Abstract 353: Sunitinib Induces Endoplasmic Reticulum Stress in Cardiomyocytes
Introduction: Chemotherapy-induced cardiac toxicities are the main obstacle for effective treatment of cancer, particularly in patients with pre-existing heart disease. This often results in premature termination of cancer treatment. Prominent among these agents is sunitinib (Sutent), which causes cardiac dysfunction in nearly 20% of cancer patients. It has recently been suggested that cardiac microvascular dysfunction, particularly loss of pericyte coverage, underlies sunitinib-induced cardiac dysfunction. However the exact mechanisms of sunitinib-induced cardiotoxicites are still unknown.
Results: Neonatal rat ventricular myocytes were treated with increasing concentrations (100nM-5uM) of sunitinib. Irrespective of the dose, there was a significant increase in markers of ER stress (Grp78, Grp 94, Erp72 and phospo/total-eIF2a) after 24 hours of treatment. The ER stress inducer thapsigargin was used as a positive control. Concordant with an increase in ER stress was the activation of mTOR in sunitinib (but not thapsigargin) treated NRVMs, suggesting a possible role of mTOR-mediated proteotoxicity in sunitinib-induced cardiac dysfunction. Protein synthesis, evaluated by 14C-phenylalanine incorporation into proteins, was moderately elevated in cells treated with sunitinib.
Conclusions: In addition to impairment of angiogenesis and pericyte loss, sunitinib induces mTOR activation and ER stress. We propose that the cardiac myocyte secretes paracrine factors that stabilize the cardiac microcirculation. This process is disrupted by sunitinib and ultimately leads to heart failure.
- © 2012 by American Heart Association, Inc.