Reduction in mitochondrial potential constitutes an early irreversible step of programmed lymphocyte death in vivo.

Zamzami, Naoufal; Marchetti, Philippe; Castedo, Maria; Zanin, Carole; Vayssière, Jean-Luc; Petit, Patrice X.; Kroemer, Guido

doi:10.1084/jem.181.5.1661

Cited by 1,116 publications

(755 citation statements)

References 45 publications

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“…Bcl-2 on the endoplasmic reticulum membrane has been suggested to regulate intracellular calcium levels (Ba y et al, 1993;Lam et al, 1994;Marin et al, 1996), but its importance in anti-apoptotic activity depends on the unsolved question of whether Bcl-2 regulates calcium levels upstream of the caspase cascade. We recently showed that Bcl-2 and Bcl-x L , but not inhibitors of caspases, prevent apoptotic and necrotic stimuli-induced loss of mitochondrial membrane potential, whereas both Bcl-2 family proteins and caspase inhibitors prevent cell death (Zamzami et al, 1995;Shimizu et al, 1996b). The membrane potential loss leading to membrane permeability transition results in the release of an mitochondrial apoptogenic factor, AIF, which in turn, activates caspases as well as induces apoptotic change of the nucleus (Susin et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

“…Bcl-2 blocks the activation of caspases (Chinnaiyan et al, 1996;Shimizu et al, 1996a;Boulakia et al, 1996), probably by preventing the cell death-induced loss of mitochondrial membrane potential (Zamzami et al, 1995;Shimizu et al, 1996b). It has recently been described that Bcl-x L indirectly binds pro-FLICE (caspase-8) (Chinnaiyan et al, 1997), raising the possibility that Bcl-x L prevents the activation of caspases by sequestering pro-caspases.…”

Section: Introductionmentioning

confidence: 99%

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Evidence against a functional site for Bcl-2 downstream of caspase cascade in preventing apoptosis

et al. 1997

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Apoptotic cell death is driven by ICE family proteases (caspases) and negatively regulated by Bcl-2 family proteins. Although it has been shown that Bcl-2 exerts anti-apoptotic activity by blocking a step(s) leading to the activation of caspases, a role for Bcl-2 and Bcl-x L downstream of the caspase cascade has remained unclear. Here, we show that puri®ed active caspase-3 (CPP32/Yama/apopain) and caspase-1 (ICE) induces apoptosis when microinjected into the cytoplasm of cells, con®rming our recent observations, and that the apoptosis is not at all prevented by Bcl-2 and Bcl-x L , which are overexpressed more than su ciently to prevent Fas-mediated and overexpressed procaspase-1-mediated apoptosis. Thus, Bcl-2 and Bcl-x L do not act downstream of the caspase cascade.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Evidence against a functional site for Bcl-2 downstream of caspase cascade in preventing apoptosis

et al. 1997

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“…The consequence of a partial IM permeabilization, which does not result in the release of matrix proteins but contribute to cell death, is that mitochondria lose their vital metabolic and redox functions (Zamzami et al, 1995;Metivier et al, 1998;Poncet et al, 2003). Mitochondrial permeabilization is therefore recognized as a crucial checkpoint in programmed cell death of both normal and cancer cells.…”

Section: Mitochondrial Membrane Permeabilization: the Central Event Omentioning

confidence: 99%

Mitochondria as therapeutic targets for cancer chemotherapy

et al. 2006

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Mitochondria are vital for cellular bioenergetics and play a central role in determining the point-of-no-return of the apoptotic process. As a consequence, mitochondria exert a dual function in carcinogenesis. Cancer-associated changes in cellular metabolism (the Warburg effect) influence mitochondrial function, and the invalidation of apoptosis is linked to an inhibition of mitochondrial outer membrane permeabilization (MOMP). On theoretical grounds, it is tempting to develop specific therapeutic interventions that target the mitochondrial Achilles' heel, rendering cancer cells metabolically unviable or subverting endogenous MOMP inhibitors. A variety of experimental therapeutic agents can directly target mitochondria, causing apoptosis induction. This applies to a heterogeneous collection of chemically unrelated compounds including positively charged a-helical peptides, agents designed to mimic the Bcl-2 homology domain 3 of Bcl-2-like proteins, ampholytic cations, metals and steroid-like compounds. Such MOMP inducers or facilitators can induce apoptosis by themselves (monotherapy) or facilitate apoptosis induction in combination therapies, bypassing chemoresistance against DNA-damaging agents. In addition, it is possible to design molecules that neutralize inhibitor of apoptosis proteins (IAPs) or heat shock protein 70 (HSP70). Such IAP or HSP70 inhibitors can mimic the action of mitochondrion-derived mediators (Smac/DIABLO, that is, second mitochondria-derived activator of caspases/direct inhibitor of apoptosis-binding protein with a low isoelectric point, in the case of IAPs; AIF, that is apoptosis-inducing factor, in the case of HSP70) and exert potent chemosensitizing effects.

