Anticancer Activity and Mechanisms of Action of MAPK pathway inhibitors

´╗┐Cardiotoxicity results include little adjustments in blood circulation pressure in addition to cardiomyopathy and arrhythmias [3]

´╗┐Cardiotoxicity results include little adjustments in blood circulation pressure in addition to cardiomyopathy and arrhythmias [3]. toxicity for both sufferers during therapy and in addition for healthcare employees during the stages of manipulation of antiblastic medications (Desk 1). Actually, many scientific studies show that in exposed workers the presence of several cardiotoxic drugs like doxorubicin, epirubicin, cyclophosphamide, and 5-fluourouracil was often identified in urine [1, 2]. Cardiotoxicity effects include small changes in blood pressure as well as arrhythmias and cardiomyopathy [3]. Mechanisms of cardiotoxicity by antiblastic drugs comprise cellular damage, with the LAMC2 formation of free oxygen radicals and the induction of immunogenic reactions with the presence of antigen presenting cells in the heart [4]. Early and late onset cardiac effects are reported; the first effect can be acute, DBeq subacute, or chronically progressive [5]. Acute or subacute cardiotoxicity effects of antiblastic drugs are rare; they occur during or immediately following infusion and are usually transient (e.g., electrocardiographic abnormalities such as nonspecific ST-T changes and QT prolongation, pericarditis-myocarditis syndrome, and ventricular dysfunction with congestive heart failure) [6]. The late effect generally starts within one year after the beginning of antiblastic therapy with chronic cardiac abnormalities and can progress to overt cardiac disease. However a sudden atrial fibrillation was observed at the third week of chemotherapy administration in patients with myotonic dystrophy [7]. The clinical symptoms may include all signs of cardiomyopathy with electrophysiologic changes, decrease of left ventricular function, changes in exercise-stress capacity, and overt signs of congestive heart failure [8]. During administration of taxoids, as paclitaxel, combined or with cisplatin, various cardiac disturbances, like brady- and tachyarrhythmias, atrioventricular and bundle branch blocks, and cardiac ischemia were reported [9]. Evidence of hypotension is also described, probably correlated to hypersensitivity reaction. A combination of doxorubicin and paclitaxel administration in rats is correlated to an increase of myocardial necrosis compared with those treated with DOX alone [10]. Table 1 Effects of antiblastic drugs on heart. and em /em , c-Kit, FLT3, CSF1R, and RET [66]. However, care should be taken when cardiotoxicity in humans and animal models is compared. In fact it has been reported [67] that while the TKIs pazopanib, sunitinib and sorafenib, showed cardiotoxic effects in humans, studies in animal model failed to show cardiac toxicities for all of these TKIs. TKIs can be divided into two general classes: (i) humanized monoclonal antibodies directed against the tyrosine kinase receptor or their ligands and (ii) small molecules interacting with kinases inhibiting their activity. The use of both classes of TKIs revealed a relatively high rate of adverse cardiac events in the clinic, with systolic dysfunction and resultant heart failure as one of the most common and important side effects. TKIs are frequently used for the DBeq treatment of renal-cell carcinoma, gastrointestinal stromal tumors, and other tumor types in which these drugs are still under investigation. It seems that TKIs have as target AMPK which is a critical kinase controlling the balance between ATP and AMP levels [66]. Following conditions of energy stress, AMPK may act as a metabolic switch, increasing energy generation and inhibiting anabolic pathways. Studies on animals treated with sunitinib suggest that together with a potential misregulation in AMPK signaling a possible role is played by mitochondrial dysfunction leading to alterations in cardiac energy homeostasis. Most probably sunitinib induces a cardiac dysfunction that could be dependent on the simultaneous inhibition of multiple signaling pathways all of which are necessary for the preservation of cardiac function and which could DBeq play a pivotal role in the increased cardiac stress such as hypertension [68]. 3. Other Cardiotoxicity Mechanisms 3.1. Taxoids Paclitaxel is formulated DBeq in a cremophor EL vehicle to enhance the drug solubility and it is suggested that the vehicle and not the cytotoxic drug itself is responsible for the cardiac disturbances. However, the cardiac rhythm disturbances are not reported with use of other drugs containing cremophor EL such as cyclosporine [69, 70]. The possible mechanism by which cremophor EL would cause cardiotoxicity is massive histamine release. Indeed, stimulation of histamine receptors in cardiac tissue in animal studies has resulted in conduction disturbances and arrhythmias. An alternative explanation for paclitaxel induced cardiotoxicity could be the induction of cardiac muscle damage by affecting subcellular organelles. DBeq Enhanced cardiac toxicity has been found in combined therapy of paclitaxel and doxorubicin. A similar effect has been shown for epirubicin. Docetaxel shows no increase in cardiac toxicity when combined with doxorubicin. 3.2. Cyclophosphamide and Ifosfamide High dose cyclophosphamide is used in transplant regimens and is associated with acute cardiotoxicity such as cardiac decompensation as well as fatal cardiomyopathy. Acute reversible decrease in systolic function has been described. Ifosfamide cardiotoxicity is reported in only a single study. The pathogenesis is not fully understood but an increase in free oxygen radicals seems to play.