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: Raminder Singh, Julia Fröbel, Ron-Patrick Cadeddu, Ingmar Bruns, Thomas Schroeder, Daniela Brünnert, Christian Matthias Wilk, Luiz Fernando Zerbini, Rainer Haas, Akos Czibere
• Journal: Annals of hematology (Ann Hematol) Vol. 91 Issue 2 Pg. 173-81 (Feb 2012) ISSN: 1432-0584 [Electronic] Germany
• PMID: 21717102 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• (5-fluoro-2-methyl-1-(4-pyridyl)methylene-3-(N-benzyl)-indene)-acetamide hydrochloride
• Phosphodiesterase Inhibitors
• Sulindac

Topics

• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Cell Line, Tumor (drug effects)
• Clinical Trials as Topic
• Gene Expression (drug effects)
• Humans
• Leukemia, Myeloid, Acute (drug therapy, pathology)
• Phosphodiesterase Inhibitors (pharmacology, therapeutic use)
• Sulindac (analogs & derivatives, pharmacology, therapeutic use)