The novel compound OSI-461 induces apoptosis and growth arrest in human acute myeloid leukemia cells |
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Authors: | Raminder?Singh Julia?Fr?bel Ron-Patrick?Cadeddu Ingmar?Bruns Thomas?Schroeder Daniela?Brünnert Christian?Matthias?Wilk Luiz?Fernando?Zerbini Rainer?Haas Email author" target="_blank">Akos?CzibereEmail author |
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Institution: | 1.Department of Hematology, Oncology and Clinical Immunology,Heinrich Heine University,Düsseldorf,Germany;2.International Center for Genetic Engineering and Biotechnology (ICGEB) and Medical Biochemistry Division, Faculty of Health Sciences,University of Cape Town,Cape Town,South Africa;3.Beth Israel Deaconess Medical Center, Department of Hematology,Harvard Medical School,Boston,USA |
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Abstract: | Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy. Treatment of patients suffering from high-risk AML
as defined by clinical parameters, cytogenetics, and/or molecular analyses is often unsuccessful. OSI-461 is a pro-apoptotic
compound that has been proposed as a novel therapeutic option for patients suffering from solid tumors like prostate or colorectal
carcinoma. But little is known about its anti-proliferative potential in AML. Hence, we treated bone marrow derived CD34+ selected blast cells from 20 AML patients and the five AML cell lines KG-1a, THP-1, HL-60, U-937, and MV4-11 with the physiologically
achievable concentration of 1 μM OSI-461 or equal amounts of DMSO as a control. Following incubation with OSI-461, we found
a consistent induction of apoptosis and an accumulation of cells in the G2/M phase of the cell cycle. In addition, we demonstrate
that the OSI-461 mediated anti-proliferative effects observed in AML are associated with the induction of the pro-apoptotic
cytokine mda-7/IL-24 and activation of the growth arrest and DNA-damage inducible genes (GADD) 45α and 45γ. Furthermore, OSI-461
treated leukemia cells did not regain their proliferative potential for up to 8 days after cessation of treatment following
the initial 48 h treatment period with 1 μM OSI-461. This indicates sufficient targeting of the leukemia-initiating cells
in our in vitro experiments through OSI-461. The AML samples tested in this study included samples from patients who were
resistant to conventional chemotherapy and/or had FLT3-ITD mutations demonstrating the high potential of OSI-461 in human
AML. |
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