Background/Introduction: The proteasomal inhibitor Carfilzomib is an effective chemotherapy, clinically used for multiple myeloma. However, Carfilzomib use has been associated with cardiovascular complications (cardiotoxicities) such as heart failure, arrhythmias, hypertension, and ischemic heart disease, with prevalence ranging from 1-25%. To date, the underlying mechanism(s) remain poorly understood and there is a lack of effective treatments in mitigating Carfilzomib-induced cardiotoxicities. Interestingly, the sodium-glucose cotransporter 2 (SGLT2) inhibitor Dapagliflozin was reported to improve cardiovascular outcomes, including reduce the risk of hospitalization and mortality due cardiovascular adverse events. The cardioprotective effects of Dapagliflozin has not been assessed in the context of cardiotoxicities induced by chemotherapies, particularly Carfilzomib.
Purpose: In this study, we aim to 1) elucidate the underlying mechanism(s) of Carfilzomib-induced cardiotoxicities; and 2) assess the cardioprotective potential of Dapagliflozin in mitigating Carfilzomib-induced cardiotoxicities.
Methods: Primary human cardiomyocytes (HCMs) were either treated with 1% DMSO (vehicle) or Carfilzomib for 72 hours. The effects of co-treatment with Carfilzomib (1 µM) and Dapagliflozin (1µM) on cell viabilities were also examined in HCMs and NCI-H929 multiple myeloma cell line. Cell viabilities were assessed via Cell Titre Glo®. Differential mRNA expression changes between treatments were examined via qPCR.
Results: Carfilzomib caused a dose-dependent decrease in HCM viability, whereby reduction of HCM viability to approximately 55% was observed at 1 µM dose. Cardiomyocyte-specific genes TOP2B and several critical metabolic regulators (FOXO1, PARP1, AMPK, and PPARGC1A) were also reduced in Carfilzomib-treated HCM compared to vehicle-treated controls. Moreover, key biomarker of heart failure, cardiac troponin 2 (TNNT2) and Follistatin-like 3 (FSLT3), were elevated in Carfilzomib-treated HCM. Sodium-hydrogen exchangers SLC9A2 and SLC9A4 were increased in Carfilzomib-treated HCMs. The calcium/calmodulin-dependent protein kinase 2 (CAMKK2) was also reduced in Carfilzomib-treated HCMs. RNA demethylase FTO, RNA methyltransferases (METTL4 and METTL14) and m6A readers (YTHDF1 and YTHDF2) were reduced in Carfilzomib-treated HCMs. Importantly, co-treatment with 1 μM Dapagliflozin increased cell viability (~10%) in Carfilzomib-treated HCM. Furthermore, Dapagliflozin did not alter the potency of Carfilzomib in reducing NCI-H929 viability.
Conclusion: Our study has identified 1) potential mechanisms of carfilzomib-induced cardiotoxicities, and 2) demonstrated that Dapagliflozin as a potential therapeutic agent to mitigate Carfilzomib-induced cardiotoxicities. Further investigation will be required to validate these mechanisms and evaluate the effectiveness of SGLT2 inhibitors for Carfilzomib-induced cardiotoxicities.