Cancer Therapies and Cardiomyocyte Viability: Which Drugs are Directly Cardiotoxic?

BackgroundIncreased cancer survivorship represents a remarkable achievement for modern medicine. Unfortunately, cancer treatments have inadvertently contributed to cardiovascular (CV) damage, significantly threatening the health and quality of life of patients living with, through and beyond cancer. Without understanding the mechanisms, including whether the cardiotoxicity is due to the direct or indirect effects on cardiomyocytes, prevention and management of cardiotoxicity can pose challenges in many patients. To date, the cardiotoxicity profiles of most of the chemotherapy drugs are still poorly understood.AimTo conduct a pilot study to investigate the direct effects of a range of cancer therapies on cardiomyocyte viability.MethodsPrimary human cardiomyocytes (HCM) were cultured and seeded into 96-well culture plates. A total of 35 different Food and Drug Administration-approved anti-cancer drugs were added to the HCM cells with a concentration of 1uM for 72 hours. The viability of HCMs was determined using CellTitre-Glo. The experiments were repeated at least three times for each drug with HCMs of different passages.ResultsWe identified 15 anti-cancer agents that significantly reduced HCM viability. These drugs were: (1) anthracyclines (daunorubicin HCM viability, mean %±standard error, 13.7±3.2%, epirubicin 47.6±5.3%), (2) antimetabolite (azacitidine 67.1±2.4%), (3) taxanes (paclitaxel 60.2±3.0%), (4) protein kinase inhibitors (lapatinib 49.8±7.0%, ponatinib 42.4±9.0%, pemigatinib 68.1±2.3%, sorafenib 52.9±10.6%, nilotinib 64.4±4.5%, dasatinib 38.5±3.6%), (5) proteasome inhibitors (ixazomib citrate 65.4±7.2%), (6) non-selective histone-deacetylase inhibitor (panobinostat 19.1±4.1%), poly adenosine diphosphate-ribose polymerase inhibitor (olaparib 68.2±1.7%) and (7) vinca alkaloids (vincristine 44.6±7.4%, vinblastine 31.2±3.9%).ConclusionsIn total, 15 of the 35 commercially available anti-cancer drugs have direct cardiotoxic effects on HCM. Some of those, have not been associated with clinical cardiotoxicity, while others, known to be cardiotoxic do not appear to mediate it via direct effects on cardiomyocytes. More detailed investigations of the effects of cancer therapies on various cardiovascular cells should be performed to comprehensively determine the mechanisms of cardiotoxicity. Increased cancer survivorship represents a remarkable achievement for modern medicine. Unfortunately, cancer treatments have inadvertently contributed to cardiovascular (CV) damage, significantly threatening the health and quality of life of patients living with, through and beyond cancer. Without understanding the mechanisms, including whether the cardiotoxicity is due to the direct or indirect effects on cardiomyocytes, prevention and management of cardiotoxicity can pose challenges in many patients. To date, the cardiotoxicity profiles of most of the chemotherapy drugs are still poorly understood. To conduct a pilot study to investigate the direct effects of a range of cancer therapies on cardiomyocyte viability. Primary human cardiomyocytes (HCM) were cultured and seeded into 96-well culture plates. A total of 35 different Food and Drug Administration-approved anti-cancer drugs were added to the HCM cells with a concentration of 1uM for 72 hours. The viability of HCMs was determined using CellTitre-Glo. The experiments were repeated at least three times for each drug with HCMs of different passages. We identified 15 anti-cancer agents that significantly reduced HCM viability. These drugs were: (1) anthracyclines (daunorubicin HCM viability, mean %±standard error, 13.7±3.2%, epirubicin 47.6±5.3%), (2) antimetabolite (azacitidine 67.1±2.4%), (3) taxanes (paclitaxel 60.2±3.0%), (4) protein kinase inhibitors (lapatinib 49.8±7.0%, ponatinib 42.4±9.0%, pemigatinib 68.1±2.3%, sorafenib 52.9±10.6%, nilotinib 64.4±4.5%, dasatinib 38.5±3.6%), (5) proteasome inhibitors (ixazomib citrate 65.4±7.2%), (6) non-selective histone-deacetylase inhibitor (panobinostat 19.1±4.1%), poly adenosine diphosphate-ribose polymerase inhibitor (olaparib 68.2±1.7%) and (7) vinca alkaloids (vincristine 44.6±7.4%, vinblastine 31.2±3.9%). In total, 15 of the 35 commercially available anti-cancer drugs have direct cardiotoxic effects on HCM. Some of those, have not been associated with clinical cardiotoxicity, while others, known to be cardiotoxic do not appear to mediate it via direct effects on cardiomyocytes. More detailed investigations of the effects of cancer therapies on various cardiovascular cells should be performed to comprehensively determine the mechanisms of cardiotoxicity.