title: The novel compound OSI-461 induces apoptosis and growth arrest in human acute myeloid leukemia cells.
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.
authors: Department of Hematology, Oncology and Clinical Immunology, Heinrich Heine University, Düsseldorf, Germany.
authors: Raminder
authors: R
authors: Singh
authors: Julia
authors: J
authors: Fröbel
authors: Ron-Patrick
authors: RP
authors: Cadeddu
authors: Ingmar
authors: I
authors: Bruns
authors: Thomas
authors: T
authors: Schroeder
authors: Daniela
authors: D
authors: Brünnert
authors: Christian Matthias
authors: CM
authors: Wilk
authors: Luiz Fernando
authors: LF
authors: Zerbini
authors: Rainer
authors: R
authors: Haas
authors: Akos
authors: A
authors: Czibere
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D002986:Clinical Trials as Topic; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C439285:(5-fluoro-2-methyl-1-(4-pyridyl)methylene-3-(N-benzyl)-indene)-acetamide hydrochloride; D010726:Phosphodiesterase Inhibitors; D013467:Sulindac