This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Treatment of high risk acute lymphoblastic leukemia patients whom are positive for the Philadelphia chromosome mutation (ALL Ph+) which results in the fusion of BCR and Abl kinase (BCR/Abl), patients over the years have been extremely difficult. Recently, the standard hyperCVAD (Cyclophosphamide, Vincristine, Dexamethasone, and Doxorubicin) treatment for these patients was modified to include Gleevec (imatinib). The addition of Imatinib has been extremely successful and has increased the complete remission (CR) rate from 60 to 96% and the 2 year survival rate from about 40% of 85%. The mechanism by which Imatinib increases the efficacy of treatment is unclear. Cyclophosphamide metabolites, doxorubicin, and vincristine are all substrates of multidrug resistance protein 1 (MRP1/ABCC1). Recent studies have shown that increased expression and function of MRP1 is associated with a much poorer prognosis, a reduced CR, and a decreased 2 year survival (over 65% reduction) in ALL patients. Preliminary studies carried out in our lab suggest that BCR/Abl regulates MRP1 function via casein kinase 2 (CK2). CK2 is regulated by BCR/Abl and Src kinases. Interestingly, treatment of ALL Ph+ cells with CK2 inhibitors in combination with Imatinib has been shown to increase Gleevec efficacy (a decrease in the IC50 by 35%) (21). Therefore we hypothesize that inhibition of BCR-Abl with Imatinib down regulates CK2 activity and CK2-mediated induction of MRP1 function, this results in increased cellular accumulation of the CVAD chemotherapeutics (BCR-Abl?CK2?MRP1). In this proposal we will: 1) Determine the direct mechanism by which BCR/Abl induces MRP1 function, 2) Determine the role of CK2 in BCR/Abl-mediated induction of MRP1 function, and 3) Test our hypothesis in a Ph+ ALL tissue culture model system, Sup-B15 cells and directly in patient primary cells obtained from the University of Kentucky clinic in collaboration with Dr. Dianna Howard.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR020171-08
Application #
8360576
Study Section
Special Emphasis Panel (ZRR1-RI-B (01))
Project Start
2011-07-01
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
8
Fiscal Year
2011
Total Cost
$249,930
Indirect Cost
Name
University of Kentucky
Department
Biochemistry
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Frasinyuk, Mykhaylo S; Zhang, Wen; Wyrebek, Przemyslaw et al. (2017) Developing antineoplastic agents that target peroxisomal enzymes: cytisine-linked isoflavonoids as inhibitors of hydroxysteroid 17-beta-dehydrogenase-4 (HSD17B4). Org Biomol Chem 15:7623-7629
Shrestha, Sanjib K; Kril, Liliia M; Green, Keith D et al. (2017) Bis(N-amidinohydrazones) and N-(amidino)-N'-aryl-bishydrazones: New classes of antibacterial/antifungal agents. Bioorg Med Chem 25:58-66
Burikhanov, Ravshan; Hebbar, Nikhil; Noothi, Sunil K et al. (2017) Chloroquine-Inducible Par-4 Secretion Is Essential for Tumor Cell Apoptosis and Inhibition of Metastasis. Cell Rep 18:508-519
Kenlan, Dasha E; Rychahou, Piotr; Sviripa, Vitaliy M et al. (2017) Fluorinated N,N'-Diarylureas As Novel Therapeutic Agents Against Cancer Stem Cells. Mol Cancer Ther 16:831-837
Cifuentes-Muñoz, Nicolás; Sun, Weina; Ray, Greeshma et al. (2017) Mutations in the Transmembrane Domain and Cytoplasmic Tail of Hendra Virus Fusion Protein Disrupt Virus-Like-Particle Assembly. J Virol 91:
Edgar, Rebecca J; Chen, Jing; Kant, Sashi et al. (2016) SpyB, a Small Heme-Binding Protein, Affects the Composition of the Cell Wall in Streptococcus pyogenes. Front Cell Infect Microbiol 6:126
Matveeva, Elena; Maiorano, John; Zhang, Qingyang et al. (2016) Involvement of PARP1 in the regulation of alternative splicing. Cell Discov 2:15046
Furman, Jennifer L; Sompol, Pradoldej; Kraner, Susan D et al. (2016) Blockade of Astrocytic Calcineurin/NFAT Signaling Helps to Normalize Hippocampal Synaptic Function and Plasticity in a Rat Model of Traumatic Brain Injury. J Neurosci 36:1502-15
Huang, Yunjie; Joshi, Smita; Xiang, Binggang et al. (2016) Arf6 controls platelet spreading and clot retraction via integrin ?IIb?3 trafficking. Blood 127:1459-67
Jeoung, Myoungkun; Jang, Eun Ryoung; Liu, Jinpeng et al. (2016) Shoc2-tranduced ERK1/2 motility signals--Novel insights from functional genomics. Cell Signal 28:448-459

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