Agmatine induces apoptosis in rat hepatocyte cultures

Gardini, Giulia; Cabella, Claudia; Cravanzola, Carlo; Vargiu, Cristina; Belliardo, Sabina; Testore, Giovanni; Solinas, Sandro P.; Toninello, Antonio; Grillo, M.A.; Colombatto, Sebastiano

doi:10.1016/s0168-8278(01)00153-2

Cited by 33 publications

(18 citation statements)

References 37 publications

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“…Contrary to our results in RKM, low concentrations of agmatine exacerbated Ca 2ϩ -and phosphate-induced mitochondrial swelling and ⌬⌿ collapse in RLM preparations as well as induced apoptosis in hepatocytes in culture (7,21). However, at high concentrations, agmatine affords protection against mitochondrial swelling and ⌬⌿ collapse in RLM, similar to our findings in RKM.…”

supporting

confidence: 57%

“…In further support of this cell specificity in liver cells, we observed only an incremental, nonsignificant increase in SSAT expression in Ras/3T3 cells when exposed to agmatine over the course of 10 days (unpublished observations). Agmatine induction of SSAT in hepatocytes has been shown to deplete intracellular polyamines, with a correlative increase in hydrogen peroxide production in association with apoptosis (21). SSAT and amine oxidase comprise a two-step interconversion of higher-order polyamines to lower-order polyamines, i.e., spermine to spermidine and spermidine to putrescine.…”

mentioning

confidence: 99%

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The arginine metabolite agmatine protects mitochondrial function and confers resistance to cellular apoptosis

Arndt¹,

Battaglia²,

Parisi³

et al. 2009

American Journal of Physiology-Cell Physiology

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confidence: 57%

mentioning

confidence: 99%

The arginine metabolite agmatine protects mitochondrial function and confers resistance to cellular apoptosis

Arndt¹,

Battaglia²,

Parisi³

et al. 2009

American Journal of Physiology-Cell Physiology

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“…Induction of programmed cell death by agmatine has been described previously in isolated rat hepatocytes (Gardini et al, 2001). However, only a cytostatic effect of agmatine without induction of apoptosis has been observed in transformed NIH/3T3 fibroblasts (Isome et al, 2003) and the rat hepatoma cells HTC and JM2 .…”

Section: Molecular Basis For the Antiproliferative Effect Of Agmatinementioning

confidence: 85%

Molecular Basis for the Antiproliferative Effect of Agmatine in Tumor Cells of Colonic, Hepatic, and Neuronal Origin

Wolf

Brüss²,

Hanisch³

et al. 2007

Molecular Pharmacology

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The aim of the present study was to challenge potential mechanisms of action underlying the inhibition of tumor cell proliferation by agmatine. Agmatine inhibited proliferation of the human hepatoma cells HepG2, the human adenocarcinoma cells HT29, the rat hepatoma cells McRH7777, and the rat pheochromocytoma cells PC-12. Inhibition of proliferation of HepG2 cells was associated with an abolition of expression of ornithine decarboxylase (ODC) protein and a doubling of mRNA content encoding ODC. In HepG2 cells, silencing of ODC-antizyme-1, but not of antizyme inhibitor, by RNA interference resulted in an increase of agmatine's antiproliferative effect. Thus, the distinct decrease in intracellular polyamine content by agmatine was due to a reduced translation of the synthesizing protein ODC but was not essentially mediated by induction of ODC-antizyme or blockade of antizyme inhibitor. In interaction experiments 1 mM L-arginine, 1 mM D-arginine, 1 mM citrulline, 100 M N -nitro-L-arginine methyl ester, 1 and 10 M sodium nitroprusside, and 1 M N 1 -guanyl-1,7-diaminoheptane failed to alter agmatine's antiproliferative effect. Hence, the antiproliferative effect of agmatine in HT29 and HepG2 cells is due to an interaction with neither the NO synthases, the hypusination of eIF5A, nor an agmatine-induced reduction in availability of intracellular L-arginine. L-Arginine and citrulline, but not D-arginine, inhibited tumor cell proliferation by themselves. Their inhibitory effect was abolished after silencing of arginine decarboxylase (ADC) expression by RNA interference indicating the conversion to agmatine by ADC. Finally, in the four cell lines under study, agmatine-induced inhibition of cell proliferation was paralleled by an increase in intracellular caspase-3 activity, indicating a promotion of apoptosis.Agmatine, a cationic amine formed by decarboxylation of L-arginine by the mitochondrial enzyme arginine decarboxylase, initially attracted attention as an endogenous ligand at imidazoline receptors (Li et al., 1994). However, independent of binding to those receptors, agmatine induces a variety of physiological and pharmacological effects (Raasch et al., 2001). In particular, the antiproliferative effect of agmatine has aroused interest as a new alternative in the treatment of neoplasms. Agmatine administration to tumor cells in vitro results in a suppression of cell proliferation (Satriano et al., 1998;Choi and Cho, 1999;Vargiu et al., 1999;Babal et al., 2001;Dudkowska et al., 2003;Higashi et al., 2004;Kribben et al., 2004;Molderings et al., 2004;Mayeur et al., 2005). At the intracellular level, agmatine-induced decrease of cell proliferation was shown to be due to a decrease in the intracellular levels of the polyamines putrescine, spermidine, and spermine (Satriano et al., 1998;Choi and Cho, 1999;Vargiu et al., 1999;Babal et al., 2001;Dudkowska et al., 2003;Higashi et al., 2004;Mayeur et al., 2005), which are pivotal for cell growth (Igarashi and Kashiwagi, 2000). The intracellular concentration of polyam...

