Arsenic trioxide (AS2O3) is a heavy metal derivative that has potent antileukemic properties in vitro and in vivo. This agent is used in the treatment of patients with acute promyelocytic leukemia (APL), but the precise mechanisms by which it induces its antileukemic effects are not known. We have identified a novel signaling pathway activated by arsenic trioxide in APL cells, involving the p38 Map kinase. Our data suggest that activation of this signaling cascade exhibits a negative regulatory role on the induction of apoptosis and cell differentiation of APL cells. The overall goal of this grant application is to understand the mechanisms by which p38 negatively regulates the induction of AS2O3-responses in APL cells.
Specific aim A is to determine the mechanisms of activation of the p38 Map kinase by AS2O3 in APL cells. Studies will be performed to examine the roles of the small GTPases Rac1 and Cdc42, and the Pak1 kinase, and to identify the Map kinase kinase (Mkk) that directly phosphorylates and activates p38.
Specific aim B is to identify the downstream effector mechanisms by which the p38 Map kinase controls AS2O3-dependent apoptosis. Studies are proposed to examine the patterns of activation of different p38-isoforms in APL cells and to determine their roles in the generation of AS2O3-responses. Experiments will be also performed to dissect the contributions of different downstream effectors of the p38 pathway in the regulation of such responses.
Specific aim C is to examine the activation of p38 in primary leukemic blasts from APL patients or patients with other subtypes of acute myeloid leukemia (AML), and determine whether such activation correlates with sensitivity or resistance to the effects of arsenic trioxide. Altogether, these studies should advance our overall understanding of the mechanisms by which AS2O3 generates its effects on malignant cells. They may also provide the basis for future clinical-translational efforts of combinations of AS2O3 and p38 inhibitors for the treatment of APL, and possibly other forms of AML. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA121192-03
Application #
7482975
Study Section
Special Emphasis Panel (ZRG1-ONC-Q (01))
Program Officer
Mufson, R Allan
Project Start
2006-09-01
Project End
2011-08-31
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
3
Fiscal Year
2008
Total Cost
$260,253
Indirect Cost
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Bell, Jonathan B; Eckerdt, Frank; Dhruv, Harshil D et al. (2018) Differential Response of Glioma Stem Cells to Arsenic Trioxide Therapy Is Regulated by MNK1 and mRNA Translation. Mol Cancer Res 16:32-46
Bell, Jonathan B; Rink, Jonathan S; Eckerdt, Frank et al. (2018) HDL nanoparticles targeting sonic hedgehog subtype medulloblastoma. Sci Rep 8:1211
Kosciuczuk, Ewa M; Saleiro, Diana; Platanias, Leonidas C (2017) Dual targeting of eIF4E by blocking MNK and mTOR pathways in leukemia. Cytokine 89:116-121
Kroczynska, Barbara; Blyth, Gavin T; Rafidi, Robert L et al. (2017) Central Regulatory Role for SIN1 in Interferon ? (IFN?) Signaling and Generation of Biological Responses. J Biol Chem 292:4743-4752
Saleiro, Diana; Kosciuczuk, Ewa M; Platanias, Leonidas C (2016) Beyond autophagy: New roles for ULK1 in immune signaling and interferon responses. Cytokine Growth Factor Rev 29:17-22
Shah, Chirag A; Bei, Ling; Wang, Hao et al. (2016) Cooperation between AlphavBeta3 integrin and the fibroblast growth factor receptor enhances proliferation of Hox-overexpressing acute myeloid leukemia cells. Oncotarget 7:54782-54794
Kosciuczuk, Ewa M; Saleiro, Diana; Kroczynska, Barbara et al. (2016) Merestinib blocks Mnk kinase activity in acute myeloid leukemia progenitors and exhibits antileukemic effects in vitro and in vivo. Blood 128:410-4
Eckerdt, Frank; Alvarez, Angel; Bell, Jonathan et al. (2016) A simple, low-cost staining method for rapid-throughput analysis of tumor spheroids. Biotechniques 60:43-6
Bell, Jonathan B; Eckerdt, Frank D; Alley, Kristen et al. (2016) MNK Inhibition Disrupts Mesenchymal Glioma Stem Cells and Prolongs Survival in a Mouse Model of Glioblastoma. Mol Cancer Res 14:984-993
Iqbal, Asneha; Eckerdt, Frank; Bell, Jonathan et al. (2016) Targeting of glioblastoma cell lines and glioma stem cells by combined PIM kinase and PI3K-p110? inhibition. Oncotarget 7:33192-201

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