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Abstract
Acute myeloid leukemia (AML) is the most common malignant myeloid disorder of progenitor cells in myeloid hematopoiesis and exemplifies a genetically heterogeneous disease. The patients with AML also show a heterogeneous response to therapy. Although all-trans retinoic acid (ATRA) has been successfully introduced to treat acute promyelocytic leukemia (APL), it is rather ineffective in non-APL AML. In our present study, 1200 off-patent marketed drugs and natural compounds that have been approved by the Food and Drug Administration (FDA) were screened for anti-leukemia activity using the retrovirus transduction/transformation assay (RTTA). Furazolidone (FZD) was shown to inhibit bone marrow transformation mediated by several leukemia fusion proteins, including AML1-ETO. Furazolidone has been used in the treatment of certain bacterial and protozoan infections in human and animals for more than sixty years. We investigated the anti-leukemic activity of FZD in a series of AML cells. FZD displayed potent antiproliferative properties at submicromolar concentrations and induced apoptosis in AML cell lines. Importantly, FZD treatment of certain AML cells induced myeloid cell differentiation by morphology and flow cytometry for CD11b expression. Furthermore, FZD treatment resulted in increased stability of tumor suppressor p53 protein in AML cells. Our in vitro results suggest furazolidone as a novel therapeutic strategy in AML patients.
Highlights
Acute myeloid leukemia (AML), which is thought to require cooperation between pro-proliferative mutations and defects in myeloid differentiation, is the most common malignant myeloid disorder of progenitor cells in myeloid hematopoiesis [1]
We applied our retrovirus transduction/ transformation assay (RTTA) [5,6,7], in which leukemic fusion proteins such as AML1-ETO were expressed under the control of long terminal repeat of the murine stem cell virus (MSCV) after transduction into c-Kit+ murine hematopoietic progenitor/stem cells [8] (Figure 1A)
We investigated the anti-leukemic activity of a chemical library containing more than 1000 Food and Drug Administration (FDA) approved drugs and identified furazolidone (FZD) as a potent inhibitor that suppressed the self-renewal of murine bone marrow cells transformed by AML1-ETO
Summary
Acute myeloid leukemia (AML), which is thought to require cooperation between pro-proliferative mutations and defects in myeloid differentiation, is the most common malignant myeloid disorder of progenitor cells in myeloid hematopoiesis [1]. Patients with AML show a heterogeneous response to therapy. Treatment responses and outcome for this regimen vary [2,3]. These therapies usually only result in less than 2 years of median survival and no more than 40% of 5-year overall survival (OS). ATRA only works well in APL, not in other AML These compounds can elicit serious side effects, such as cardiotoxicity and therapy-related cancer. In our study, we aimed to identify a relatively safe and useful compound as a novel treatment for AML patients by screening a library with 1200 FDA approved drugs using the retrovirus transduction/transformation assay (RTTA)
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