SRC Family Kinase Inhibition in Ewing Sarcoma Cells Induces p38 MAP Kinase-Mediated Cytotoxicity and Reduces Cell Migration.

Ewing sarcoma (ES) is a highly aggressive bone and soft tissue cancer, representing the second most common primary malignant bone tumor in children and adolescents. Although the development of a multimodal therapy, including both local control (surgery and/or radiation) and systemic multidrug chemotherapy, has determined a significant improvement in survival, patients with metastatic and recurrent disease still face a poor prognosis. Moreover, considering that ES primarily affects young patients, there are concerns about long-term adverse effects of the therapy. Therefore, more rational strategies, targeting specific molecular alterations underlying ES, are required. Recent studies suggest that SRC family kinases (SFKs), which are aberrantly activated in most cancer types, could represent key therapeutic targets also for ES. Here, we challenged ES cell lines with a recently developed selective SFK inhibitor (a pyrazolo[3,4-d]pyrimidine derivative, called SI221), which was previously shown to be a valuable proapoptotic agent in other tumor types while not affecting normal cells. We observed that SI221 significantly reduced ES cell viability and proved to be more effective than the well-known SFK inhibitor PP2. SI221 was able to induce apoptosis in ES cells and also reduced ES cell clonogenic potential. Furthermore, SI221 was also able to reduce ES cell migration. At the molecular level, our data suggest that SFK inhibition through SI221 could reduce ES cell viability at least in part by hindering an SFK-NOTCH1 receptor-p38 mitogen-activated protein kinase (MAPK) axis. Overall, our study suggests a potential application of specific SFK inhibition in ES therapy. J. Cell. Physiol. 232: 129-135, 2017. © 2016 Wiley Periodicals, Inc.

Comparison of Dasatinib, Nilotinib, and Imatinib in the Treatment of Chronic Myeloid Leukemia.

To overcome the drug resistance phenomenon induced by Imatibib (IM), in clinical practice, are often used second generation of tyrosine kinase inhibitors as Nilotinib (NIL); a such potent inhibitor of the BCR/ABL kinase and Dasatinib (DAS), a inhibitor of BCR/ABL kinase, and inhibitor SrC family kinase. In this study we evaluated the in vivo effect of DAS, NIL, and IM on intracellular calcium concentration, oxidative stress, and apoptosis in peripheral blood leukocytes of 45 newly diagnosed patients with chronic myeloid leukaemia (CML-PBM). Our data demonstrated that treatment with DAS and NIL showed an higher modulating potential than IM on intracellular calcium concentration by inhibiting the thapsigargin, a sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitor, and Lithium (Li) an inositol 1,4,5-triphosphate (InsP3) receptor inhibitor activities. Moreover our data demonstrated that NIL and DAS have significantly increased apoptosis more than IM by involving both intracellular calcium signaling as well as oxidative stress. The acquisition of the oxidative stress and calcium channels receptors values data could help the hematologist to modulate and improve the treatment of chronic myeloid leukaemia (CML) pathology.

Prevention of nephrotoxicity induced by cyclosporine-A: role of antioxidants.

Cyclosporine A (CsA) is a powerful immunosuppressive drug used to prevent allograft rejection after organ transplantation as well as in human and veterinary medicine. Unfortunately, its use is hampered by its nephrotoxic effects. The mechanisms of CsA-induced hypertension and nephrotoxicity are not clear, but several studies suggest the possible involvement of free radicals. In this review we have summarized the effect of some antioxidants that we have used in the recent years, in combination with CsA, to better understand the exact mechanism of action of CsA and to try to open new perspectives in the treatment of CsA nephrotoxicity.

The Protective Effect of Apocynin on Cyclosporine A-Induced Hypertension and Nephrotoxicity in Rats.

