Ballot 2010 Apoptosis: Difference between revisions
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|preparations=Intact cells, Isolated Mitochondria | |preparations=Intact cells, Isolated Mitochondria | ||
|enzymes=Complex III, Complex V; ATP Synthase | |enzymes=Complex III, Complex V; ATP Synthase | ||
| | |diseases=Cancer | ||
|topics=Inhibitor, Substrate | |topics=Inhibitor, Substrate | ||
|instruments=Oxygraph-2k | |instruments=Oxygraph-2k | ||
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Revision as of 13:00, 3 December 2013
Ballot C, Kluza J, Lancel S, Martoriati A, Hassoun SM, Mortier L, Vienne JC, Briand G, Formstecher P, Bailly C, Nevière R, Marchetti P (2010) Inhibition of mitochondrial respiration mediates apoptosis induced by the anti-tumoral alkaloid lamellarin D. Apoptosis 15: 769-781. |
Ballot C, Kluza J, Lancel S, Martoriati A, Hassoun SM, Mortier L, Vienne JC, Briand G, Formstecher P, Bailly C, Neviere R, Marchetti P (2010) Apoptosis
Abstract: Lamellarin D (Lam D), a marine alkaloid, exhibits a potent cytotoxicity against many different tumors. The pro-apoptotic function of Lam D has been attributed to its direct induction of mitochondrial permeability transition (MPT). This study was undertaken to explore the mechanisms through which Lam D promotes changes in mitochondrial function and as a result apoptosis. The use of eight Lam derivatives provides useful structure-apoptosis relationships. We demonstrate that Lam D and structural analogues induce apoptosis of cancer cells by acting directly on mitochondria inducing reduction of mitochondrial membrane potential, swelling and cytochrome c release. Cyclosporin A, a well-known inhibitor of MPT, completely prevents mitochondrial signs of apoptosis. The drug decreases calcium uptake by mitochondria but not by microsomes indicating that Lam D-dependent permeability is specific to mitochondrial membranes. In addition, upon Lam D exposure, a rapid decline of mitochondrial respiration and ATP synthesis occurs in isolated mitochondria as well as in intact cells. Evaluation of the site of action of Lam D on the electron-transport chain revealed that the activity of respiratory chain complex III is reduced by a half. To determine whether Lam D could induce MPT-dependent apoptosis by inhibiting mitochondrial respiration, we generated respiration-deficient cells (rho0) derived from human melanoma cells. In comparison to parental cells, rho0 cells are totally resistant to the induction of MPT-dependent apoptosis by Lam D. Our results indicate that functional mitochondria are required for Lam D-induced apoptosis. Inhibition of mitochondrial respiration is responsible for MPT-dependent apoptosis of cancer cells induced by Lam-D. β’ Keywords: Cytotoxicity, pro-apoptotic Lamellarin D (Lam D), mitochondrial permeability transition (MPT), human melanoma cells, respiration-deficient cells (rho0)
β’ O2k-Network Lab: FR Lille Neviere R
Labels: MiParea: Respiration, Pharmacology;toxicology
Pathology: Cancer
Organism: Human
Preparation: Intact cells, Isolated Mitochondria"Isolated Mitochondria" is not in the list (Intact organism, Intact organ, Permeabilized cells, Permeabilized tissue, Homogenate, Isolated mitochondria, SMP, Chloroplasts, Enzyme, Oxidase;biochemical oxidation, ...) of allowed values for the "Preparation" property. Enzyme: Complex III, Complex V; ATP Synthase"Complex V; ATP Synthase" is not in the list (Adenine nucleotide translocase, Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Complex V;ATP synthase, Inner mt-membrane transporter, Marker enzyme, Supercomplex, TCA cycle and matrix dehydrogenases, ...) of allowed values for the "Enzyme" property. Regulation: Inhibitor, Substrate
HRR: Oxygraph-2k