TNF-mediated killing of human leukaemic cells: effects of endogenous antioxidant levels and TNF alpha expression in leukaemic cell lines.
Using the human erythroleukaemic cell line K562 cl.6 and its daunorubicin-resistant subline K/DAU600, and the human T-lymphoblastic leukaemic cell line CCRF-CEM and its vinblastine-resistant subline CEM/VLB100, we have shown that the drug-resistant cell lines were more sensitive to cytotoxicity induced by tumour necrosis factor-alpha (TNF alpha). Drug-resistant cell lines showed increased activities of copper/zinc superoxide dismutase (Cu/ZnSOD) and catalase compared with their parental drug-sensitive cell lines. However, the greater susceptibility of drug-resistant cells to TNF alpha cytotoxicity was, in part, related to their decreased activities of manganese superoxide dismutase (MnSOD). Persistence of this differential sensitivity when MnSOD is inhibited by sodium nitroprusside (SNP) suggests that the greater susceptibility of drug-resistant cells to TNF alpha was not entirely due to their decreased level of MnSOD activity. K562 cl.6 and K/DAU600, which were more resistant to TNF alpha, both expressed greater levels of endogenous plasma membrane-bound TNF alpha than the CCRF-CEM cell line. All cell lines examined were (more or less) equal in susceptibility to the cytolytic effect of exogenous O2-. generated by xanthine/xanthine oxidase. These results demonstrate that both MnSOD and endogenous TNF alpha play a role in protecting leukaemic cells against TNF alpha cytotoxicity, but there is an unknown mechanism that causes drug-resistant cells to be more susceptible to TNF alpha cytotoxicity.
Jia
L
L
Department of Haematology, London Hospital Medical College, U.K.
Jiang
X R
XR
Razak
K
K
Wu
Y L
YL
Newland
A C
AC
Kelsey
S M
SM
D002374:Catalase / Q000378:metabolism; D003630:Daunorubicin; D004351:Drug Resistance; D006801:Humans; D066298:In Vitro Techniques; D004915:Leukemia, Erythroblastic, Acute / Q000188:drug therapy* / Q000201:enzymology; D013482:Superoxide Dismutase / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000633:toxicity*; D014747:Vinblastine
D014409:Tumor Necrosis Factor-alpha; D014747:Vinblastine; D002374:Catalase; D013482:Superoxide Dismutase; D003630:Daunorubicin