Resistance to cytotoxic chemotherapy induced by CD40 ligand in lymphoma cells.
The modulation of the cytotoxic effects of an anthracyclin by CD40L was investigated in five non-Hodgkin's lymphoma (NHL) cell lines (Daudi, Raji, BJAB, BL36, BL70). Incubation with doxorubicin (DOX) increased in a dose-dependent manner the percentage of apoptosis in NHL cells. Coculture with irradiated L cells expressing CD40L (CD40L L cells), but not CDw32 (CDw32 L cells), significantly reduced (33% to 89%) the percentage of apoptosis in all five cell lines treated with 0.1 to 0.5 microgram/mL of DOX, but in only three cell lines at 1 microgram/mL. Interleukin-10 (IL-10), IL-6, IL-2, or tumor necrosis factor (TNF) induced no additive protective effects with CD40L L cells. In all five cell lines, DOX induced a concentration-dependent increase of the activity of the cysteine-protease caspase 3. Coculture with CD40L L cells, but not with CDw32 L cells, inhibited (38% to 100%) the activation of caspase 3 induced by 0.1 to 0.5 microgram/mL of DOX in all five NHL cell lines, but in only two cell lines at 1 microgram/mL. Finally, the antiproliferative effect of 0.1 to 0.5 microgram/mL concentrations of DOX was also partially abrogated on coculture with CD40L L cells in all five cell lines, but in only two cell lines at 1 microgram/mL. Cytokines, either alone or in combination with CD40L L cells, did not affect DOX-induced inhibition of proliferation. These results indicate that CD40L inhibits the apoptosis and antiproliferative effect induced by DOX and interferes with caspase 3 activation in B NHL cell lines.
Voorzanger-Rousselot
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Unité Cytokine et Cancer, Unité INSERM U453, Centre Léon Bérard, Lyon, France.
Favrot
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M
Blay
J Y
JY
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000187:drug effects / Q000473:pathology; D023201:CD40 Ligand; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D018920:Coculture Techniques; D016207:Cytokines / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007739:L Cells; D008228:Lymphoma, Non-Hodgkin / Q000201:enzymology / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D016207:Cytokines; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D023201:CD40 Ligand; D004317:Doxorubicin; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases