S. Fulda et al., CHEMOSENSITIVITY OF SOLID TUMOR-CELLS IN-VITRO IS RELATED TO ACTIVATION OF THE CD95 SYSTEM, International journal of cancer, 76(1), 1998, pp. 105-114
We have identified the CD95 system as a key mediator of chemotherapy-i
nduced apoptosis in leukemia and neuroblastoma cells. Here, we report
that sensitivity of various solid tumor cell lines for drug-induced ce
ll death corresponds to activation of the CD95 system, Upon drug treat
ment, strong induction of CD95 ligand (CD95-L) and caspase activity we
re found in chemosensitive tumor cells (Hodgkin, Ewing's sarcoma, colo
n carcinoma and small cell lung carcinoma) but not in tumor cells whic
h responded poorly to drug treatment (breast carcinoma and renal cell
carcinoma). Blockade of CD95 using F(ab')(2) anti-CD95 antibody fragme
nts markedly reduced drug-induced apoptosis, suggesting that drug-trig
gered apoptosis depended on CD95-L/receptor interaction. Moreover, dru
g treatment induced CD95 expression, thereby increasing sensitivity fo
r CD95-induced apoptosis, Drug-induced apoptosis critically depended o
n activation of caspases (ICE/Ced-3-like proteases) since the broad-sp
ectrum inhibitor of caspases zVAD-fmk strongly reduced drug-mediated a
poptosis, The prototype substrate of caspases, poly(ADP-ribose) polyme
rase, was cleaved upon drug treatment, suggesting that CD95-L triggere
d autocrine/paracrine death via activation of caspases, Our data sugge
st that chemosensitivity of solid tumor cells depends on intact apopto
sis pathways involving activation of the CD95 system and processing of
caspases. Our findings may have important implications for new treatm
ent approaches to increase sensitivity and to overcome resistance of s
olid tumors. (C) 1998 Wiley-Liss, Inc.