title: Breaking chemoresistance and radioresistance with [213Bi]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 alpha-particles is a promising treatment approach for high-risk leukemia. We found that targeted radiotherapy using monoclonal CD45 antibodies radiolabeled with the alpha-emitter (213)Bi ([(213)Bi]anti-CD45) induces apoptosis, activates apoptosis pathways, and breaks beta-irradiation-, gamma-irradiation-, doxorubicin-, and apoptosis-resistance in leukemia cells. In contrast to beta-irradiation-, gamma-irradiation-, and doxorubicin-mediated apoptosis and DNA damage, [(213)Bi]anti-CD45-induced DNA damage was not repaired, and apoptosis was not inhibited by the nonhomologous end-joining DNA repair mechanism. Depending on the activation of caspase-3, caspase-8, and caspase-9, [(213)Bi]anti-CD45 activated apoptosis pathways in leukemia cells through the mitochondrial pathway but independent of CD95 receptor/CD95 ligand interaction. Furthermore, [(213)Bi]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 [(213)Bi]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.
authors.affiliation: Nuclear Medicine Clinic, Department of Transfusion Medicine, and University Children's Hospital, University of Ulm, Ulm, Germany. claudia.friesen@uni-ulm.de
authors.forename: Claudia
authors.initials: C
authors.lastname: Friesen
authors.forename: Gerhard
authors.initials: G
authors.lastname: Glatting
authors.forename: Bernd
authors.initials: B
authors.lastname: Koop
authors.forename: Klaus
authors.initials: K
authors.lastname: Schwarz
authors.forename: Alfred
authors.initials: A
authors.lastname: Morgenstern
authors.forename: Christos
authors.initials: C
authors.lastname: Apostolidis
authors.forename: Klaus-Michael
authors.initials: KM
authors.lastname: Debatin
authors.forename: Sven N
authors.initials: SN
authors.lastname: Reske
mesh_terms: D000906:Antibodies; D017209:Apoptosis / Q000528:radiation effects; D001729:Bismuth / Q000627:therapeutic use*; D020169:Caspases / Q000378:metabolism; D004260:DNA Repair / Q000528:radiation effects; D004273:DNA, Neoplasm / Q000528:radiation effects; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000276:immunology / Q000532:radiotherapy*; D017493:Leukocyte Common Antigens / Q000276:immunology*; D008928:Mitochondria / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011836:Radiation Tolerance / Q000276:immunology; D016499:Radioimmunotherapy; D011868:Radioisotopes / Q000627:therapeutic use*
chemical_list: D000906:Antibodies; D004273:DNA, Neoplasm; D011868:Radioisotopes; D004317:Doxorubicin; D011065:Poly(ADP-ribose) Polymerases; D017493:Leukocyte Common Antigens; C516769:PTPRC protein, human; D020169:Caspases; D001729:Bismuth