Breaking Chemo- and Radioresistance with [Bi-213]anti-CD45 Antibodies in Leukemia Cells

Abstract

Chemoresistance and radioresistance are considered one of the primary reasons for therapeutic failure in leukemias and solid tumors. Targeted radiotherapy using monoclonal antibodies radiolabeled with A-particles is a promising treatment approach for high-risk leukemia. We found that targeted radiotherapy using monoclonal CD45 antibodies radiolabeled with the A-emitter 213Bi ([213Bi]anti-CD45) induces apoptosis, activates apoptosis pathways, and breaks B-irradiation–, ;-irradiation–, doxorubicin-, and apoptosis-resistance in leukemia cells. In contrast to B-irradiation–, ;-irradiation–, and doxorubicin-mediated apoptosis and DNA damage, [213Bi] anti-CD45–induced DNA damage was not repaired, and apoptosis was not inhibited by the nonhomologous endjoining DNA repair mechanism. Depending on the activation of caspase-3, caspase-8, and caspase-9, [213Bi]anti-CD45 activated apoptosis pathways in leukemia cells through the mitochondrial pathway but independent of CD95 receptor/ CD95 ligand interaction. Furthermore, [213Bi]anti-CD45 reversed deficient activation of caspase-3, caspase-8, and caspase-9, deficient cleavage of poly(ADP-ribose) polymerase, and deficient activation of mitochondria in chemoresistant and in radioresistant and apoptosis-resistant leukemia cells. These findings show that [213Bi]anti-CD45 is a promising therapeutic agent to break chemoresistance and radioresistance by overcoming DNA repair mechanisms in leukemia cells and provide the foundation for discovery of novel anticancer compounds.JRC.E.5-Nuclear chemistr