Implications du stress oxydant et du fer dans la cardiotoxicité des anthracyclines et du trastuzumab

Involvement of oxidative stress and of iron in anthracycline and trastuzumab cardiotoxicity

• Auteur / Autrice : Charles Guenancia
• Direction : Luc Rochette, Catherine Vergely-Vandriesse
• Type : Thèse de doctorat
• Discipline(s) : Médecine
• Date : Soutenance le 17/11/2015
• Etablissement(s) : Dijon
• Ecole(s) doctorale(s) : École doctorale Environnements, Santé (Dijon ; Besançon ; 2012-....)
• Partenaire(s) de recherche : Laboratoire : Lipides, Nutrition, Cancer (LNC) (Dijon)
• Jury : Président / Présidente : Alain Cohen Solal
• Jury : Rapporteurs / Rapporteuses : Bernard Geny, Atul Pathak

Mots clés

Mots clés contrôlés

Cardiotoxicité

Trastuzumab

Anthracyclines

Stress oxydatif

Cancer

Mots clés libres

Cancer

Cardiotoxicité

Anthracyclines

Trastuzumab

Surpoids

Stress oxydant

Cancer

Cardiotoxicity

Résumé

Notre deuxième travail expérimental visait à élucider le rôle de la surcharge pondérale dans le développement de la cardiotoxicité des anthracyclines et du trastuzumab. Grâce à un modèle murin de surpoids modéré et de risque cardio-métabolique accru induits par programmation post-natale, nous avons mis en évidence le rôle potentiateur d’une surcharge pondérale sur le développement de la cardiotoxicité aux anthracyclines ; alors que la cardiotoxicité du trastuzumab ne semble pas être en revanche majorée par le surpoids. Nos travaux ont également permis de préciser les conditions dans lesquelles existent des potentialisations des effets lors de l’association doxorubicine et trastuzumab.

Cancer treatment has advanced considerably in recent years, allowing a reduction in mortality. Longer life expectancy of patients has helped to highlight the delayed onset of cardiovascular toxicity induced by these chemotherapies. The pathophysiological mechanisms responsible for these cardiac dysfunctions are complex, entangled and remain partially unknown. A better understanding of the phenomena involved in these cardiotoxicities is needed to prevent their occurrence. Therefore, we have developed two different experimental approaches to understand the pathophysiological mechanisms involved in the cardiac toxicity of anthracyclines and trastuzumab.A first experimental study aimed to clarify the role of iron in heart failure induced by anthracyclines. We have demonstrated that a tissular iron overload in mice prior to doxorubicin injection does not increase the cardiotoxicity of chemotherapy. On the contrary, the involvement of anti-radical defenses following the iron load could reduce cardiac oxidative damage generated by doxorubicin. In view of these data, the role of iron chelators in cardioprotection against anthracyclines has to be questioned.Our second experimental work was to elucidate the role of overweight in the development of anthracycline and trastuzumab cardiotoxicity. Using a mouse model of moderate overweight and of increased risk of cardiometabolic induced postnatal programming, we have highlighted the role of overweight on the development of anthracycline cardiotoxicity; whereas trastuzumab cardiotoxicity did not appear to be increased by overweight. Our work also clarified the conditions in which there are cumulative cardiac alterations when doxorubicin and trastuzumab are associated.