The polyamine oxidase inactivator MDL 72527

Seiler, Nikolaus; Duranton, B; Raul, Françis

doi:10.1007/978-3-0348-8171-5_1

Cited by 45 publications

(45 citation statements)

References 77 publications

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“…MDL 72527 is known as an inactivator of polyamine oxidase, but also as a cytotoxic agent with lysosomotropic properties (28,37). In our experimental conditions both sensitive and multidrug-resistant M14 cells were quite insensitive to MDL 72527 when added alone: incubation with 300 μM of this drug for 24 h at 37˚C had no significant effect on cell survival (Fig.…”

Section: Sensitization Of M14 Cells To Bsao/spermine-induced Toxicitymentioning

confidence: 71%

Cytotoxicity of spermine oxidation products to multidrug resistant melanoma M14 ADR2 cells: Sensitization by the MDL 72527 lysosomotropic compound

Agostinelli

Condello²,

Molinari³

et al. 2009

Int J Oncol

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Abstract. It has been confirmed that multidrug resistant (MDR) human melanoma cells are more sensitive than their wild-type counterparts to H 2 O 2 and aldehydes, the products of bovine serum amine oxidase (BSAO)-catalyzed oxidation of spermine. The metabolites formed by BSAO and spermine are more toxic than exogenous H 2 O 2 and acrolein, even though their concentration is lower during the initial phase of incubation due to their more gradual release than the exogenous products. Both wild-type and MDR cells, after pre-treatment with MDL 72527, an inactivator of polyamine oxidase and a lysosomotropic compound, show to be sensitized to subsequent exposure to BSAO/spermine. Evidence of ultrastructural aberrations and acridine orange release from lysosomes is presented in this work that is in favor of the permeabilization of the lysosomal membrane as the major cause of sensitization by MDL 72527. Owing to its lysosomotropic effect, pre-treatment with MDL 72527 amplifies the ability of the metabolites formed from spermine by oxidative deamination to induce cell death. Since it is conceivable that combined treatment with a lysosomotropic compound and BSAO/spermine would be effective against tumor cells, it is of interest to search for such novel compounds, which might be promising for application in a therapeutic setting.

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Section: Sensitization Of M14 Cells To Bsao/spermine-induced Toxicitymentioning

confidence: 71%

Cytotoxicity of spermine oxidation products to multidrug resistant melanoma M14 ADR2 cells: Sensitization by the MDL 72527 lysosomotropic compound

Agostinelli

Condello²,

Molinari³

et al. 2009

Int J Oncol

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“…Wild-type C57BL/6 littermates were used for two independent 1-wk experiments (n = 24-26 each). As described, some groups were administered the polyamine oxidase inhibitor MDL 72527 (52)(53)(54). Two doses of MDL 72527 (20 mg/kg in sterile 1× PBS by i.p.…”

Section: Methodsmentioning

confidence: 99%

Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis -induced colon tumorigenesis

Goodwin¹,

Shields²,

Wu³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

465

353

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It is estimated that the etiology of 20-30% of epithelial cancers is directly associated with inflammation, although the direct molecular events linking inflammation and carcinogenesis are poorly defined. In the context of gastrointestinal disease, the bacterium enterotoxigenic Bacteroides fragilis (ETBF) is a significant source of chronic inflammation and has been implicated as a risk factor for colorectal cancer. Spermine oxidase (SMO) is a polyamine catabolic enzyme that is highly inducible by inflammatory stimuli resulting in increased reactive oxygen species (ROS) and DNA damage. We now demonstrate that purified B. fragilis toxin (BFT) upregulates SMO in HT29/c1 and T84 colonic epithelial cells, resulting in SMO-dependent generation of ROS and induction of γ-H2A.x, a marker of DNA damage. Further, ETBF-induced colitis in C57BL/6 mice is associated with increased SMO expression and treatment of mice with an inhibitor of polyamine catabolism, N 1 ,N 4 -bis(2,3-butandienyl)-1,4-butanediamine (MDL 72527), significantly reduces ETBF-induced chronic inflammation and proliferation. Most importantly, in the multiple intestinal neoplasia (Min) mouse model, treatment with MDL 72527 reduces ETBF-induced colon tumorigenesis by 69% (P < 0.001). The results of these studies indicate that SMO is a source of bacteria-induced ROS directly associated with tumorigenesis and could serve as a unique target for chemoprevention.inflammatory bowel diseases | adenomatous polyposis coli I t is estimated that chronic inflammation associated with microbial infection directly contributes to the etiology of about 20% of epithelial cancers. The chronic inflammatory microenvironment is characterized by immune dysregulation and elevated levels of reactive oxygen species [ROS; including superoxide, hydrogen peroxide (H 2 O 2 ), and singlet oxygen]. These features result in activation of stress response pathways and oncogenes, down-regulation of tumor suppressor genes, cell and tissue damage, and contribute to tumor initiation, promotion, and progression. However, the precise molecular links between inflammation and carcinogenesis remain to be clarified (1, 2).In the colon, alterations in the physiological balance between the diverse and abundant microbiota (w10 12 organisms per gram feces) and the host are a common source of inflammation. Bacteroides spp comprise a significant proportion of colonic commensal bacteria and members of this group include symbionts and the leading human anaerobic pathogen, Bacteroides fragilis. Enterotoxigenic B. fragilis (ETBF) represent a molecular subtype characterized by a single unique virulence determinant, the production and secretion of a 20-kDa metalloprotease enterotoxin (B. fragilis toxin; BFT). ETBF have been epidemiologically associated with acute diarrheal diseases in humans and livestock, inflammatory bowel diseases (IBD), and colorectal cancer (reviewed in ref.3). Exposure of intestinal epithelial cell lines to BFT results in cleavage of the cell adhesion and tumor suppressor protein E-cadherin, ...

