TY - JOUR
T1 - Physiological levels of chromogranin A prevent doxorubicin-induced cardiotoxicity without impairing its anticancer activity
AU - Rocca, Carmine
AU - Scavello, Francesco
AU - Colombo, Barbara
AU - Gasparri, Anna Maria
AU - Dallatomasina, Alice
AU - Granieri, Maria Concetta
AU - Amelio, Daniela
AU - Pasqua, Teresa
AU - Cerra, Maria Carmela
AU - Tota, Bruno
AU - Corti, Angelo
AU - Angelone, Tommaso
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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 regulation of the cardiotoxic and antitumor activities of Doxo. The effects of a physiologic dose of full-length recombinant CgA on Doxo-induced cardiotoxicity and antitumor activity were investigated in rats using in vivo and ex vivo models and in murine models of melanoma, fibrosarcoma, lymphoma, and lung cancer, respectively. The effect of Doxo on circulating levels of CgA was also investigated. In vivo and ex vivo mechanistic studies showed that CgA can prevent Doxo-induced heart inflammation, oxidative stress, apoptosis, fibrosis, and ischemic injury.On the other hand,CgA did not impair the anticancer activity of Doxo in all the murinemodels investigated. Furthermore,we observed that Doxo can reduce the intracardiac expression and release of CgA in the blood (i.e., an important cardioprotective agent). These findings suggest that administration of low-dose CgA to patientswith low levels of endogenous CgA might represent a novel approach to prevent Doxo-induced adverse events without impairing antitumor effects.
AB - 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 regulation of the cardiotoxic and antitumor activities of Doxo. The effects of a physiologic dose of full-length recombinant CgA on Doxo-induced cardiotoxicity and antitumor activity were investigated in rats using in vivo and ex vivo models and in murine models of melanoma, fibrosarcoma, lymphoma, and lung cancer, respectively. The effect of Doxo on circulating levels of CgA was also investigated. In vivo and ex vivo mechanistic studies showed that CgA can prevent Doxo-induced heart inflammation, oxidative stress, apoptosis, fibrosis, and ischemic injury.On the other hand,CgA did not impair the anticancer activity of Doxo in all the murinemodels investigated. Furthermore,we observed that Doxo can reduce the intracardiac expression and release of CgA in the blood (i.e., an important cardioprotective agent). These findings suggest that administration of low-dose CgA to patientswith low levels of endogenous CgA might represent a novel approach to prevent Doxo-induced adverse events without impairing antitumor effects.
KW - Cancer
KW - Cardioprotection
KW - Intracellular signaling
UR - http://www.scopus.com/inward/record.url?scp=85067266107&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85067266107&partnerID=8YFLogxK
U2 - 10.1096/fj.201802707R
DO - 10.1096/fj.201802707R
M3 - Article
C2 - 30973759
AN - SCOPUS:85067266107
VL - 33
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 6
M1 - 000-000
ER -