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.
Highlights
Diffuse large B cell lymphoma (DLBCL) is the most common diagnosed form of non-Hodgkin lymphoma (NHL)
Recent studies suggest that the protective function of Bcl-2, in part, is due to its ability to regulate mitochondrial respiration [9]
In previous studies we have shown that ATN-224 inhibits cytochrome c oxidase (CcOX) and decreases ∆Ψm in murine thymic lymphoma cells that overexpress Bcl-2 [12]
Summary
The non-canonical function of Bcl-2 and other anti‐apoptotic proteins is to maintain mitochondrial homeostasis by regulating mitochondrial membrane potential (∆Ψm) and/or mitochondrial respiration [8,9,10]. Regulation of these mitochondrial processes may or may not contribute to the ability of anti-apoptotic proteins to prevent apoptosis. Data from their study suggest that the ability to modulate CcOX activity contributes to the ability of Bcl-2 to inhibit caspase-dependent cell death. ATN-224 enhanced the overall effect of the BH3 mimetic, ABT-263, in apoptosis-resistant DLBCL Taken together these data suggest that ATN-224 has therapeutic potential as a single agent or as an adjuvant, in patients with apoptosis‐resistant disease
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