C. Friesen et al., Induction of CD95 ligand and apoptosis by doxorubicin is modulated by the redox state in chemosensitive- and drug-resistant tumor cells, CELL DEAT D, 6(5), 1999, pp. 471-480
Induction of CD95 ligand (CD95-L) may contribute to drug-induced apoptosis
in chemosensitive leukemias and solid tumors, Here we report that induction
of CD95-L and apoptosis by doxorubicin in leukemic and neuroblastoma cells
is regulated by the redox state and reactive oxygen species (ROS), Preincu
bation of chemosensitive cells with antioxidants such as N-acetyl-cysteine
(NAC) or glutathione (GSH), significantly reduced doxorubicin-induced apopt
osis, hyperexpression of ROS, loss of mitochondrial membrane potential (Del
ta Psi(m)) and upregulation of CD95-L expression. Doxorubicin-resistant cel
ls exhibited higher levels of GSH in comparison to chemosensitive cells and
were deficient in hyperproduction of ROS, loss of Delta Psi(m) and upregul
ation of CD95-L in response to cytotoxic drugs, Downregulation of intracell
ular GSH concentrations reversed deficient drug-induced hyperproduction of
ROS and CD95-L upregulation, In addition, overexpression of Bcl-X-L in CEM
cells blocked doxorubicin-triggered ROS and CD95-L expression, These findin
gs suggest that induction of CD95-L by cytotoxic drugs is modulated by the
cellular redox state and mitochondria derived ROS.