The overall goal of this proposal is to develop vitamin D-based therapeutic regimens to supplement the treatment, and design strategies for the prevention, of human acute myeloid leukemia (AML). Specifically, we will focus on the identification of analogs of the physiological form of vitamin D, 1,25- dihydroxyvitamin D3 (1,25D and analogs are collectively dubbed "deltanoids") which are the most effective when administered to leukemia cells in combination with Carnosic acid . We will study the alterations in gene expression, and other cellular changes that can be used as biomarkers of response to this treatment. AML cells ex vivo, freshly obtained from patients, and cells in established cultur will be used for studies of cell differentiation, resistance to differentiation, cell cycle arrest,and survival mechanisms in the presence of therapeutic toxic agents. The rationale is provided by numerous previous observations that deltanoids induce expression of genes which regulate monocytic differentiation but also can cause resistance to differentiation (Specific Aim 1), the differentiation-associated cell cycle arrest (Specific Aim 2), and cell survival changes dependent on microRNA32 and on signaling pathways that link the scaffold protein hKSR2 with NFkB complex(Specific Aim 3). Special attention will be given to deltanoids already approved for human administration the differentiation activity of which is highly enhanced by Carnosic acid. This project will be accomplished by a variety of approaches, including addition to cultured cells of pharmacological agents, antisense oligonucleotides, siRNAs, molecular decoys, and transfected plasmid constructs to study the molecular consequences of these manipulations, which will be determined by immunoblotting, quantitative RT-PCR, immunoprecipitation, and other molecular techniques. Differentiating cells will be monitored by determination of cell surface and molecular markers, as well as by the activity and the expression of various enzymes. The information obtained in basic studies will be utilized to guide development of Clinical Trials of deltanoids, and their combinations with the differentiation enhancer carnosic acid, while translational studies on leukemic cells ex vivo will serve to identify biomarkers of responsiveness to deltanoids and the recognition of subgroups of myeloid leukemias which will be the most suitable for the initiation of planned clinical trials.
Differentiation therapy, which depends on the activation of existing cellular programs rather than on toxic drugs to combat cancers and blood malignancies is already effective as the treatment of some of these diseases. We propose to develop it as treatment and prevention of blood malignancy known as acute myeloid leukemia which, although kills approximately 15,000 people in USA every year, is unlikely to receive attention for finding its cure from commercial sources. Therefore, acute myeloid leukemia can be considered an orphan disease and merits support from public sources for the development of novel therapy.
|Pesakhov, Stella; Nachliely, Matan; Barvish, Zeev et al. (2016) Cancer-selective cytotoxic Ca2+ overload in acute myeloid leukemia cells and attenuation of disease progression in mice by synergistically acting polyphenols curcumin and carnosic acid. Oncotarget 7:31847-61|
|Wang, Xuening; Harrison, Jonathan S; Studzinski, George P (2016) BRAF signals to pro-apoptotic BIM to enhance AraC cytotoxicity induced in AML cells by Vitamin D-based differentiation agents. J Steroid Biochem Mol Biol :|
|Harrison, Jonathan S; Wang, Xuening; Studzinski, George P (2016) The role of VDR and BIM in potentiation of cytarabine-induced cell death in human AML blasts. Oncotarget 7:36447-36460|
|Wang, Xuening; Harrison, Jonathan S; Studzinski, George P (2016) Enhancement of arabinocytosine (AraC) toxicity to AML cells by a differentiation agent combination. J Steroid Biochem Mol Biol 164:72-78|
|Zheng, Ruifang; Wang, Xuening; Studzinski, George P (2015) 1,25-Dihydroxyvitamin D3 induces monocytic differentiation of human myeloid leukemia cells by regulating C/EBPÎ² expression through MEF2C. J Steroid Biochem Mol Biol 148:132-7|
|Wang, Xuening; Pesakhov, Stella; Harrison, Jonathan S et al. (2015) The MAPK ERK5, but not ERK1/2, inhibits the progression of monocytic phenotype to the functioning macrophage. Exp Cell Res 330:199-211|
|Studzinski, George P; Harrison, Jonathan S; Wang, Xuening et al. (2015) Vitamin D Control of Hematopoietic Cell Differentiation and Leukemia. J Cell Biochem 116:1500-12|
|Wang, Xuening; Pesakhov, Stella; Harrison, Jonathan S et al. (2014) ERK5 pathway regulates transcription factors important for monocytic differentiation of human myeloid leukemia cells. J Cell Physiol 229:856-67|
|Gocek, Elzbieta; Moulas, Anargyros N; Studzinski, George P (2014) Non-receptor protein tyrosine kinases signaling pathways in normal and cancer cells. Crit Rev Clin Lab Sci 51:125-37|
|Wang, Xuening; Pesakhov, Stella; Weng, Ashley et al. (2014) ERK 5/MAPK pathway has a major role in 1Î±,25-(OH)2 vitamin D3-induced terminal differentiation of myeloid leukemia cells. J Steroid Biochem Mol Biol 144 Pt A:223-7|
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