Basal levels and patterns of anticancer drug-induced activation of nuclear factor-kappaB (NF-kappaB), and its attenuation by tamoxifen, dexamethasone, and curcumin in carcinoma cells.
Nuclear factor-kappaB (NF-kappaB) has been implicated in the development of drug resistance in cancer cells. We systematically examined the baseline levels of NF-kappaB activity of representative carcinoma cell lines, and the change of NF-kappaB activity in response to a challenge with four major anticancer drugs (doxorubicin, 5-fluorouracil, cisplatin, and paclitaxel). We found that the basal level of NF-kappaB activity was heterogeneous and roughly correlated with drug resistance. When challenged with various drugs, all the cell lines examined responded with a transient activation of NF-kappaB which then declined to basal level despite variation in the concentration of the agent and the timing of the treatment. In contrast to tumor necrosis factor-alpha (TNF-alpha), which activates NF-kappaB in minutes, NF-kappaB activation induced by anticancer drugs usually occurred more than 1hr after stimulation. A gradual increase of total NF-kappaB and its nuclear translocation, and cytoplasmic translocation of nuclear IkappaBalpha and its degradation were involved in this process. In particular, when cells were pretreated with common biologic modulators such as tamoxifen, dexamethasone, and curcumin, the doxorubicin-induced NF-kappaB activation was attenuated significantly. This inhibition may play a role in sensitizing cancer cells to chemotherapeutic drugs. This study has demonstrated that activation of NF-kappaB is a general cellular response to anticancer drugs, and the mechanism of activation appears to be distinct from that induced by TNF-alpha. These observations may have implications for improving the efficacy of systemic chemotherapy for cancer patients.
Chuang
Shuang En
SE
Division of Cancer Research, National Health Research Institutes, Taipei, Taiwan, ROC 11529.
Yeh
Pei Yen
PY
Lu
Yen Shen
YS
Lai
Gi Ming
GM
Liao
Chao Ming
CM
Gao
Ming
M
Cheng
Ann Lii
AL
D021581:Active Transport, Cell Nucleus; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003474:Curcumin / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D004342:Drug Hypersensitivity; D004347:Drug Interactions; D006801:Humans; D020672:I-kappa B Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D013629:Tamoxifen; D000072000:NF-KappaB Inhibitor alpha; D003907:Dexamethasone; D004317:Doxorubicin; D003474:Curcumin; D013755:Tetradecanoylphorbol Acetate