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      • HARVEST
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      Characterization of the anti-leukemia stem cell activity of chaetocin

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      HUTCHINSON-THESIS.pdf (4.251Mb)
      Date
      2013-05-30
      Author
      Hutchinson, Catherine
      Type
      Thesis
      Degree Level
      Masters
      Metadata
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      Abstract
      Chronic myelogenous leukemia is a myeloproliferative hematopoietic stem cell disease resulting from a reciprocal translocation that gives rise to BCR-ABL, a constitutively active tyrosine kinase. Imatinib and other tyrosine kinase inhibitors are currently standard therapy; however, point mutations often lead to drug resistance and disease relapse often occurs due to the persistence of quiescent leukemia stem cells that are shielded by stromal factors within the bone marrow microenvironment. In an effort to develop new therapies capable of eradicating these elusive cells, a novel approach has been proposed in which the biochemical properties of cancer cells are targeted. It has been established that one such property is oxidative stress due to the increased production of reactive oxygen species, which makes cancer cells especially dependent on their antioxidant systems to maintain redox homeostasis. Recent studies demonstrate that chaetocin, a mycotoxin produced by Chaetomium species fungi, possesses potent and specific antimyeloma activity due in part to its ability to inhibit thioredoxin reductase-1, a central oxidative stress remediation enzyme. In this study, the effectiveness of chaetocin against leukemia stem cells has been investigated using in vitro and in vivo murine chronic myelogenous leukemia models. Our results indicate that: chaetocin and imatinib function synergistically in decreasing cell viability, inducing apoptosis, and inhibiting the colony formation of chronic myelogenous leukemia cells in vitro; that chaetocin in combination with imatinib reduces leukemia stem cell frequency in vivo; that chaetocin increases intracellular reactive oxygen species levels; and that chaetocin does not disrupt the proliferation and differentiation of normal murine hematopoietic stem cells. Surprisingly, our results also show that while bone marrow stromal factors inhibit the activity of imatinib, they potentiate the activity of chaetocin, indicating that chaetocin could potentially be used to target leukemia stem cells within the bone marrow niche.
      Degree
      Master of Science (M.Sc.)
      Department
      Biochemistry
      Program
      Biochemistry
      Supervisor
      Geyer, Clarence R.
      Committee
      Lukong, Kiven E.; Lee, Jeremy E.
      Copyright Date
      April 2013
      URI
      http://hdl.handle.net/10388/ETD-2013-04-1040
      Subject
      chaetocin
      bone marrow stromal factors
      cancer stem cells
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