Apoptosis and TRAF-1 cleavage in Epstein-Barr virus-positive nasopharyngeal carcinoma cells treated with doxorubicin combined with a farnesyl-transferase inhibitor.
Epstein-Barr virus (EBV)-associated nasopharyngeal carcinomas (NPC) are much more sensitive to chemotherapy than other head and neck carcinomas. Spectacular regressions are frequently observed after induction chemotherapy. However, these favorable responses are difficult to predict and often of short duration. So far there have been only few experiments to investigate the mechanisms which underline the cytotoxic effects of anti-neoplastic drugs against NPC cells. In addition, these studies were performed almost entirely on EBV-negative cell lines therefore not truly representative of NPC cells. For the first time, we have used two EBV-positive NPC tumor lines derived from a North African (C15) and a Chinese (C666-1) patient as in vitro targets for a panel of anti-neoplastic agents. Doxorubicin, taxol and in a lesser extent cis-platinum efficiently inhibited NPC cell proliferation at clinically relevant concentrations, but all three agents failed to induce apoptosis. However, massive apoptosis of C15 cells was achieved when doxorubicin (1 microM) was combined with a farnesyl-transferase inhibitor, BIM 2001 (5 microM). Moreover, this apoptotic process was associated with a caspase-dependent early cleavage of the TNF-receptor associated factor 1 (TRAF-1) molecule, a signaling adaptor which is specifically expressed in latently EBV-infected cells. TRAF-1 cleavage might become a useful indicator of chemo-induced apoptosis in EBV-associated NPCs.
Vicat
Jean Michel
JM
UMR 1598, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France.
Ardila-Osorio
Hector
H
Khabir
Abdelmajid
A
Brezak
Marie Christine
MC
Viossat
Isabelle
I
Kasprzyk
Philip
P
Jlidi
Rachid
R
Opolon
Paule
P
Ooka
Tadamassa
T
Prevost
Grégoire
G
Huang
Dolly P
DP
Busson
Pierre
P
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D005260:Female; D004854:Herpesvirus 4, Human / Q000302:isolation & purification; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D009303:Nasopharyngeal Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D009570:Nitriles / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism*; D047990:TNF Receptor-Associated Factor 1; D014407:Tumor Cells, Cultured
C471008:BIM 2001; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D009570:Nitriles; D011506:Proteins; D047990:TNF Receptor-Associated Factor 1; D004317:Doxorubicin; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase