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Uckun F.M.,Institute for Peadiatric Clinical Research | Uckun F.M.,University of Southern California | Uckun F.M.,Parker Hughes Institute | Uckun F.M.,Institute for Pediatric Clinical Research | And 6 more authors.
British Journal of Haematology | Year: 2010

The present study found that the pentapeptide mimic C-61, targeting the substrate binding P-site of SYK tyrosine kinase acted as a potent inducer of apoptosis in chemotherapy-resistant SYK-expressing primary leukemic B-cell precursors taken directly from relapsed B-precursor leukaemia (BPL) patients (but not SYK-deficient infant pro-B leukaemia cells), exhibited favourable pharmacokinetics in mice and non-human primates, and eradicated in vivo clonogenic leukaemia cells in severe combined immunodeficient mouse xenograft models of chemotherapy-resistant human BPL at dose levels non-toxic to mice and non-human primates. These in vitro and in vivo findings provide proof of principle for effective treatment of chemotherapy-resistant BPL by targeting SYK-dependent anti-apoptotic blast cell survival machinery with a SYK P-Site inhibitor. Further development of C-61 may provide the foundation for therapeutic innovation against chemotherapy-resistant BPL. © 2010 Blackwell Publishing Ltd. Source


Uckun F.M.,University of Southern California | Uckun F.M.,Institute for Pediatric Clinical Research | Uckun F.M.,Parker Hughes Institute | Ozer Z.,Institute for Pediatric Clinical Research | And 5 more authors.
British Journal of Haematology | Year: 2010

SYK tyrosine kinase has emerged as a master regulator of cellular resistance to oxidative stress (OS) by mediating the activation of the anti-apoptotic nuclear factor κB and phosphatidylinositol-3 kinase/AKT pathways after OS exposure. Here, we present unprecedented experimental evidence that polo-like kinase 1 (PLK1) is the upstream regulator of SYK in B-lineage acute lymphoblastic leukaemia (ALL) cells. Selective inhibition of PLK-1 with the leflunomide metabolite analogue α-cyano-β-hydroxy-β-methyl- N-[4-(trifluoromethoxy) phenyl]-propenamide/LFM-A12 abolished the resistance of B-lineage ALL cells to OS by preventing the activation of the anti-apoptotic SYK signal transduction pathway. Notably, LFM-A12 treatments at non-cytotoxic concentrations resulted in marked augmentation of clonogenic death in resistant human B-lineage ALL cell lines challenged with OS. Further, LFM-A12 augmented OS-induced apoptosis of chemotherapy-resistant primary leukaemic cells from relapsed B-lineage ALL patients in vitro and markedly potentiated the in vivo anti-leukaemic activity of total body irradiation (TBI) against leukaemia-initiating cells in severe combined immunodeficient mouse xenograft models of B-lineage ALL. This study is the first to identify PLK1 as a regulator of SYK tyrosine kinase and a molecular target to overcome SYK-mediated resistance of B-lineage ALL cells to OS. © 2009 Blackwell Publishing Ltd. Source


Uckun F.M.,University of Southern California | Uckun F.M.,Parker Hughes Institute | Dibirdik I.,Parker Hughes Institute
Nutrition and Cancer | Year: 2010

The effects of the rationally designed JAK3 inhibitor JANEX-1 on the development of intestinal tumors in the APCmin mouse model of familial adenomatous polyposis were examined. At a non-toxic dose level, >4 times lower than its day 30 LD10, JANEX-1 was highly effective in preventing intestinal tumor development in Min mice, resulting in markedly improved survival outcomes. JAK3 inhibitors may, therefore, be useful in the chemoprevention of colorectal cancer. Here, an overview regarding the potential of JANEX-1 as a chemopreventive agent is provided. Copyright © 2010, Taylor & Francis Group, LLC. Source


Uckun F.M.,Institute for Pediatric Clinical Research | Uckun F.M.,University of Southern California | Uckun F.M.,Parker Hughes Institute | Sun L.,Parker Hughes Institute | And 6 more authors.
British Journal of Haematology | Year: 2011

We report the cloning and characterization of a novel 54-kDa high-mobility group (HMG)-box protein as the ligand for the human pan-B cell co-receptor CD19 (CD19-L), which interacts with the extracellular domain of CD19 in trans. CD19-L is the first CD19-specific recombinant human protein with potent anti-leukaemic activity against B-lineage acute lymphoblastic leukaemia (ALL), the most common form of childhood cancer and the second most common form of acute leukaemia in adults. Soluble recombinant CD19-L protein exhibited exquisite specificity for the extracellular domain of CD19 and strong binding to the surface of B-lineage leukaemia/lymphoma cells. Engagement of CD19 co-receptor on B-lineage ALL cells with CD19-L perturbed the CD19-associated signalling network, altering the expression levels of multiple genes directly involved in regulation of apoptosis, and triggered rapid apoptotic cell death in a CD19-specific manner. The identification of human CD19-L may lead to therapeutic innovation for B-lineage ALL and other B-lineage lymphoid malignancies as well as B-cell lymphoproliferative states and systemic autoimmunity. © 2011 Blackwell Publishing Ltd. Source


Qazi S.,Gustavus Adolphus College | Qazi S.,Parker Hughes Institute | Qazi S.,Childrens Center for Cancer and Blood Diseases | Uckun F.M.,Parker Hughes Institute | And 2 more authors.
Journal of AIDS and Clinical Research | Year: 2012

Here we report that our lead anti-retroviral (ARV) drug candidate Stampidine [2,'3'-didehydro-3'-deoxythymidine-5'-(p-bromophenyl methoxy alaninyl phosphate)] results in methylation of a network of HIV-responsive regulatory genes in T-cells, including several genes for HIV-dependency factors (HDFs). Stampidine epigenetically modulates the host transcriptome in a unique manner, silences expression of a distinct set of genes encoding transcription factors and signal transduction molecules, and prevents HIV infection from distorting and disrupting key cellular transcriptional networks. At nanomolar concentrations that are 4-logs lower than those achieved at its non-toxic dose levels in mice, rats, cats, and dogs, Stampidine switched off genes for several HDFs that are required for HIV replication in T-cells. Notably, Stampidine reversed the effects of HIV exposure on the host transcriptome regardless of NRTI-sensitivity or RT mutations of the HIV isolate used and inhibited the replication of 17 NRTI-resistant HIV- 1 strains, including recombinant HIV clones containing common patterns of RT mutations responsible for NRTI resistance, in human peripheral blood mononuclear cells (PBMC) with subnanomolar-nanomolar IC50 values (Mean ± SEM = 12.0 ± 3.2 nM). Unlike available ARV agents that disrupt a specific step in the life-cycle of HIV, Stampidine has the potential to abrogate all steps in the life cycle of HIV. © 2012 Qazi S, et al. Source

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