Inhibition of mitochondrial respiration mediates apoptosis induced by the anti-tumoral alkaloid lamellarin D

被引:96
作者
Ballot, Caroline [1 ,2 ]
Kluza, Jerome [1 ,2 ]
Lancel, Steve [5 ]
Martoriati, Alain [1 ,2 ]
Hassoun, Sidi Mohamed [5 ]
Mortier, Laurent [1 ,2 ]
Vienne, Jean-Claude [3 ]
Briand, Gilbert [3 ]
Formstecher, Pierre [1 ,2 ]
Bailly, Christian [1 ,2 ]
Neviere, Remi [5 ]
Marchetti, Philippe [1 ,2 ,4 ]
机构
[1] Univ Lille 2, INSERM, U837, F-59045 Lille, France
[2] Univ Lille 2, Fac Med, F-59045 Lille, France
[3] CHRU, Ctr Biol Pathol, Lille, France
[4] CHRU, Ctr Biol Pathol & Banque Tissus, Lille, France
[5] Univ Lille 2, Fac Med, EA 2689, F-59045 Lille, France
关键词
Mitochondria; Apoptosis; Cancer; Chemotherapy; Metabolism; PERMEABILITY TRANSITION PORE; CELL-DEATH; MYOCARDIAL DYSFUNCTION; ANTICANCER DRUGS; CANCER; CHEMORESISTANCE; DERIVATIVES; ADAPHOSTIN; PROMOTES; PATHWAY;
D O I
10.1007/s10495-010-0471-2
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 (rho 0) derived from human melanoma cells. In comparison to parental cells, rho 0 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.
引用
收藏
页码:769 / 781
页数:13
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