Primary Endothelial Damage Is the Mechanism of Cardiotoxicity of Tubulin-Binding Drugs

Abstract

The use of tubulin binders (TBs) in the treatment of cancer often is associated with cardiotoxicity, the mechanism of which has not been elucidated. To test the hypothesis that interstitial cells of the myocardium are the primary target of TBs, we evaluated the acute effects of a single iv administration of three reference TBs: colchicine (0.2 and 2 mg/kg), vinblastine (0.5 and 3 mg/kg), and vincristine (0.1 and 1 mg/kg) 6 and 24 h after dosing. Mitotic arrest was identified at 24 h in all high-dose groups based on an increase in the number of mitotic figures in the interstitium coupled with a decrease in the number of Ki67-positive interstitial cells. Analysis of the myocardial transcriptomic data further supported G2/M cell cycle arrest 6 h after dosing with the high-dose groups of all three compounds. Apoptotic figures and an increase in the number of cleaved caspase 3-positive cells were identified at 6 and 24 h at the highest dose of each compound predominantly in interstitial cells, whereas a few cardiomyocytes were affected as well. Transcriptomic profiling of the myocardium further suggested that some of the affected interstitial cells were endothelial cells based on the upregulation of genes typically associated with vascular damage and downregulation of endothelial cell-specific molecule 1 and apelin. Taken together, these data identify endothelial cells of the myocardium as the primary target of the cardiotoxicity of TBs and identify cell cycle arrest as the mechanism of this toxicity.

Rituximab-Vincristine Chemotherapy-Induced Acute Anterior Wall Myocardial Infarction with Cardiogenic Shock

“…2,6,7 A study by Mikaelian and colleagues 8 showed that tubulin-binding drugs (including vincristine and vinblastine) can induce cell-cycle arrest of the rapidly proliferating cardiac endothelial cells and cause myocardial infarction. Vincristine is more often reported to cause ischemic syndromes than is rituximab, but a catastrophic synergism of vincristine and rituximab certainly cannot be ruled out.…”

Acute coronary syndrome developed after vincristine administration

“…It has been shown in the literature that vinca alkaloids, such as vincristine, cause endothelial damage and myocardial ischemia. [6,7] It has also been demonstrated that cardiotoxic effects of doxorubicin are associated with excessive free radical formation and decrease in antioxidant radicals, sarkolemmal sodium-calcium exchange deterioration, and disruption of energy metabolism in myocardial cells. [2,8] Doxorubicin has been responsible for cardiomyopathy, especially dilated cardiomyopathy, and its cardiotoxic affects are attenuated by vincristine.…”

Anticancer therapy-induced vascular toxicity: VEGF inhibition and beyond

“…Other classical chemotherapeutics, including cyclophosphamide (a nitrogen mustard inducing DNA alkylation [79]), bleomycin (antitumor antibiotic that induces DNA degradation) and vinca alkaloids (depolarizing agents causing spiral-like distortions of the cellular microtubules [80]) have been considered responsible for the endothelial damage.…”