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

Abstract

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.

Electrical Features of the Diabetic Myocardium. Arrhythmic and Cardiovascular Safety Considerations in Diabetes

“…Different mechanisms have been proposed to promote the development of diabetic cardiomyopathy and damage the heart. These include cardiac insulin resistance; metabolic remodeling with abnormal free fatty acids metabolism and lipotoxicity; mitochondrial dysfunction with increased ROS production; accumulation of advanced glycation end products and collagen; abnormalities in calcium handling; pro-inflammatory responses; activation of the renin-angiotensin-aldosterone system and autonomic neuropathy with increased sympathetic activity (reviewed in Casis and Echevarria, 2004 ; Battiprolu et al, 2013 ; Bugger and Abel, 2014 ; Onay-Besikci, 2014 ; Grisanti, 2018 ; Jia et al, 2018 ; Palomer et al, 2018 ; Quagliariello et al, 2020 ).…”

Association between Body Mass Index and Survival Outcome in Metastatic Cancer Patients Treated by Immunotherapy: Analysis of a French Retrospective Cohort

“…However, little is currently known about the situation in patients on immunotherapy. A recent in vivo study reported a decrease in the sensitivity of tumor cells to ipilimumab and an increase in cardiotoxicity in the presence of high glucose concentrations [ 61 ]. Martini et al also highlighted an association of higher BMI and subcutaneous fat index with prolonged survival on immunotherapy, whereas no such association was observed for high visceral adipose tissue levels [ 21 ].…”

“…Methods such as waist circumference determination [ 62 ] or computed tomography assessments [ 63 ] provide results more closely correlated with body composition. Biomarkers of metabolic syndrome are also being investigated [ 61 ] and may also be useful for improving the characterization of body composition and outcome on anticancer treatments, including immunotherapy. Furthermore, the percent lean tissue is often low in obese patients [ 64 ], potentially affecting pharmacokinetics and exposure to treatment [ 38 , 65 ].…”

Polydatin Reduces Cardiotoxicity and Enhances the Anticancer Effects of Sunitinib by Decreasing Pro-Oxidative Stress, Pro-Inflammatory Cytokines, and NLRP3 Inflammasome Expression

“…Intracellular reactive oxygen species (iROS) and lipid peroxidation are key mediators of several cardiac dysfunctions induced by TKi and doxorubicin (33). Cardiomyocytes and renal cancer cells were untreated (control) or treated for 12 h with polydatin (100 and 200 µM) or Sunitinib (10 µM) alone or combined to polydatin.…”