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Evidences of CTLA-4 and PD-1 Blocking Agents-Induced Cardiotoxicity in Cellular and Preclinical Models

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Division of Cardiology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Napoli, Italy
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CEINGE—Biotecnologie Avanzate s.c.a.r.l., 80131 Naples, Italy
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Animal Facility, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Napoli, Italy
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Scientific Direction, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Napoli, Italy
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Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, 80131 Napoli, Italy
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Authors to whom correspondence should be addressed.
J. Pers. Med. 2020, 10(4), 179; https://doi.org/10.3390/jpm10040179
Received: 9 September 2020 / Revised: 29 September 2020 / Accepted: 9 October 2020 / Published: 19 October 2020
(This article belongs to the Special Issue The Effect of Different Drugs on Heart Disease)
Background: Several strategies based on immune checkpoint inhibitors (ICIs) have been developed for cancer therapy, opening to advantages in cancer outcomes. However, several ICI-induced side effects have emerged in these patients, especially a rare but clinically significant cardiotoxicity with high rate of mortality. We studied the cytotoxic and pro-inflammatory properties of Ipilimumab and Nivolumab, the underlying pathways and cytokine storm involved. Methods: Co-cultures of human cardiomyocytes and lymphocytes were exposed to Ipilimumab or Nivolumab; cell viability and expression of leukotrienes, NLRP3, MyD88, and p65/NF-kB were performed. C57 mice were treated with Ipilimumab (15 mg/kg); analysis of fractional shortening, ejection fraction, radial and longitudinal strain were made before and after treatments through 2D-echocardiography. Expression of NLRP3, MyD88, p65/NF-kB, and 12 cytokines were analyzed in murine myocardium. Results: Nivolumab and Ipilimumab exert effective anticancer, but also significant cardiotoxic effects in co-cultures of lymphocytes and tumor or cardiac cells. Both ICIs increased NLRP3, MyD88, and p65/NF-kB expression compared to untreated cells, however, the most pro-inflammatory and cardiotoxic effects were seen after exposure to Ipilimumab. Mice treated with Ipilimumab showed a significant decrease in fractional shortening and radial strain with respect to untreated mice, coupled with a significant increase in myocardial expression of NLRP3, MyD88, and several interleukins. Conclusions: Nivolumab and Ipilimumab exert cytotoxic effects mediated by the NLRP3/IL-1β and MyD88 pathways, leading to pro-inflammatory cytokine storm in heart tissue. View Full-Text
Keywords: cardiotoxicity; nivolumab; ipilimumab; immune checkpoint inhibitors; cardioncology cardiotoxicity; nivolumab; ipilimumab; immune checkpoint inhibitors; cardioncology
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MDPI and ACS Style

Quagliariello, V.; Passariello, M.; Rea, D.; Barbieri, A.; Iovine, M.; Bonelli, A.; Caronna, A.; Botti, G.; De Lorenzo, C.; Maurea, N. Evidences of CTLA-4 and PD-1 Blocking Agents-Induced Cardiotoxicity in Cellular and Preclinical Models. J. Pers. Med. 2020, 10, 179. https://doi.org/10.3390/jpm10040179

AMA Style

Quagliariello V, Passariello M, Rea D, Barbieri A, Iovine M, Bonelli A, Caronna A, Botti G, De Lorenzo C, Maurea N. Evidences of CTLA-4 and PD-1 Blocking Agents-Induced Cardiotoxicity in Cellular and Preclinical Models. Journal of Personalized Medicine. 2020; 10(4):179. https://doi.org/10.3390/jpm10040179

Chicago/Turabian Style

Quagliariello, Vincenzo, Margherita Passariello, Domenica Rea, Antonio Barbieri, Martina Iovine, Annamaria Bonelli, Antonietta Caronna, Gerardo Botti, Claudia De Lorenzo, and Nicola Maurea. 2020. "Evidences of CTLA-4 and PD-1 Blocking Agents-Induced Cardiotoxicity in Cellular and Preclinical Models" Journal of Personalized Medicine 10, no. 4: 179. https://doi.org/10.3390/jpm10040179

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