Effect of the Multitargeted Tyrosine Kinase Inhibitors Imatinib, Dasatinib, Sunitinib, and Sorafenib on Mitochondrial Function in Isolated Rat Heart Mitochondria and H9c2 Cells

Abstract

Cardiovascular disease has recently been suggested to be a significant complication of cancer treatment with several kinase inhibitors. In some cases, the mechanisms leading to cardiotoxicity are postulated to include mitochondrial dysfunction, either as a primary or secondary effect. Detecting direct effects on mitochondrial function, such as uncoupling of oxidative phosphorylation or inhibition of electron transport chain components, as well as identifying targets within the mitochondrial electron transport chain, can be accomplished in vitro. Here, we examined the effects of the tyrosine kinase inhibitor drugs imatinib, dasatinib, sunitinib, and sorafenib on ATP content in H9c2 cells grown under conditions where cells are either glycolytically or aerobically poised. Furthermore, we measured respiratory capacity of isolated rat heart mitochondria in the presence of the four kinase inhibitors and examined their effect on each of the oxidative phosphorylation complexes. Of the four kinase inhibitors examined, only sorafenib directly impaired mitochondrial function at clinically relevant concentrations, potentially contributing to the cytotoxic effect of the drug. For the other three kinase inhibitors lacking direct mitochondrial effects, altered kinase and other signaling pathways, are a more reasonable explanation for potential toxicity.

Phase 1 pharmacokinetic and drug‐interaction study of dasatinib in patients with advanced solid tumors

“…25 In our study, when dasatinib and ketoconazole were coadministered, the mean increase in plasma concentration of dasatinib (4.8 times) was associated with an increase in the QTc interval of about 6 msec. Our QTc interval findings were consistent with those from studies of dasatinib in patients with leukemia.…”

Pulmonary Arterial Hypertension in Patients Treated by Dasatinib

“…44 Several TKIs or multiple kinase inhibitors, including imatinib, sorafenib, and sunitinib exhibit cardiotoxicity both in experimental models and in humans. 39,40,45 Kerkela et al 40 demonstrated that the cardiotoxicity of TKIs was an unanticipated side effect of inhibition of c-Abl, a common characteristics of TKIs used in the treatment of CML. In addition, Chintalgattu et al 46 reported that cardiomyocyte platelet-derived growth factor receptor-beta is a regulator of the compensatory cardiac response to pressure overload-induced stress, suggesting that inhibition of platelet-derived growth factor pathway may be at least in part responsible for cardiotoxicity due to TKIs.…”

New Insights into Molecular Mechanisms of Sunitinib-Associated Side Effects

“…Finally, mitochondrial damage was observed in human biopsies and in mice treated with sunitinib (26). However, studies in vitro using isolated rat heart mitochondria failed to find a direct effect of sunitinib on mitochondrial function at clinically relevant concentrations (27). These data do not preclude a secondary effect of sunitinib on mitochondria, which are sensitive to host stress and are often disrupted during necrosis or apoptosis, regardless of cause.…”