Cancer–heart cross talk: Cytokine release pattern from anthracycline-treated cancer cell lines and their impact on cardiomyocyte metabolism.

Abstract

e24015 Background: Anthracyclines are effective cancer therapeutics but can cause cardiotoxicity. Recent studies suggest a connection between efficacy and toxicity in that the effects of anthracyclines on cancer cells leads to the release of interleukin 1-alpha (IL-1⍺), which negatively impacts cardiomyocyte metabolism and thereby cardiac function. This observation was made in in vivo and in vitro models of acute myeloid leukemia (AML); whether this holds true for other cancer cell lines remains unclear. Methods: Herein we characterized the cytokine profile of 9 cancer cell lines exposed to doxorubicin (1 µM for 24 hours) and then tested the effects of interleukin 1-alpha (IL-1⍺, 50-150 ng/mL) on the viability and metabolism of neonatal cardiomyocyte. We used Seahorse to assess cardiomyocyte glycolysis via extracellular acidification rate (ECAR) and mitochondrial oxidative phosphorylation based on the oxygen consumption rate (OCR). Results: As outlined in Table 1, different hematological and breast cancer cell lines showed a range of cytokine profile in response to doxorubicin exposure. Of the cytokines with putative action on cardiomyocyte metabolism IL-1⍺was one of the most induced in 3 out of 5 murine breast cancer, murine B- and T-cell lymphoma, as well as murine and human AML human and murine cell lines. Doxorubicin did not induce IL-1⍺ expression in macrophage cell lines (RAW) or directly in cardiomyocytes. Exposing neonatal cardiomyocytes to different concentrations of IL-1⍺ did not decrease but rather increased OCR and especially ECAR. Conclusions: These data confirm the release of IL-1⍺ from AML as well as several, but not all breast cancer cell lines. Furthermore, purified IL-1⍺ increased oxidative phosphorylation and glycolysis in murine neonatal cardiomyocytes. These data point out heterogeneity in the cytokine release pattern from anthracycline-treated cancer cell lines and their impact on cardiomyocyte metabolism. Further studies are required to define the nuances of crosstalk between cancer and the heart and its contribution to the variation in cardiotoxicity risk. Cytokine profile of cancer cell lines. Cytokines RAW Neonatal MC38HuPD-L1 EMT6 JC E0771 4T1 B Lymphoma: A20 T Lymphoma: E.G7-OVA AML Human: THP-1 AML mouse: C1498 ICAM-1, CD54 ++ ++ ++ ++ ++ ++ IL-1α IL-1F1 + + + + + + + IL-10 + + IL-16 ++ ++ ++ CXCL10/CRG-2 ++ + ++ ++ ++ ++ ++ ++ ++ M-CSF ++ ++ ++ + ++ ++ ++ ++ + RANTES CCL5 + ++ ++ ++ ++ TNF-α +++ + ++ + + + + +