TY - JOUR
T1 - Acquisition of cellular resistance to 9-nitro-camptothecin correlates with suppression of transcription factor NF-κB activation and potentiation of cytotoxicity by tumor necrosis factor in human histiocytic lymphoma U-937 cells
AU - Singh, Sanjaya
AU - Raju, Uma
AU - Mendoza, John
AU - Pantazis, Panayotis
AU - Aggarwal, Bharat B.
N1 - Copyright:
Copyright 2007 Elsevier B.V., All rights reserved.
PY - 1998
Y1 - 1998
N2 - Resistance of tumor cells to chemotherapeutic agents is a major problem in cancer therapy. Continuous exposure of human histiocytic lymphoma U-937 cells to 9-nitro-camptothecin (9NC), an inhibitor of the nuclear DNA topoisomerase I, induces resistance to this drug. Because of the involvement of the nuclear factor NF-κB in the expression of several growth regulatory genes, we examined the activation of this transcription factor in 9NC-resistant U-937 cells. We found that resistance to increasing concentrations of 9NC correlated with resistance to tumor necrosis factor (TNF)-dependent activation of NF-κB. However, the constitutive synthesis of NF-κB proteins remained unaffected. Cellular resistance was not unique to TNF, as other activators of NF-κB, including interleukin-1, phorbol ester and hydrogen peroxide, also had no effect. There was no difference between 9NC-sensitive and -resistant cells in the activation of NF-κB by okadaic acid. Other transcription factors, including AP-1 and Oct-1, were not affected in the resistant cells. When examined for the inhibitory subunit of NF-κB (IκBα), resistant cells showed a faster rate of resynthesis than the control. Interestingly, although 9NC resistance correlated with resistance to TNF-dependent NF-κB activation, TNF-dependent cytotoxicity in these cells was enhanced by several hundred fold despite a significant decrease in the number of TNF receptors. In conclusion, our results suggest that NF-κB activation may play a role in tumor cell killing by 9NC but not by TNF.
AB - Resistance of tumor cells to chemotherapeutic agents is a major problem in cancer therapy. Continuous exposure of human histiocytic lymphoma U-937 cells to 9-nitro-camptothecin (9NC), an inhibitor of the nuclear DNA topoisomerase I, induces resistance to this drug. Because of the involvement of the nuclear factor NF-κB in the expression of several growth regulatory genes, we examined the activation of this transcription factor in 9NC-resistant U-937 cells. We found that resistance to increasing concentrations of 9NC correlated with resistance to tumor necrosis factor (TNF)-dependent activation of NF-κB. However, the constitutive synthesis of NF-κB proteins remained unaffected. Cellular resistance was not unique to TNF, as other activators of NF-κB, including interleukin-1, phorbol ester and hydrogen peroxide, also had no effect. There was no difference between 9NC-sensitive and -resistant cells in the activation of NF-κB by okadaic acid. Other transcription factors, including AP-1 and Oct-1, were not affected in the resistant cells. When examined for the inhibitory subunit of NF-κB (IκBα), resistant cells showed a faster rate of resynthesis than the control. Interestingly, although 9NC resistance correlated with resistance to TNF-dependent NF-κB activation, TNF-dependent cytotoxicity in these cells was enhanced by several hundred fold despite a significant decrease in the number of TNF receptors. In conclusion, our results suggest that NF-κB activation may play a role in tumor cell killing by 9NC but not by TNF.
KW - 9-Nitro-camptothecin
KW - Cellular resistance
KW - Cytotoxicity
KW - NF-κB
KW - Tumor necrosis factor
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U2 - 10.1097/00001813-199809000-00006
DO - 10.1097/00001813-199809000-00006
M3 - Article
C2 - 9823429
AN - SCOPUS:0031762652
SN - 0959-4973
VL - 9
SP - 703
EP - 714
JO - Anti-cancer drugs
JF - Anti-cancer drugs
IS - 8
ER -