Cardiotoxicity in cancer immune-checkpoint therapy: Mechanisms, clinical evidence, and management strategies.

Immune-checkpoint inhibitors (ICIs), a unique antibody-based therapeutic strategy, have revolutionized the treatment landscape of solid and hematological cancers. Despite the proven benefits of ICIs, the cardiotoxicity from unspecific immune activation (uncommon but potentially fatal) is a continuing concern. Accumulating preclinical research has demonstrated that ICIs initiate inflammation in the myocardium, while clinically significant cardiotoxicity were reported in few patients receiving ICI therapy, probably due to the low incidence and unspecific symptoms. The subtle signs and symptoms (e.g., chest pain, dizziness, and dyspnea) were likely attributed to cancer and/or non-cardiac events by previous studies, thus limiting the understanding of the incidence, outcomes, risk factors, and management of ICI-related cardiotoxicity. The heterogeneous clinical presentation and complex diagnostic procedure further make it challenging to accurately identify ICI-related cardiac events in clinical trials. Therefore, ICI-related cardiotoxicity, whose incidence is probably underestimated, has not been well recognized. In this article, we provide an overview of potential mechanisms underlying ICI-related cardiotoxicity and review accumulating clinical evidence of ICI-related cardiotoxicity, with a focus on myocarditis. Moreover, we discuss possible strategies to manage ICI-related cardiotoxicity and highlight the importance of developing cardio-oncology.

Endoplasmic reticulum (ER) stress inhibitor salubrinal protects against ceramide-induced SH-SY5Y cell death.

In the present study, we examined the mechanisms of ceramide-induced cell death in SH-SY5Y human neuroblastoma cells. Our results demonstrate a significant endoplasmic reticulum (ER) stress response in SH-SY5Y cells after short-chain ceramide (C6) treatment. Administration of ceramide (C6) to SH-SY5Y human neuroblastoma cells caused apoptotic cell death, which was inhibited by ER stress inhibitor salubrinal. Further, ceramide-induced cell death reduced significantly in stable SH-SY5Y cells expressing C/EBP homologous protein (CHOP) shRNA. Salubrinal inhibited ceramide-induced inositol-requiring enzyme 1α (IRE1α)/apoptosis signal regulating kinase 1 (ASK1)/c-Jun N-terminal kinase (JNK) phosphorylation. Taken together, these data suggest that ceramide-induced SH-SY5Y cell death may be linked to the ER stress-regulated intrinsic pathway, and proposed the potential protective effects of salubrinal.