The copper chelator ATN-224 induces caspase-independent cell death in diffuse large B cell lymphoma

Lee,Kristy; Hart,Matthew R.; Briehl,Margaret M.; Mazar,Andrew P.; Tome,Margaret E.

doi:10.3892/ijo.2014.2396

The copper chelator ATN-224 induces caspase-independent cell death in diffuse large B cell lymphoma

Authors:
- Kristy Lee
- Matthew R. Hart
- Margaret M. Briehl
- Andrew P. Mazar
- Margaret E. Tome
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Affiliations: Department of Pathology, University of Arizona, Tucson, AZ 85724, USA, Department of GIPD Genetics, University of Arizona, Tucson, AZ 85724, USA, Department of Life Processes Institute, Northwestern University, Evanston, IL 85724, USA, Department of Medical Pharmacology, University of Arizona, Tucson, AZ 85724, USA
Published online on: April 23, 2014 https://doi.org/10.3892/ijo.2014.2396
Pages: 439-447

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Abstract

Bcl-2 and other anti-apoptotic proteins are associated with defective caspase-dependent apoptotic pathways, resulting in chemoresistance. We have previously shown that ATN-224, a copper chelator drug, induces cell death in murine thymic lymphoma cells transfected with Bcl-2. In the current study, we tested whether ATN-224 was effective in diffuse large B cell lymphoma (DLBCL) cells, which have increased anti‑apoptotic proteins through translocation or amplification. We found that nanomolar concentrations of ATN-224 induced cell death in DLBCL cells independent of Bcl-2, Bcl-xL or Mcl-1 status. ATN-224 treatment resulted in mitochondrial dysfunction, release of apoptosis-inducing factor (AIF) and induction of caspase‑independent cell death. In addition, ATN-224 degraded Mcl-1 and enhanced the effect of the BH3 mimetic ABT-263. These findings indicate that ATN-224 has potential as a therapeutic for the treatment of DLBCL. Induction of caspase‑independent cell death in apoptosis‑resistant DLBCL would provide a therapeutic alternative for the treatment of refractory disease.

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