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

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.