Timing determines dexamethasone and rituximab induced synergistic cell death.
Dysregulation of cell death signaling pathways in many cell types such as B lymphocytes (B-cells) can lead to cancer, for example to B-cell lymphomas. Rituximab (RTX) and glucocorticoids such as dexamethasone (Dex) are widely used to treat hematological malignancies including B-cell lymphomas. Although the combination of Dex and RTX improves the treatment outcome of lymphoma patients, most lymphomas remain incurable diseases. Therefore, a detailed investigation of Dex- and RTX-induced signaling might provide new insights into the therapeutic benefits of these drugs. In this paper, we describe Dex- and RTX-induced signaling pathways and their downstream target proteins/cells. In addition, we also overview how the signaling initiated by Dex and RTX modulate the outcome of Dex- and RTX-mediated cell death in lymphoma cells. The combination of Dex and RTX results in massive cell death in lymphoma cells. However, pretreatment of lymphoma cells or mononuclear cytotoxic cells with Dex followed by RTX leads to a decrease in apoptosis or it impairs antibody-dependent cellular cytotoxicity (ADCC). RTX-mediated ADCC is impaired by Dex-induced depletion of cytotoxic cells, whereas RTX-mediated short-term ERK1/2 activation decreases Dex-induced apoptosis. Therefore, the timing of the combination of Dex and RTX is a determining factor for the synergistic effect of these cell death inducing agents.
Department of Clinical Microbiology, Institute of Clinical Medicine, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland. Electronic address: jemal.adem@uef.fi.
Jemal
J
Adem
Fimlab Laboratories Oy, Tampere University Hospital, PL66, 33101 Tampere, Finland; Department of Medicine, University of Tampere, Kalevantie 4, 33014 Tampere, Finland.
Mine
M
Eray
Department of Clinical Microbiology, Institute of Clinical Medicine, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland.
Jonna
J
Eeva
Department of Clinical Microbiology, Institute of Clinical Medicine, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland.
Ulla
U
Nuutinen
Department of Clinical Microbiology, Institute of Clinical Medicine, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland; Eastern Finland Laboratory Centre (ISLAB), Puijonlaaksontie 2, 70210 Kuopio, Finland; Cancer Center of University of Eastern Finland, Finland.
Jukka
J
Pelkonen
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D016923:Cell Death / Q000187:drug effects*; D003907:Dexamethasone / Q000008:administration & dosage*; D004357:Drug Synergism; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy*; D000069283:Rituximab / Q000008:administration & dosage*
D000069283:Rituximab; D003907:Dexamethasone
Antibody-dependent cellular cytotoxicity; Apoptosis; Dexamethasone; Lymphoma; Rituximab