Abstract
Tyrosine kinase inhibitors (TKIs) can cause skeletal muscle toxicity in patients, but the underlying mechanisms are mostly unclear. The goal of the current study was to better characterize the role of mitochondria in TKI-associated myotoxicity. We exposed C2C12 murine myoblasts and myotubes as well as human rhabdomyosarcoma cells (RD cells) for 24 h to imatinib (1–100 µM), erlotinib (1–20 µM), and dasatinib (0.001–100 µM). In C2C12 myoblasts, imatinib was membrane toxic at 50 µM and depleted the cellular ATP pool at 20 µM. In C2C12 myotubes exposed to imatinib, ATP depletion started at 50 µM whereas membrane toxicity was not detectable. In myoblasts and myotubes exposed to dasatinib, membrane toxicity started at 0.5 µM and 2 µM, respectively, and the ATP drop was visible at 0.1 µM and 0.2 µM, respectively. When RD cells were exposed to imatinib, ATP depletion started at 20 µM whereas membrane toxicity was not detectable. Dasatinib was membrane toxic at 20 µM and depleted the cellular ATP pool already at 0.5 µM. Erlotinib was not toxic in both cell models. Imatinib (20 µM) and dasatinib (1 µM) reduced complex I activity in both cell models. Moreover, the mitochondrial membrane potential (Δψm) was dissipated for both TKIs in myotubes. In RD cells, the Δψm was reduced only by dasatinib. Both TKIs increased mitochondrial superoxide accumulation and decreased the mitochondrial copy number in both cell lines. In consequence, they increased protein expression of superoxide dismutase (SOD) 2 and thioredoxin 2 and cleavage of caspase 3, indicating apoptosis in C2C12 myotubes. Moreover, in both cell models, the mRNA expression of Sod1 and Sod2 increased when RD cells were exposed to dasatinib. Furthermore, dasatinib increased the mRNA expression of atrogin-1 and murf-1, which are important transcription factors involved in muscle atrophy. The mRNA expression of atrogin-1 increased also in RD cells exposed to imatinib. In conclusion, imatinib and dasatinib are mitochondrial toxicants in mouse C2C12 myotubes and human RD cells. Mitochondrial superoxide accumulation induced by these two TKIs is due to the inhibition of complex I and is probably related to impaired mitochondrial and myocyte proliferation.
Highlights
Tyrosine kinases (TKs) are a large family of enzymes, which are responsible for catalyzing phosphorylation reactions of the tyrosine molecules using ATP (Robinson et al, 2000)
As the first approved tyrosine kinase inhibitors (TKIs) of this new generation of anticancer drugs in 2001, imatinib is used for the treatment of Philadelphia-chromosomepositive chronic myelogenous leukemia (CML), which opened the way for the development of many more TKIs (Kantarjian et al, 2002)
C2C12 myoblasts, myotubes, and human RD cells exposed to imatinib and dasatinib showed a more pronounced decrease in the cellular ATP content compared to membrane damage, a pattern suggesting mitochondrial toxicity
Summary
Tyrosine kinases (TKs) are a large family of enzymes, which are responsible for catalyzing phosphorylation reactions of the tyrosine molecules using ATP (Robinson et al, 2000) Through this phosphorylation, they play key roles in cell proliferation, differentiation, migration, metabolism, and programmed cell death (Hubbard and Miller, 2007). They play key roles in cell proliferation, differentiation, migration, metabolism, and programmed cell death (Hubbard and Miller, 2007) This enzyme family has become one of the most important drug targets in the past 20 years because mutations, overexpression, and dysregulation of TKs play crucial roles in the pathogenesis of cancer (BlumeJensen and Hunter, 2001; Roskoski, 2020). Erlotinib and dasatinib, both multi-targeted TKIs, were approved in the USA and in Europe for the treatment of patients with lung cancer and CML, respectively (Duckett and Cameron, 2010)
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