In Vitro Cardiotoxicity Potential Comparative Assessments of Chronic Myelogenous Leukemia Tyrosine Kinase Inhibitor Therapies: Dasatinib, Imatinib and Nilotinib.

Abstract

Tyrosine kinase inhibitors (TKI) selective for Bcr-Abl, such as dasatinib, imatinib, and nilotinib have had remarkable success in the clinic, potentially shifting the prognosis of chronic myelogenous leukemia (CML) to a manageable chronic disease. With the increase in longevity of CML patients, there is rising concern of co-morbidities that may be influenced by chemotherapy (Force et al., Nature Rev.2007;7:332–340). Recently, congestive heart failure (CHF) and direct cellular cardiotoxicity have been reported in CML patients on imatinib therapy (Kerkela et al., Nature Medicine2006;12:908–916). Ultrastructural mitochondrial abnormalities in cardiomyocytes were observed in CML patients with severe CHF and, interestingly, similar abnormalities were observed in cardiomyocytes of imatinib-treated mice, thus providing a prospective in vivo animal model for imatinib-induced cardiotoxicity. Furthermore, correlative findings of mitochondrial membrane potential loss, decreased cell viability, and increased apoptosis resulted from an array of cell-based assays in imatinib-treated primary rat cardiomyocytes, consequentially affording a supportive, if not predictive, in vitro cardiomyocyte toxicity model. Since imatinib-induced inhibition of the native form of c-Abl kinase was speculated to cause the observed cardiotoxicity and c-Abl is a shared target of dasatinib, imatinib, and nilotinib, the in vitro cardiotoxicity potential of dasatinib and nilotinib at pharmacologically relevant concentrations (0.09 μM and 5 μM, respectively) and up to 10-fold higher concentrations were compared side-by-side with imatinib in primary rat cardiomyocytes. Dasatinib did not significantly affect mitochondrial membrane potential, cell viability, apoptosis, or cellular ultrastructure in vitro, whereas imatinib significantly affected these parameters. Nilotinib at pharmacologically relevant concentration demonstrated decreased cell viability, but differed from imatinib in that mitochondrial membrane potential integrity was not affected under identical experimental conditions. Results suggest that at pharmacologically relevant concentrations, dasatinib does not induce cardiotoxicity, as does imatinib and nilotinib, and the molecular mechanisms of the observed cardiotoxicities may differ between imatinib and nilotinib. Of indirect relation, results from assessing another cardiovascular liability, namely hERG K+ channel blockade, demonstrated that dasatinib, imatinib and nilotinib differentially inhibited the hERG currents in vitro with IC50 of 14.3, 15.6 and 0.66 μM, respectively. These in vitro findings occurred at concentration levels approximately 150, 3 and 0.1-fold the expected human Cmax for the three TKIs, respectively. Thus, although TKI therapies may share similar targeting and clinical indications, differentiating specific toxicity profiles may be predictive of differences in potential clinical adversities.

Mechanisms, monitoring, and management of tyrosine kinase inhibitors-associated cardiovascular toxicities

“… 13 Taken together, these results suggest that adverse effects are not originating at the level of the mitochondria and are supported by a separate study comparing dasatinib and imatinib in terms of their effects on mitochondrial structure or apoptosis. 5 …”

“… 1 The downstream effects of some of these kinases appear to play a role in ion channel activation. Reduced phosphorylation of the hERG potassium channel in particular has been explored; 5 ion channel blockade manifests as QT prolongation in the clinic, which has been connected with the use of some TKIs. It is possible that observed cardiac adverse effects occur secondary to TKI binding in the vasculature.…”

QT prolongation due to targeted anticancer therapy

“…Oxaliplatin ↑ [60] Intercalating agents amsacrine ↓ [61] SERMs Tamoxifen ↓ [62] ↓ [63] ↓ [63] Toremifene ↓ [64] TKIs Dasatinib ↓ [17] Crizotinib ↓ [15] - [15] ↓ [15] ↓ [15] Nilotinib ↓ [14] ↑ [14] ↓ [14] ↓ [14] ↓ [14] Sunitinib ↓ [15] - [15] ↓ [15] ↓ [15] erlotinib ↓ [15] - [15] ↓ [15] ↓ [15] lapatinib - [65] - [65] ↓ [65] ↓ [65] HDAC inhibitors Panobinostat ↓ [41] Other antineoplastics aTO ↑ [66] ↓ [67] ↓ [67] INa -peak sodium current, INal -late sodium current, ICal -l-type calcium current, IKr -rapid component of the delayed rectifier potassium current, IKs -slow component of the delayed rectifier potassium current, SeRMs -selective estrogen receptor modulators, TKIs -tyrosine kinase inhibitors, HDaC -histone deacetylase inhibitors, aTO -arsenic trioxide,  -activation,  -inhibition, --no effect.…”

“…In the study by Freebern et al, dasatinib, which is known to cause only mild QT prolongation, did not decrease cardiomyocytes viability neither resulted in their loss [17]. On the other hand, nilotinib associated with the risk of sudden death, significantly affected these characteristics [15,17]. Sunitinib also induced mitochondrial injury and the loss of cardiomyocytes in mice and in cultured rat myocardial cells [18].…”

“…Decrease in myocytes viability and their loss is also induced by some of TKIs [16]. In the study by Freebern et al, dasatinib, which is known to cause only mild QT prolongation, did not decrease cardiomyocytes viability neither resulted in their loss [17]. On the other hand, nilotinib associated with the risk of sudden death, significantly affected these characteristics [15,17].…”