Cyclosporine A (CsA) is the prototype of immunosuppressant drugs that has provided new perspectives in human and veterinary medicine to prevent organ transplant rejection and to treat certain autoimmune diseases and dermatologic diseases. Unfortunately, the treatment with CSA is often limited by severe adverse effects such as hypertension and nephrotoxicity. Some data suggest that reactive oxygen species (ROS) and the oxidative stress play an important role in its pathogenesis, in particular the superoxide (O2 (-)) that is the most powerful free radical generated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase present mainly in the kidney. The present study has been designed to investigate the role of Apocynin a selective inhibitor of NADPH oxidase activity on cyclosporine-induced adverse effect. In this study, we have evaluated the effect of CsA, used alone or in association with Apocynin on blood pressure (BP), on glomerular filtration rate (GFR), on absoluted fluid reabsorption (Jv) in proximal tubule (PT), on O2 (-) concentration, and on nitric oxide (NO) production. We have demonstrated that CsA administration increases superoxide concentration in the aorta, decreases the NO concentration, reduces GFR and the Jv in PT, and induces a significant increase in BP. Moreover, we have shown that Apocynin treatment restores these hemodynamic alterations, as well as NO and superoxide productions. In conclusion, the reported data indicate that CsA induced nephrotoxicity and hypertension are related to NADPH oxidase activity, in fact Apocynin protects the kidney function and BP from toxic effects induced by CsA through the inhibition of NADPH oxidase activity.

Response to eribulin in a difficult-to-treat, heavily pretreated breast cancer patient: a case report.

In this short paper, we report our experience with eribulin mesylate in a heavily pretreated breast cancer patient with multiple bone metastases. The patient had been treated with doxorubicin, cyclophosphamide, methotrexate, fluorouracil, tamoxifen, letrozole, LH-RH analogs, fulvestrant, bevacizumab and paclitaxel and liposomal doxorubicin. In November 2013 treatment with eribulin ready to use solution (1.23 mg/m(2) days 1 and 8 of a 21-day cycle) was started and administered for a total of 14 courses. After six cycles of eribulin, evaluation with MRI showed a marked decrease in neoplastic involvement and replacement of osteolytic lesions with osteoblastic ones. No unexpected acute toxicity was observed. Although with all the limitations of any anecdotal report, our experience documents the efficacy and safety of eribulin in this difficult-to-treat patient who had been treated with multiple lines of chemotherapy.

Polyunsaturated fatty acids, thrombosis and vascular disease.

In the 80's, retrospective studies showed an inverse relation between fish consumption and ischemic heart disease (IHD) mortality. In parallel, fish fats containing the polyunsaturated fatty acid (PUFA) eicosapentaenoic (EPA) were shown to impair platelet aggregation and thromboxane formation. The results of the large prospective trials, the Diet and Reinfarction Trial (DART) and the Lyon Heart Study in the secondary prevention of myocardial infarction, have further supported the interrelationships between diet and dietary prevention of IHD. In the DART Study, the cardioprotection by EPA was paralleled by an increase plasma content of EPA. In the Lyon, in addition to changes in the content of EPA, changes in other well known variables (i.e. leukocytes and vitamin E), often abnormal in subjects prone to arterial thrombosis, have been found. The GISSI Prevenzione Trial was a prospective, multicentric, open labeled trial with a factorial design, in which 11,324 recent (<3 mo) survivors of a first myocardial infarction were assigned to receive, in addition to the usual strategy, a supplementation of n-3 PUFA, vitamin E, or the combination of the two. Cardiovascular death (-30%), coronary heart disease death (-35%), total death (-20%) and sudden death (-45%) were all significantly reduced by the n-3 PUFA supplementation. The reduced tendency to sudden death of survivors of myocardial infarction on treatment with n-3 PUFA are in keeping with a series of scanty but reliable clinical data as well as of experimental studies. However, we believe that large-scale prospective multicentric randomized trials aimed at preventing sudden death in high-risk patients as well as at testing the effects of n-3 PUFA in patients with intracoronary devices and sustained ventricular arrhythmias, are a major direction to be followed to better understand the n-3 PUFA and sudden death issue.