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.
Department of Pathology, University of Arizona, Tucson, AZ 85724, USA.
Kristy
K
Lee
Department of GIPD Genetics, University of Arizona, Tucson, AZ 85724, USA.
Matthew R
MR
Hart
Department of Pathology, University of Arizona, Tucson, AZ 85724, USA.
Margaret M
MM
Briehl
Department of Life Processes Institute, Northwestern University, Evanston, IL 85724, USA.
Andrew P
AP
Mazar
Department of Medical Pharmacology, University of Arizona, Tucson, AZ 85724, USA.
Margaret E
ME
Tome
D000814:Aniline Compounds / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism / Q000473:pathology*; D008928:Mitochondria / Q000187:drug effects; D008982:Molybdenum / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology
D000814:Aniline Compounds; D051033:Apoptosis Inducing Factor; D002614:Chelating Agents; D013449:Sulfonamides; D008982:Molybdenum; C020809:tetrathiomolybdate; D020169:Caspases; C528561:navitoclax