ON 01910.Na is selectively cytotoxic for chronic lymphocytic leukemia cells through a dual mechanism of action involving PI3K/AKT inhibition and induction of oxidative stress.

Abstract

PURPOSE:

Chronic lymphocytic leukemia (CLL), a malignancy of mature B cells, is incurable with chemotherapy. Signals from the microenvironment support leukemic cell survival and proliferation and may confer chemotherapy resistance. ON 01910.Na (Rigosertib), a multikinase phosphoinositide 3-kinase (PI3K) inhibitor, is entering phase III trials for myelodysplastic syndrome. Our aim was to analyze the efficacy of ON 01910.Na against CLL cells in vitro and investigate the molecular effects of this drug on tumor biology.

EXPERIMENTAL DESIGN:

Cytotoxicity of ON 01910.Na against CLL cells from 34 patients was determined in vitro with flow cytometry of cells stained with Annexin V and CD19. Global gene expression profiling on Affymetrix microarrays, flow cytometry, Western blotting, and cocultures with stroma cells were used to delineate ON 01910.Na mechanism of action.

RESULTS:

ON 01910.Na induced apoptosis in CLL B cells without significant toxicity against T cells or normal B cells. ON 01910.Na was equally active against leukemic cells associated with a more aggressive disease course [immunoglobulin heavy-chain variable region unmutated, adverse cytogenetics] than against cells without these features. Gene expression profiling revealed two main mechanisms of action: PI3K/AKT inhibition and induction of ROS that resulted in an oxidative stress response through activating protein 1 (AP-1), c-jun-NH(2)-terminal kinase, and ATF3 culminating in the upregulation of NOXA. ROS scavengers and shRNA mediated knockdown of ATF3- and NOXA-protected cells from drug-induced apoptosis. ON 01910.Na also abrogated the prosurvival effect of follicular dendritic cells on CLL cells and reduced SDF-1-induced migration of leukemic cells.

CONCLUSIONS:

These data support the clinical development of ON 01910.Na in CLL.

• Authors: Colby M Chapman, Xiameng Sun, Mark Roschewski, Georg Aue, Mohamed Farooqui, Lawrence Stennett, Federica Gibellini, Diane Arthur, Patricia Pérez-Galán, Adrian Wiestner
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 7 Pg. 1979-91 (Apr 01 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 22351695 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
• Copyright: ©2012 AACR.

Chemical References

• ATF3 protein, human
• Activating Transcription Factor 3
• Immunoglobulin Heavy Chains
• Immunoglobulin Variable Region
• PMAIP1 protein, human
• Proto-Oncogene Proteins c-bcl-2
• Sulfones
• ON 01910
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• Glycine

Topics

• Activating Transcription Factor 3 (genetics, metabolism)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Line, Tumor
• Female
• Gene Expression Profiling
• Glycine (analogs & derivatives, pharmacology)
• HEK293 Cells
• HL-60 Cells
• Humans
• Immunoglobulin Heavy Chains (genetics)
• Immunoglobulin Variable Region (genetics)
• Leukemia, Lymphocytic, Chronic, B-Cell (genetics, metabolism, pathology)
• Male
• Membrane Potential, Mitochondrial (drug effects)
• Mutation
• Oligonucleotide Array Sequence Analysis
• Oxidative Stress (drug effects)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• RNA Interference
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (drug effects)
• Sulfones (pharmacology)
• Tumor Cells, Cultured