title: Beta-irradiation used for systemic radioimmunotherapy induces apoptosis and activates apoptosis pathways in leukaemia cells.
abstract: Beta-irradiation used for systemic radioimmunotherapy (RIT) is a promising treatment approach for high-risk leukaemia and lymphoma. In bone marrow-selective radioimmunotherapy, beta-irradiation is applied using iodine-131, yttrium-90 or rhenium-188 labelled radioimmunoconjugates. However, the mechanisms by which beta-irradiation induces cell death are not understood at the molecular level. Here, we report that beta-irradiation induced apoptosis and activated apoptosis pathways in leukaemia cells depending on doses, time points and dose rates. After beta-irradiation, upregulation of CD95 ligand and CD95 receptor was detected and activation of caspases resulting in apoptosis was found. These effects were completely blocked by the broad-range caspase inhibitor zVAD-fmk. In addition, irradiation-mediated mitochondrial damage resulted in perturbation of mitochondrial membrane potential, caspase-9 activation and cytochrome c release. Bax, a death-promoting protein, was upregulated and Bcl-x(L), a death-inhibiting protein, was downregulated. We also found higher apoptosis rates and earlier activation of apoptosis pathways after gamma-irradiation in comparison to beta-irradiation at the same dose rate. Furthermore, irradiation-resistant cells were cross-resistant to CD95 and CD95-resistant cells were cross-resistant to irradiation, indicating that CD95 and irradiation used, at least in part, identical effector pathways. These findings demonstrate that beta-irradiation induces apoptosis and activates apoptosis pathways in leukaemia cells using both mitochondrial and death receptor pathways. Understanding the timing, sequence and molecular pathways of beta-irradiation-mediated apoptosis may allow rational adjustment of chemo- and radiotherapeutic strategies.
authors.affiliation: University Children's Hospital, Prittwitzstrasse 43, 89075 Ulm, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Friesen
authors.forename: Annelie
authors.initials: A
authors.lastname: Lubatschofski
authors.forename: Jörg
authors.initials: J
authors.lastname: Kotzerke
authors.forename: Inga
authors.initials: I
authors.lastname: Buchmann
authors.forename: Sven N
authors.initials: SN
authors.lastname: Reske
authors.forename: Klaus-Michael
authors.initials: KM
authors.lastname: Debatin
mesh_terms: D017209:Apoptosis / Q000528:radiation effects*; D001610:Beta Particles; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor / Q000378:metabolism / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D004789:Enzyme Activation / Q000528:radiation effects; D005720:Gamma Rays; D018922:HL-60 Cells; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism* / Q000528:radiation effects*; D011829:Radiation Dosage; D011836:Radiation Tolerance; D016499:Radioimmunotherapy / Q000379:methods; D011874:Radiometry / Q000379:methods; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D019014:fas Receptor; D020169:Caspases