Inhibition of mitochondrial respiration mediates apoptosis induced by the anti-tumoral alkaloid lamellarin D.
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.
Inserm U837 and Faculté de Médecine, Université de Lille II, 1 Place Verdun, 59045, Lille Cedex, France.
Caroline
C
Ballot
Jérome
J
Kluza
Steve
S
Lancel
Alain
A
Martoriati
Sidi Mohamed
SM
Hassoun
Laurent
L
Mortier
Jean-Claude
JC
Vienne
Gilbert
G
Briand
Pierre
P
Formstecher
Christian
C
Bailly
Remi
R
Nevière
Philippe
P
Marchetti
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000633:toxicity*; D017209:Apoptosis; D045744:Cell Line, Tumor; D019069:Cell Respiration / Q000187:drug effects; D003374:Coumarins / Q000737:chemistry / Q000633:toxicity*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000633:toxicity*; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000633:toxicity*; D019169:Jurkat Cells; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats
D000970:Antineoplastic Agents; D003374:Coumarins; D006576:Heterocyclic Compounds, 4 or More Rings; D007546:Isoquinolines; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C455554:lamellarin D