NLRP3 as Putative Marker of Ipilimumab-Induced Cardiotoxicity in the Presence of Hyperglycemia in Estrogen-Responsive and Triple-Negative Breast Cancer Cells

• Published in: International journal of molecular sciences Vol. 21; no. 20; p. 7802
• Main Authors: Quagliariello, Vincenzo, De Laurentiis, Michelino, Cocco, Stefania, Rea, Giuseppina, Bonelli, Annamaria, Caronna, Antonietta, Lombari, Maria Cristina, Conforti, Gabriele, Berretta, Massimiliano, Botti, Gerardo, Maurea, Nicola
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 21.10.2020; MDPI
• Subjects: Antineoplastic Agents, Immunological - adverse effects; Benzhydryl Compounds - pharmacology; Biomarkers, Pharmacological - metabolism; Breast cancer; Cardiomyocytes; cardioncology; Cardiotoxicity; Cardiotoxicity - etiology; Cardiotoxicity - metabolism; Cell Line, Tumor; Cell viability; Clinical trials; CTLA-4 Antigen - metabolism; Cytokines; Cytotoxicity; Diabetes; Estrogens; Female; Gene expression; Glucose; Glucose - metabolism; Glucose - pharmacology; Glucosides - pharmacology; Humans; Hyperglycemia; Hyperglycemia - etiology; Immune checkpoint inhibitors; Immunotherapy; Ipilimumab - adverse effects; Leukotriene B4 - metabolism; Medical prognosis; Metabolic disorders; Metabolic syndrome; Metabolism; Metastasis; Monoclonal antibodies; MyD88 protein; Myeloid Differentiation Factor 88 - metabolism; Myocarditis; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; nivolumab; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Proteins; Sodium-Glucose Transporter 2 Inhibitors - pharmacology; Targeted cancer therapy; Transcription Factor RelA - metabolism; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Tumor cell lines; hyperglycemia; breast cancer; cardiotoxicity; cardioncology; cytokines; nivolumab
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21207802

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.