Acquisition of cellular resistance to 9-nitro-camptothecin correlates with suppression of transcription factor NF-kappa B activation and potentiation of cytotoxicity by tumor necrosis factor in human histiocytic lymphoma U-937 cells.
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-kappa B 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-kappa B. However, the constitutive synthesis of NF-kappa B proteins remained unaffected. Cellular resistance was not unique to TNF, as other activators of NF-kappa B, 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-kappa B 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-kappa B (I kappa B alpha), resistant cells showed a faster rate of resynthesis than the control. Interestingly, although 9NC resistance correlated with resistance to TNF-dependent NF-kappa B 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-kappa B activation may play a role in tumor cell killing by 9NC but not by TNF.
Singh
S
S
Department of Molecular Oncology, University of Texas MD Anderson Cancer Center, Houston 77030, USA.
Raju
U
U
Mendoza
J
J
Pantazis
P
P
Aggarwal
B B
BB
D000970:Antineoplastic Agents / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D051863:Host Cell Factor C1; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020672:I-kappa B Proteins; D007375:Interleukin-1 / Q000494:pharmacology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000378:metabolism; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D050811:Octamer Transcription Factor-1; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C497692:HCFC1 protein, human; D051863:Host Cell Factor C1; D020672:I-kappa B Proteins; D007375:Interleukin-1; D016328:NF-kappa B; D050811:Octamer Transcription Factor-1; C494165:POU2F1 protein, human; D018124:Receptors, Tumor Necrosis Factor; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D006861:Hydrogen Peroxide; C079905:rubitecan; D013755:Tetradecanoylphorbol Acetate; D002166:Camptothecin