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comparable to those of NSC130362. Their pharmacokinetic profile is currently under investigation. As soon as we identify stable NSC130362 analogs, we will test them in combination with TRAIL in vivo. In the current studies, we selected ATO as an agent that could substitute TRAIL in in vivo studies and confirm the anti-tumor activity and safety to normal cells of NSC130362 in mice. In agreement with the cell-based assays, combination of ATO and NSC130362 retarded growth of MIA PaCa-2 xenografts. Importantly, this combined treatment was not toxic to normal tissue as was evidenced by the H&E staining of liver and heart tissue sections, which are the most sensitive to oxidative stress. In summary, we have demonstrated that phenotypic TRAIL-based HTS and in silico methods can be employed to identify chemical compounds that specifically induce cytotoxicity in cancer cells while sparing normal cells. In our study we identified a specific inhibitor of GSR activity, which, when combined with other oxidative stress inducers, may provide the basis for a potent and non-toxic cancer therapy. Our results suggest that increased ROS generation in transformed cells, compared with normal cells, is the primary cause for the selectivity and the potency of the described treatment. 22 / 26 Discovery of a New Component in the TRAIL Pathway ~~ The BCR-ABL tyrosine kinase formed by the balanced translocation t is the “key player” in the pathogenesis of chronic myeloid leukemia. Its deregulated TK activity affects various downstream signaling pathways and results in reprogramming of the prior lineage commitment of hematopoietic stem PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19705642 and early progenitor cells. Compromising multiple aspects of the affected hematopoietic stem cell, including proliferation, apoptosis, cell to cell signaling and differentiation, the BCR-ABL oncoprotein triggers aberrant clonal hematopoiesis and drives disease progression from chronic phase toward the fully transformed phenotype of blast crisis. Imatinib is a selective TK inhibitor and represents one of the current first line treatment options for CML. However, persistence of so-called leukemia stem cells with low BCR-ABL PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19704080 expression, insensitivity to IM treatment and long term survival capacity has been observed. Acquisition of additional genetic lesions in LSCs or their progeny drives leukemic transformation from CML CP to accelerated phase or BC. Genomic instability and aneuploidy are hallmarks of the progressing CML and concur with BCR-ABL mutations encoding resistance to TKI and/or development of additional chromosomal aberrations in addition to the Philadelphia chromosome . About 35% of MedChemExpress SB-590885 patients in CP develop resistance or intolerance to IM and frequently undergo clonal evolution. While approximately 1012% of patients in CML CP display ACA at diagnosis, this proportion of patients rises to approximately 30% and 80% in AP and BC, respectively. Recently, we have shown that major route ACA at diagnosis are associated with a negative impact on survival and signify progression to AP and BC. Moreover, clonal evolution during the course of CML is considered a feature of acceleration and indicate poor prognosis as patients with ACA show lower cytogenetic response rates under IM. According to the European LeukemiaNet recommendations newly arising ACA under IM treatment define failure of therapy. The occurrence of supernumerary centrosomes is the major cause of multipolar mitotic spindle formation and chromosomal missegregation leading