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“…The cells were harvested, nuclei were stained with propidium iodide and the changes of fluorescence were measured by flow cytometry. 34 …”

Section: Measurement Of Mitochondrial Membrane Potentialmentioning

confidence: 99%

In vitro and in vivo antitumor effect of 2‐methoxyestradiol on human melanoma

Dobos

Tı́már

Bocsi

et al. 2004

Intl Journal of Cancer

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2-methoxyestradiol (2ME 2 ) is an endogenous metabolite of estradiol with estrogen-receptor-independent antitumor and antiangiogenic activity. We examined the effects of 2ME 2 on the cellular proliferation of 8 human melanoma cell lines. We show that 2ME 2 inhibited cell proliferation by inducing apoptosis and an arrest in the G 2 /M phase, and the mechanism of action involved microtubules, mitochondrial damage and caspase activation. In male SCID mice, 2ME 2 was effective in reducing primary tumor weight and the number of liver metastases after intrasplenic injection of human melanoma cells. In the metastases, we found a significantly higher rate of apoptotic cells after 2ME 2 treatment. These findings on the antitumor effect of 2ME 2 in cell culture as well as in an animal model may have implications for designing alternative treatment options for patients with advanced malignant melanoma. © 2004 Wiley-Liss, Inc. Key words: 2-methoxyestradiol; melanoma; apoptosis; metastasisThe possibility that endocrine factors may influence the clinical course of human malignant melanoma is suggested by the higher survival rate in premenopausal vs. postmenopausal women or men of any ages. 1,2 The epidemiological data were supported by studies using melanoma cell lines grown in experimental animals. 3,4 Our previous experiments showed that intrasplenic injection of human melanoma cells resulted in a significantly higher number of liver metastases in male than in female SCID mice. 5 On the other hand, investigations on the sex hormone receptor status of human cutaneous melanomas yielded conflicting results; while earlier studies applying biochemical methods for the detection of estrogen receptors (ER) gave positive results in some cases, other approaches using monoclonal anti-ER antibodies generally failed to demonstrate the presence of type I receptors in melanoma tissues. 1,6 It has been suggested that low-affinity type II ERs may be responsible for the observed hormone binding. Nevertheless, most investigators have shown the lack of an effect of estrogens on the proliferative activity of human melanoma cells. 7,8 There are less data available on the presence of other sex hormone receptors (progesterone and androgens) and their effect on the biological behavior of melanoma cells. 1,9 One possible mechanism behind the observed female superiority in survival of melanoma patients is the tumor growth inhibitory effect of 2-methoxyestradiol (2ME 2 ), an endogenous metabolite of estradiol exerting its activities independently of the ERs. 2ME 2 is formed by the sequential hydroxylation and methylation at the 2-position; it is produced during the normal route of detoxification, especially in the liver, and excreted through the urinary system. 10 -12 This is the only estradiol metabolite devoid of estrogenic activity in vivo and has no known physiological function. Its affinity to ER␣ and to ER␤ is 500-fold and 3,200-fold lower than that of estradiol, respectively, and its activity is independent of the presence of estrogen receptor...

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Reduction in mitochondrial potential constitutes an early irreversible step of programmed lymphocyte death in vivo.

Cited by 1,116 publications

References 45 publications

Evidence against a functional site for Bcl-2 downstream of caspase cascade in preventing apoptosis

Evidence against a functional site for Bcl-2 downstream of caspase cascade in preventing apoptosis

Mitochondria as therapeutic targets for cancer chemotherapy

In vitro and in vivo antitumor effect of 2‐methoxyestradiol on human melanoma

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