moreover, the cytolytic functions of freshly isolated CD8brightCD56+ T cells were up-regulated against both K562 (NK-sensitive) and Raji (NK-resistant) cells, which were effectively inhibited by perforin inhibitor (concanamycin A) [16].
• We studied the mechanisms of human umbilical vein endothelial cell (EC) detachment from matrix-coated plastic following contact by concanamycin A-treated lymphocytes as an in vitro model of perforin-independent modulation of EC basement membrane adhesion [17].
• Mutations of pma-1, the gene encoding the plasma membrane H+-ATPase of Neurospora crassa, suppress inhibition of growth by concanamycin A, a specific inhibitor of vacuolar ATPases [18].
• Functional studies demonstrated that 1) concanamycin A, a selective inhibitor of perforin/granzyme B-based cytolysis, blocked DC-stimulated NK cytotoxicity against K562 cells; and 2) neutralizing mAb against Fas ligand (FasL) significantly reduced DC-stimulated NK cytotoxicity against Fas-positive Jurkat cells [19].
• The role that endosomal acidification plays during influenza virus entry into MDCK cells has been analyzed by using the macrolide antibiotics bafilomycin A1 and concanamycin A as selective inhibitors of vacuolar proton-ATPase (v-[H+]ATPase), the enzyme responsible for the acidification of endosomes [2].

Associations of X 4357 B with other chemical compounds

• Treatment with concanamycin A or EGTA abrogated CD8+ NKT cytotoxicity indicating that perforin is a major pathway of tumor cell lysis [20].
• Bafilomycin A1 and its analog, concanamycin A, were found to up-regulate HIF-1alpha in eight human cancer cell-lines, and this effect is attributed to inhibited degradation of HIF-1alpha protein [21].
• An inhibitor of vacuolar type H+-ATPase, concanamycin A, and an inhibitor of papain-type cysteine proteinase, E-64d, abolished both the light-dependent disappearance of GFP fluorescence and GFP degradation in the vacuoles [22].
• We purified the cytosol from concanamycin A-treated HS-72 cells by a four-step procedure: ultracentrifugation; HiTrap heparin column chromatography; HiTrap Q column chromatography; and reverse-phase high performance liquid chromatography on a C18 hydrophobic support [14].
• Here, we report that incubation of 3T3-L1 adipocytes with specific inhibitors of V-type ATPase, concanamycin A and bafilomycin A1, inhibits insulin-regulated glucose transport and results in accumulation of GLUT4 in heavy, rapidly sedimenting intracellular membranes [23].

Gene context of X 4357 B

• The cytotoxicity was dose-dependently inhibited by either a Con A ligand, alpha-methyl mannoside, or a perforin inhibitor, concanamycin A (CMA), but not by anti-Fas ligand antiserum [24].
• CMA treatment showed that while the cytotoxicity of IL-2-activated CHS PBL against K562 was largely dependent on perforin, that against Jurkat was largely not [25].
• In contrast, the CHS PBL exhibited substantial cytotoxicity against Jurkat cells, which was only partially inhibited by CMA treatment but not by the addition of neutralizing anti-FasL or anti-TNF-alpha antibodies [25].
• However, pretreatment with concanamycin A completely inhibited this IL-18- and/or IL-12-augmented NK activity [26].
• Constitutive expression of Bcl-2 but not Bcl-XL inhibited concanamycin A-induced apoptosis [27].

Analytical, diagnostic and therapeutic context of X 4357 B

• The TdT-mediated dUTP-nick-end labeling (TUNEL) reaction confirmed the apoptotic features of OCLs treated with concanamycin A [13].
• Here we show that the CD40 ligation rescues WEHI-231 cells from apoptotic cell death induced by a specific V-ATPase inhibitor, concanamycin A [27].
• We show here that concanamycin A and bafilomycin A1 induce a significant increase in the proportion of fragmented DNA in agarose gel electrophoresis [28].
• There were no significant differences in fasted insulin levels and beta cell mass between treated and control groups but oral glucose tolerance worsened with increasing age in BALB/c female mice injected with concanamycin A [29].
• Luminal perfusion of 5 nM concanamycin A, a V-type H(+)-ATPase inhibitor, reduced Nx DT JtCO2 (45 +/- 8 pmol.min-1.mm-1, P < 0.05) [30].

References