| Autor: |
Quagliariello V; Division of Cardiology, Istituto Nazionale Tumori- IRCCS- Fondazione G. Pascale, 80131 Napoli, Italy., De Laurentiis M; Breast Unit, Istituto Nazionale Tumori- IRCCS- Fondazione G. Pascale, 80131 Napoli, Italy., Cocco S; Breast Unit, Istituto Nazionale Tumori- IRCCS- Fondazione G. Pascale, 80131 Napoli, Italy., Rea G; UOC Bersagli Molecolari del Microambiente, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80131 Naples, Italy., Bonelli A; Division of Cardiology, Istituto Nazionale Tumori- IRCCS- Fondazione G. Pascale, 80131 Napoli, Italy., Caronna A; Division of Cardiology, Istituto Nazionale Tumori- IRCCS- Fondazione G. Pascale, 80131 Napoli, Italy., Lombari MC; Division of Cardiology, Istituto Nazionale Tumori- IRCCS- Fondazione G. Pascale, 80131 Napoli, Italy., Conforti G; Division of Cardiology, Istituto Nazionale Tumori- IRCCS- Fondazione G. Pascale, 80131 Napoli, Italy., Berretta M; Department of MedicalOncology-Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy., Botti G; Scientific Direction, Istituto Nazionale Tumori- IRCCS- Fondazione G. Pascale, 80131 Napoli, Italy., Maurea N; Division of Cardiology, Istituto Nazionale Tumori- IRCCS- Fondazione G. Pascale, 80131 Napoli, Italy. |
| Abstrakt: |
Hyperglycemia, obesity and metabolic syndrome are negative prognostic factors in breast cancer patients. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, achieving unprecedented efficacy in multiple malignancies. However, ICIs are associated with immune-related adverse events involving cardiotoxicity. We aimed to study if hyperglycemia could affect ipilimumab-induced anticancer efficacy and enhance its cardiotoxicity. Human cardiomyocytes and estrogen-responsive and triple-negative breast cancer cells (MCF-7 and MDA-MB-231 cell lines) were exposed to ipilimumab under high glucose (25 mM); low glucose (5.5 mM); high glucose and co-administration of SGLT-2 inhibitor (empagliflozin); shifting from high glucose to low glucose. Study of cell viability and the expression of new putative biomarkers of cardiotoxicity and resistance to ICIs (NLRP3, MyD88, cytokines) were quantified through ELISA (Cayman Chemical) methods. Hyperglycemia during treatment with ipilimumab increased cardiotoxicity and reduced mortality of breast cancer cells in a manner that is sensitive to NLRP3. Notably, treatment with ipilimumab and empagliflozin under high glucose or shifting from high glucose to low glucose reduced significantly the magnitude of the effects, increasing responsiveness to ipilimumab and reducing cardiotoxicity. To our knowledge, this is the first evidence that hyperglycemia exacerbates ipilimumab-induced cardiotoxicity and decreases its anticancer efficacy in MCF-7 and MDA-MB-231 cells. This study sets the stage for further tests on other breast cancer cell lines and primary cardiomyocytes and for preclinical trials in mice aimed to decrease glucose through nutritional interventions or administration of gliflozines during treatment with ipilimumab. |
