Livelli fisiologici della Cromogranina A esercitano potente effetto cardioprotettivo contro la cardiotossicità indotta da doxorubicina

Abstract

The clinical use of doxorubicin (Doxo), a widely used anticancer chemotherapeutic drug, is limited by dose-dependent cardiotoxicity. We have investigated whether chromogranin A (CgA), a cardioregulatory protein released in the blood by the neuroendocrine system and by the heart itself, may contribute to the regulation of cardiotoxic and antitumor activities of Doxo. We evaluated whether and to which extent, the in vivo administration of physiological doses of recombinant full-length CgA may exert cardioprotection in a Doxo-induced cardiotoxicity rat model and modulate the anticancer activity of Doxo in murine models of melanoma, fibrosarcoma, lymphoma, and lung cancer, respectively. The effect of Doxo on circulating levels of CgA was also investigated. At the end of the treatment, hearts were perfused by Langendorff method and Ischemic protocols were used. Western Blot, Immunohistochemistry techniques, and ELISA assay were used for molecular analysis and plasma measurements of TNFα, IL-1β, ROS, LDH, cTnT and CgA. We found that CgA mitigated Doxo-dependent adverse effects, as revealed by the reduction of pro-inflammatory and cardiotoxic markers. Doxo reduced CgA plasma levels. When given together with Doxo, CgA increased the systolic function after ischemia and reduced the infarct size, compared to the Doxo group alone. Molecular analysis indicated that CgA reduced CTGF expression, induced activation of the RISK and SAFE pathways and of AMPK, and reduced inflammatory targets such as iNOS, COX2, NLRP3. CgA reduced intracardiac ROS and the expression of AOX-1 and XO. CgA-dependent cardioprotection was mediated by ARC activation, by the increase of Bcl2 and the reduction of BAX, Caspase3 and the apoptotic nuclei. Furthermore, we observed that Doxo reduces the intracardiac expression and release of CgA (i.e., an important cardioprotective agent) in the blood. On the other hand, CgA did not impair the anticancer activity of Doxo in all the investigated murine models. These data suggest that CgA could mitigate Doxo-induced cardiotoxicity by limiting ischemic injury. The protein can be proposed as a possible biomarker and the administration of exogenous CgA to patients with low levels of the endogenous protein might represent a novel approach to prevent Doxo-induced adverse events without impairing its antitumor effects.