ryanodine and Burkitt-Lymphoma

The therapeutic monoclonal antibody rituximab has previously been shown to kill B cells in a caspase-independent manner. The signalling pathways underpinning this novel death pathway are unknown. The present study showed that rituximab treatment of Burkitt lymphoma cell lines induced a slow rise in intracellular calcium ([Ca(2+)](i)). This rise was only witnessed in cell lines that were killed by antibody, suggesting a critical role for Ca(2+) in mediating rituximab-driven caspase-independent cell death. Inhibition of the two main intracellular store-located Ca(2+) channels, i.e. the ryanodine and inositol-1,4,5-triphosphate receptor channels by dantrolene and xestospongen-c respectively did not prevent the rise in Ca(2+) seen with rituximab or protect cells from subsequent death. In sharp contrast, inhibition of Ca(2+) entry via plasma membrane channels with (2-aminoethoxy) diphenylborate or SKF-96365 or complete chelation of extracellular Ca(2+) with ethyleneglycol bis (aminoethylether) tetra-acetate inhibited the rise in [Ca(2+)](i) and increased cell viability. Together, these data suggest that ligation of the CD20 receptor with rituximab allows a slow sustained influx of Ca(2+) from the external environment that under certain conditions can lead to cell death.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antigens, CD20; Antineoplastic Agents; B-Lymphocytes; Burkitt Lymphoma; Calcium; Calcium Channel Blockers; Caspases; Cell Death; Cell Line; Cell Membrane; Dantrolene; Endoplasmic Reticulum; Flow Cytometry; Humans; Imidazoles; Inositol 1,4,5-Trisphosphate Receptors; Macrocyclic Compounds; Oxazoles; Rituximab; Ryanodine