Kerkelä, R. et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat. Med. 12, 908-916

Center for Translational Medicine, Jefferson Medical College, 1025 Walnut Street, Philadelphia, Pennsylvania 19107, USA.
Nature Medicine (Impact Factor: 27.36). 09/2006; 12(8):908-16. DOI: 10.1038/nm1446
Source: PubMed


Imatinib mesylate (Gleevec) is a small-molecule inhibitor of the fusion protein Bcr-Abl, the causal agent in chronic myelogenous leukemia. Here we report ten individuals who developed severe congestive heart failure while on imatinib and we show that imatinib-treated mice develop left ventricular contractile dysfunction. Transmission electron micrographs from humans and mice treated with imatinib show mitochondrial abnormalities and accumulation of membrane whorls in both vacuoles and the sarco- (endo-) plasmic reticulum, findings suggestive of a toxic myopathy. With imatinib treatment, cardiomyocytes in culture show activation of the endoplasmic reticulum (ER) stress response, collapse of the mitochondrial membrane potential, release of cytochrome c into the cytosol, reduction in cellular ATP content and cell death. Retroviral gene transfer of an imatinib-resistant mutant of c-Abl, alleviation of ER stress or inhibition of Jun amino-terminal kinases, which are activated as a consequence of ER stress, largely rescues cardiomyocytes from imatinib-induced death. Thus, cardiotoxicity is an unanticipated side effect of inhibition of c-Abl by imatinib.

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    • "Protein kinases are often classified into different groups or subfamilies, but yet their entire super-family experiences a high degree of structural conservation. Structural similarity often makes them confusing to an inhibitor drug and thus, causes toxic side effects (Kerkela et al., 2006 "
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    ABSTRACT: The basic framework of understanding the mechanisms of protein functions is achieved from the knowledge of their structures which can model the molecular recognition. Recent advancement in the structural biology has revealed that in spite of the availability of the structural data, it is nontrivial to predict the mechanism of the molecular recognition which progresses via situation-dependent structural adaptation. The mutual selectivity of protein-protein and protein-ligand interactions often depends on the modulations of conformations empowered by their inherent flexibility, which in turn regulates the function. The mechanism of a protein's function, which used to be explained by the ideas of 'lock and key' has evolved today as the concept of 'induced fit' as well as the 'population shift' models. It is felt that the 'dynamics' is an essential feature to take into account for understanding the mechanism of protein's function. The design principles of therapeutic molecules suffer from the problems of plasticity of the receptors whose binding conformations are accurately not predictable from the prior knowledge of a template structure. On the other hand, flexibility of the receptors provides the opportunity to improve the binding affinity of a ligand by suitable substitution that will maximize the binding by modulating the receptors surface. In this paper, we discuss with example how the protein's flexibility is correlated with its functions in various systems, revealing the importance of its understanding and for making applications. We also highlight the methodological challenges to investigate it computationally and to account for the flexible nature of the molecules in drug design.
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    • "Numerous heart diseases are related to increases in MPTP activators such as calcium and oxidative stress and reductions in MPTP inhibitors such as ATP/ADP. Several studies have demonstrated that inhibition of the MPTP pore lessens the cardiomyocyte loss that underlies some cardiac pathologies including myocardial ischemia/reperfusion (IR) injury,57,58 calcium-induced cardiomyopathy,59 diabetic cardiomyopathy,60 and the cardiotoxicity of anti-cancer drugs.61 "
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    ABSTRACT: Traditionally, mitochondria have been regarded solely as energy generators for cells; however, accumulating data have demonstrated that these complex organelles play a variety of roles within the cardiomyocyte that extend beyond this classic function. Mitochondrial dynamics involves mitochondrial movements and morphologic alterations by tethering, fusion, and fission, which depend on cellular energy requirements and metabolic status. Many studies have indicated that mitochondrial dynamics may be a fundamental component of the maintenance of normal cellular homeostasis and cardiac function. Mitochondrial dynamics is controlled by the protein machinery responsible for mitochondrial fusion and fission, but cardiomyocytes are densely packed as part of an intricate cytoarchitecture for efficient and imbalanced contraction; thus, mitochondrial dynamics in the adult heart are restricted and occur more slowly than in other organs. Cardiac mitochondrial dynamics is important for cardiac physiology in diseased conditions such as ischemia-reperfusion (IR) injury. Changes in mitochondrial morphology through modulation of the expression of proteins regulating mitochondrial dynamics demonstrates the beneficial effects on cardiac performance after IR injury. Thus, accurately defining the roles of mitochondrial dynamics in the adult heart can guide the identification and development of novel therapeutic targets for cardioprotection. Further studies should be performed to establish the exact mechanisms of mitochondrial dynamics.
    Full-text · Article · Dec 2013
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    • "Regarding to molecular targeting, masitinib, inhibiting particularly c-KitR, but also PDGFR␣/␤ and Lck/LYn TK, as well as, in a lesser extent, FGFR3 and FAK, demonstrated weak inhibition of BCR/ABL TK and CSF-1R, compared to imatinib. In fact, it has been demonstrated in experimental animal models that masitinib has low risk of cardiotoxicity or genotoxicity compared to imatinib, due to masitinib highly selective activity, given by the absence of its interference on proteins involved in cardiotoxicity (left ventricular dysfunction or congestive heart failure), such as SRC family kinases, BCR/ABL TK, Vascular Endothelial Growth Factor Receptors (VEGFR), Epidermal Growth Factor Receptors (EGFR) [54]. Regarding to c-KitR activating mutations eventually predictive of resistance to TKI therapy, patients harboring specific c-KIT mutations, including those of the exon 9 and the exon 17 (e.g. "
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