Anthracyclines trigger apoptosis of both G0-G1 and cycling peripheral blood lymphocytes and induce massive deletion of mature T and B cells.
The anthracyclines daunorubicin and doxorubicin were shown to induce apoptosis of hematopoietic cell lines. Here we report that they induce apoptosis of both nonactivated and phytohemagglutinin-activated human peripheral blood lymphocytes. Apoptosis demonstrated by surface expression of phosphatidylserine and typical nuclear alterations reached a maximum after 48 h of incubation with these agents. In contrast to topoisomerase inhibitors (etoposide and camptothecin) and antimetabolites (methotrexate and 5-fluorouracil) that induced apoptosis of activated cells only, daunorubicin and doxorubicin triggered apoptosis of cells in the G0-G1 phases of the cell cycle. In agreement with in vitro data, a single i.p. injection of daunorubicin or doxorubicin in BALB/c mice induced T- and B-cell depletion in spleen, lymph nodes, and to a lesser extent in the thymus. Soluble Fas-Fc, CD95 antagonistic antibodies, as well as the p55 tumor necrosis factor receptor-immunoglobulin fusion protein, did not inhibit drug-induced apoptosis. The level of reactive oxygen species was significantly increased in the presence of daunorubicin or doxorubicin only in nonactivated lymphocytes. However, antioxidants such as N-acetyl-L-cysteine or glutathione did not prevent apoptosis. Activation of caspase-3 after daunorubicin or doxorubicin treatment of either nonactivated or activated lymphocytes was demonstrated by the cleavage of poly(ADP-ribose) polymerase, which was, as apoptosis, inhibited by the peptide benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone. Finally, daunorubicin and doxorubicin induced a rapid production of ceramides. These data indicate that anthracyclines may induce major peripheral T-cell deletion, a property not shared by many cytotoxic agents.
Ferraro
C
C
Laboratory of Immunology, Institut National de la Santé et de la Recherche Médicale U503 UCBL, Hospital E. Herriot, Lyon, France.
Quemeneur
L
L
Prigent
A F
AF
Taverne
C
C
Revillard
J P
JP
Bonnefoy-Berard
N
N
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects*; D002166:Camptothecin / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects*; D002478:Cells, Cultured; D003630:Daunorubicin / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D016193:G1 Phase; D006801:Humans; D008198:Lymph Nodes / Q000276:immunology; D008212:Lymphocyte Depletion; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects*; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D016192:Resting Phase, Cell Cycle; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects*; D013950:Thymus Gland / Q000276:immunology
D000970:Antineoplastic Agents; D005047:Etoposide; D004317:Doxorubicin; D005472:Fluorouracil; D002166:Camptothecin; D008727:Methotrexate; D003630:Daunorubicin