Resistance to gemcitabine in a lymphoma cell line resistant to Fas-mediated apoptosis.
BACKGROUND
The T-cell lymphoma cell line HuT78B1, selected for resistance to Fas-mediated apoptosis, resulted unexpectedly resistant to the apoptotic and cytotoxic effects of gemcitabine (dFdC). We investigated whether this resistance was due to the impairment of the Fas/Fas-ligand (FasL) system.


METHODS
dFdC effects were studied in HuT78B1 and in the parental Fas-sensitive HuT78 cells exposed to inhibitors of the Fas/FasL system.


RESULTS
FasL- and Fas-blocking antibodies did not interfere with dFdC-induced apoptosis in HuT78 cells, whereas inhibitors of caspase-8, -9, -1 or -3 had partial inhibitory effects. Notably, in HuT78B1 cells there was a markedly reduced dFdC accumulation notwithstanding a high activity of the activating enzyme deoxycytidine kinase. dFdC accumulation in HuT78 cells was unaffected by a Fas-blocking antibody.


CONCLUSIONS
This is the first time that the selection of a Fas-resistant cell line led to the isolation of a cell clone unable to accumulate the deoxycytidine analog dFdC. Our results show that this alteration is independent from the impairment of the Fas/FasL system.
Meli
Maria
M
Department of Pharmacological Sciences, Università di Palermo, Policlinico P. Giaccone, via del Vespro 129, 90127 Palermo, Italy.
Tolomeo
Manlio
M
D'Alessandro
Natale
N
Grimaudo
Stefania
S
Notarbartolo
Monica
M
Papoff
Giuliana
G
Ruberti
Giovina
G
Rausa
Luciano
L
Dusonchet
Luisa
L
D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D003842:Deoxycytidine Kinase / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D053222:Fas Ligand Protein; D006801:Humans; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D019014:fas Receptor / Q000502:physiology*; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D061945:Caspase Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019014:fas Receptor; D003841:Deoxycytidine; D003842:Deoxycytidine Kinase; D020169:Caspases; D000093542:Gemcitabine