Cardiovascular toxicity post Carfilzomib (Cfz/Kyprolis) therapy has been identified in several clinical settings. A prevalent challenge in side effects of anti-cancer drugs is the translation of findings from preclinical research into clinical practice. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are being used as a physiological
in vitro
model to overcome some of these challenges. Here we used both 2D and 3D hiPSC-CMs to elucidate the underlying mechanism of post-Cfz cardiotoxicity. hiPSC-CMs were exposed to clinically relevant doses of Cfz based on C
max
for Cfz (5.88 μM). Data normalization against the control group demonstrates significant reduction in cell viability following two days of treatment with Cfz in 3 different cell lines (IMR-90, SCVI273 and 902). Increased Caspase3/7 activity post Cfz treatment paralleled with a substantial decrease in mitochondrial membrane potential and increase in oxidative stress following Cfz treatment. Also, significant decrease in oxygen consumption rate was observed after one-day exposure. In addition, we observed impaired Ca
2+
handling at the single cell level following Cfz treatment. Using video microscopy with motion vector analysis we also observed significant decrease in contractility of 3D hiPSC-CMs following Cfz treatment. Additionally, we observed disrupted expression of α-actinin, alterations in structural organization of sarcomeres, circularity and aspect ratio. Altogether, these results suggest that Cfz induced cardiotoxicity as indicated by cell viability, oxidative stress, mitochondrial and structural damages along with abnormal Ca
2+
handing and contractility dysfunction.
Metabolomic Profiling of Pompe Disease-Induced Pluripotent Stem Cell-Derived Cardiomyocytes Reveals That Oxidative Stress Is Associated with Cardiac and Skeletal Muscle Pathology
