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

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

Research output: Contribution to journalArticle

7 Citations (Scopus)

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. We thank Amanda Bahe for technical assistance and Dr Anthony Letai (Dana-Farber Cancer Institute) for the SUDHL-8 and SUDHL-4R2 cells. This study was supported by the National Cancer Institute Grants CA09213 (K.L.), CA71768 (M.M.B.), CA130805 (K.L., M.M.B., M.E.T.) and CA023074 (M.E.T.). A.P.M. was supported by U01 CA151461-02, P50 HL 107186-01 and H Foundation Funds. A.P.M. is a consultant to Wilson Therapeutics AB who is developing ATN-224 for Wilson disease and has a small amount of equity in the company. All other authors declare no conflict of interest.

Original languageEnglish (US)
Pages (from-to)439-447
Number of pages9
JournalInternational Journal of Oncology
Volume45
Issue number1
DOIs
StatePublished - 2014

Fingerprint

Lymphoma, Large B-Cell, Diffuse
Chelating Agents
Caspases
Copper
Cell Death
Apoptosis Regulatory Proteins
Therapeutics
Apoptosis Inducing Factor
Conflict of Interest
Hepatolenticular Degeneration
National Cancer Institute (U.S.)
Organized Financing
Protein Transport
Financial Management
Consultants
tetrathiomolybdate
Lymphoma
Apoptosis
Pharmaceutical Preparations
Neoplasms

Keywords

  • Bcl-2
  • Bcl-xL
  • Cytochrome c oxidase
  • Lymphoma
  • Mcl-1
  • Mitochondria

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

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.

In: International Journal of Oncology, Vol. 45, No. 1, 2014, p. 439-447.

Research output: Contribution to journalArticle

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