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“…5). This increase in N 1 -acetyl derivatives is mainly due to prevention of PAO catalysed degradation, but the induction of SSAT can at present not be completely excluded, since MDL 72527 inhibits at concentrations ≥60 μM the growth of SW620 cells (13). In combination with procyanidins, MDL 72527 diminished within 48 h the intracellular content of putrescine and spermidine pools, and reduced the amount of spermine more efficiently than procyanidins alone.…”

Section: Cell Growth Inhibition By Procyanidins and MDL 72527mentioning

confidence: 96%

“…Our data show a previously unknown ability of procyanidins to activate polyamine acetylation and to down-regulate simultaneously polyamine biosynthesis. By using the PAO inactivator MDL 72527 at 50 μM, a dose which inactivates PAO, but does not inhibit cell growth (13), we demonstrate that the apoptotic effect of procyanidins is unrelated to the formation of reactive oxygen species (ROS), which are generated by enhanced oxidation of polyamines, and that MDL 72527 potentiates the procyanidin-triggered apoptosis. These effects seem to be correlated with the increased formation of N 1 -acetyl derivatives of spermidine and spermine.…”

Section: Introductionmentioning

confidence: 94%

Potentiation of apple procyanidin-triggered apoptosis by the polyamine oxidase inactivator MDL 72527 in human colon cancer-derived metastatic cells

Gossé

Roussi

Guyot³

et al. 2006

Int J Oncol

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Abstract. Apple procyanidins have chemopreventive properties in a model of colon cancer, they affect intracellular signalling pathways, and trigger apoptosis in a human adenocarcinoma-derived metastatic cell line (SW620). In the present study we investigated relationships between procyanidin-induced alterations in polyamine metabolism and apoptotic effects. Apple procyanidins diminish the activities of ornithine decarboxylase and S-adenosyl-Lmethionine decarboxylase, key enzymes of polyamine biosynthesis, and they induce spermidine/spermine N 1 -acetyltransferase, which initiates retroconversion of polyamines. As a consequence of the enzymatic changes polyamine concentrations are diminished, and N 1 -acetyl-polyamines accumulate in SW620 cells. In contrast with expectations MDL 72527, an inactivator of polyamine oxidase (PAO), improved the anti-proliferative effect of procyanidins, and caused an increase of the proportion of apoptotic cells, although it prevented the formation of hydrogen peroxide and 3-acetamidopropanal, the cytotoxic products of PAOcatalysed degradation of N 1 -acetylspermidine and N 1 -acetylspermine. Addition of 500 μM N 1 -acetylspermidine to the culture medium in the presence of procyanidins mimicked the effect of MDL 72527. Therefore we presume that the enhanced procyanidin-triggered apoptosis by MDL 72527 is mediated by the accumulation of N 1 -acetyl-polyamines. The observation that apple procyanidins enhance polyamine catabolism and reduce polyamine biosynthesis activity similar to known inducers of SSAT, without sharing their toxicity, and the potentiation of these effects by low concentrations of MDL 72527 suggests apple procyanidins for chemopreventive and therapeutic interventions.

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The polyamine oxidase inactivator MDL 72527

Cited by 45 publications

References 77 publications

Cytotoxicity of spermine oxidation products to multidrug resistant melanoma M14 ADR2 cells: Sensitization by the MDL 72527 lysosomotropic compound

Cytotoxicity of spermine oxidation products to multidrug resistant melanoma M14 ADR2 cells: Sensitization by the MDL 72527 lysosomotropic compound

Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis -induced colon tumorigenesis

Potentiation of apple procyanidin-triggered apoptosis by the polyamine oxidase inactivator MDL 72527 in human colon cancer-derived metastatic cells

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