title: Rituximab enhances radiation-triggered apoptosis in non-Hodgkin's lymphoma cells via caspase-dependent and - independent mechanisms.
abstract: Rituximab (RTX), a chimeric human anti-CD20 monoclonal antibody, is currently employed in the treatment of malignant non-Hodgkin's lymphoma (NHL) either alone or in combination with other cytotoxic approaches. The present study examines the effects of ionizing radiation in combination with RTX on proliferation and apoptosis development in B-lymphoma RL and Raji cells. RTX was used at a concentration of 10 microg/mL 24 hours prior to irradiation at a single dose of 9 Gy. CD20 expression, cell viability, apoptosis, mitochondrial membrane potential and apoptosis-related proteins were evaluated in the treated B cells. The constitutive level of CD20 expression in RL and Raji lymphoma cells did not play an essential role in RTX-induced cell growth delay. Both lymphoma cells showed similar inhibition of cell proliferation without apoptosis development in response to RTX treatment. Exposure to ionizing radiation induced cell growth delay and apoptosis in RL cells, whereas Raji cells showed moderate radio-resistance and activation of cell growth at 24 hours after irradiation, which was accompanied by increased radiation-triggered CD20 expression. The simultaneous exposure of lymphoma cells to ionizing radiation and RTX abrogated radioresistance of Raji cells and significantly enhanced cell growth delay and apoptosis in RL cells. X-linked inhibitor of apoptosis protein (XIAP) and the inducible form of heat shock protein 70 (Hsp70) were positively modulated by RTX in combination with ionizing radiation in order to induce apoptosis. Furthermore, it was demonstrated that mitochondrial membrane potential dissipation is not an essential component to induce apoptosis-inducing factor (AIF) maturation and apoptosis. Our results show that RTX-triggered enhancement of radiation-induced apoptosis and cell growth delay is achieved by modulation of proteins involved in programmed cell death.
authors.affiliation: Department of Therapeutic Radiology and Oncology, Innsbruck Medical University, Austria. Ira.Skvortsova@uibk.ac.at
authors.forename: Ira
authors.initials: I
authors.lastname: Skvortsova
authors.forename: Sergej
authors.initials: S
authors.lastname: Skvortsov
authors.forename: Bela-Andre
authors.initials: BA
authors.lastname: Popper
authors.forename: Alfred
authors.initials: A
authors.lastname: Haidenberger
authors.forename: Maria
authors.initials: M
authors.lastname: Saurer
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Gunkel
authors.forename: Heinz
authors.initials: H
authors.lastname: Zwierzina
authors.forename: Peter
authors.initials: P
authors.lastname: Lukas
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology* / Q000532:radiotherapy; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage; D000069283:Rituximab; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D011838:Radiation-Sensitizing Agents; D000069283:Rituximab; D020169:Caspases