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“…The experiments were carried out at 20 • C in order to compare the results with those obtained in many other previous papers on the mitochondrial permeability transition (MPT) (e.g., see Gardini et al, 2001;DallaVia et al, 2006). Whole rat liver mitochondria exhibit a reversible broad gel to liquid crystalline phase transition at 0 • C (Blazyk and Steim, 1972) and at 20 • C the membrane is in the sol form.…”

Section: Mitochondrial Isolation and Standard Incubation Proceduresmentioning

confidence: 99%

“…Standard protein markers were used for molecular weight calibration. After blotting, immunoreaction bands were detected by ECL (Gardini et al, 2001). …”

Section: Caspase-3 Activation and Hif-1˛accumulationmentioning

confidence: 99%

Cobalt induces oxidative stress in isolated liver mitochondria responsible for permeability transition and intrinsic apoptosis in hepatocyte primary cultures

Battaglia

Compagnone

Bandino

et al. 2009

The International Journal of Biochemistry & Cell Biology

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102

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a b s t r a c tIt is well established that cobalt mediates the occurrence of oxidative stress which contributes to cell toxicity and death. However, the mechanisms of these effects are not fully understood. This investigation aimed at establishing if cobalt acts as an inducer of mitochondrial-mediated apoptosis and at clarifying the mechanism of this process.Cobalt, in the ionized species Co 2+ , is able to induce the phenomenon of mitochondrial permeability transition (MPT) in rat liver mitochondria (RLM) with the opening of the transition pore. In fact, Co 2+ induces mitochondrial swelling, which is prevented by cyclosporin A and other typical MPT inhibitors such as Ca 2+ transport inhibitors and bongkrekic acid, as well as anti-oxidant agents. In parallel with mitochondrial swelling, Co 2+ also induces the collapse of electrical membrane potential. However in this case, cyclosporine A and the other MPT inhibitors (except ruthenium red and EGTA) only partially prevent « drop, suggesting that Co 2+ also has a proton leakage effect on the inner mitochondrial membrane. MPT induction is due to oxidative stress, as a result of generation by Co 2+ of the highly damaging hydroxyl radical, with the oxidation of sulfhydryl groups, glutathione and pyridine nucleotides. Co 2+ also induces the release of the pro-apoptotic factors, cytochrome c and AIF. Incubation of rat hepatocyte primary cultures with Co 2+ results in apoptosis induction with caspase activation and increased level of expression of HIF-1␣.All these observations allow us to state that, in the presence of calcium, Co 2+ is an inducer of apoptosis triggered by mitochondrial oxidative stress.

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Agmatine induces apoptosis in rat hepatocyte cultures

Cited by 33 publications

References 37 publications

The arginine metabolite agmatine protects mitochondrial function and confers resistance to cellular apoptosis

The arginine metabolite agmatine protects mitochondrial function and confers resistance to cellular apoptosis

Molecular Basis for the Antiproliferative Effect of Agmatine in Tumor Cells of Colonic, Hepatic, and Neuronal Origin

Cobalt induces oxidative stress in isolated liver mitochondria responsible for permeability transition and intrinsic apoptosis in hepatocyte primary cultures

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