Pascal Huart

Structure of the adriamycin-cardiolipin complex Role in mitochondrial toxicity

Adriamycin and its derivatives are among the most efficient antimitotics used in clinical therapy. A specific cardiotoxicity places a limit on the total dose of adriamycin that may be administered. The mechanism of cardiac toxicity is complex. Data accumulated from in vitro and in vivo studies indicate a possible common cause for the inhibition of numerous enzymes and tissue degradation by a free radical mechanism: the binding of adriamycin to the inner mitochondrial membrane cardiolipin. The structure of the adriamycin-cardiolipin complex has been investigated by using physico-chemical techniques and via conformational analysis. The results open a rational way to design new structures that are less cardiotoxic.

Mechanism of inhibition of mitochondrial enzymatic complex I–III by adriamycin derivatives

We demonstrate here that complex I-III of bovine heart mitochondrial membrane is inhibited by adriamycin derivatives. This inhibition is a cardiolipin-dependent process. This lipid, specific to the inner mitochondrial membrane, has been shown previously to interact specifically with adriamycin in model membranes (Goormaghtigh, E., Chatelain, P., Caspers, J. and Ruysschaert, J.-M. (1980) Biochim. Biophys. Acta 597, 1-14) and in mitochondrial membranes (Cheneval, D., Müller, M., Toni, R., Ruetz, S. and Carafoli, E. (1985) J. Biol. Chem. 260, 13003-13007). The differential scanning calorimetry data indicate that, in multilamellar liposomes, the formation of antibiotic-cardiolipin complexes induces a clustering of cardiolipin molecules. Conformational analysis of the antibiotic-cardiolipin complexes suggests that plane-plane interactions between the antibiotics aromatic moieties stabilize this complex formation. Possible mechanisms of inactivation of complex I-III by adriamycin are proposed.

Structural analogies between protein kinase C activators

Phorbol esters and diacylglycerols activate protein kinase C but specific structural parameters appear to be required for the enzyme activation. We have analyzed the conformation of potent and not potent diacylglycerols and phorbol esters. The orientation of the CH20H group at C3 of 1,2 diolein is remarkably similar to that of the same group at C-20 of 4 beta phorbol didecanoate and crucial for potency in activating the enzyme. Our data suggest that the new conformational approach here described could be used to rationally design specific inhibitors preventing the effects of tumor promoters and to predict the structure of potential tumor promoters.

Antimitotics induced cardiolipin cluster formation possible role in mitochondrial enzyme inactivation

We demonstrate here that drugs which inactivate cytochrome c oxidase are able to segregate cardiolipin essential for the enzyme activity, in a separate phase inaccessible for the enzyme. A molecular explanation of the drug-induced aggregation process is proposed.

Electronic properties of anthraquinone drugs in the inner mitochondrial membrane

Adriamycin was shown to affect electron transport in the inner mitochondrial membrane in two ways. In a first step, adriamycin inhibits the cytochrome c oxidase activity. In a second step, adriamycin catalyzes the deviation of the electron flow between NADH and cytochrome c towards oxygen. Most likely, highly reactive oxygen species induce polymerization of the membrane components.

Adriamycin-Mitochondrial Membrane Interactions and Cardiotoxicity

Adriamycin (ADM) is one of the most effective agents against leukemia and solid tumors. Its mode of interaction with its nuclear target has been extensively reviewed (Berman and Young 1981) and is assumed to be responsible for the antimitotic activity. Both X-ray measurements and conformational analysis indicate that the planar moiety of adriamycin intercalates between the base pairs, whereas the sugar moiety fits into the large DNA groove. Adriamycin displays also toxic side effects against a large variety of cells. Its cardiotoxicity is, however, very specific and places a limit on the total dose that may be given; the effect is cumulative over several months. Such a dose-limiting cardiotoxicity is not observed with the administration of other anticancer drugs. Interestingly, in a series of related anthracycline glycoside drugs, this cardiac toxicity can be dissociated from the antitumor activity suggesting a distinct mode of action (Casazza 1979). Much evidence suggests that the mitochondrial membrane could be the target responsible for the cardiac toxicity; indeed, the development of cardiac failure induced by adriamycin is characterized by a good correlation with the impairment of mitochondrial functions such as O2 consumption and ATP synthesis. Rhythmic contractions characteristic of myocardiac cells in culture cease with adriamycin treatment concomitant with a significant decrease of ATP and phosphocreatine concentrations.