Nlrp3 as putative marker of ipilimumab-induced cardiotoxicity in the presence of hyperglycemia in estrogen-responsive and triple-negative breast cancer cells: International Journal of Molecular Sciences

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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 MDAMB- 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. © 2020 by the authors.
Original languageEnglish
Pages (from-to)1-22
Number of pages22
JournalInt. J. Mol. Sci.
Volume21
Issue number20
DOIs
Publication statusPublished - 2020

Keywords

  • Breast cancer
  • Cardioncology
  • Cardiotoxicity
  • Cytokines
  • Hyperglycemia
  • Nivolumab
  • cryopyrin
  • cytotoxic T lymphocyte antigen 4
  • dapansutrile
  • empagliflozin
  • glucose
  • interleukin 1beta
  • interleukin 6
  • ipilimumab
  • myeloid differentiation factor 88
  • platelet derived growth factor
  • reactive oxygen metabolite
  • vasculotropin
  • animal cell
  • animal experiment
  • animal model
  • antineoplastic activity
  • Article
  • breast cancer cell line
  • cancer mortality
  • cancer resistance
  • cardiac muscle cell
  • cardiotoxicity
  • cell viability
  • controlled study
  • enzyme linked immunosorbent assay
  • female
  • fluorescence activated cell sorting
  • human
  • human cell
  • hyperglycemia
  • lipid peroxidation
  • MCF-7 cell line
  • MDA-MB-231 cell line
  • mouse
  • nonhuman
  • protein expression
  • triple negative breast cancer

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