Administration of suboptimal doses of anticancer drugs not only fails to control tumor but often results in increased drug resistance of tumor cells. However, little is known about the effects of transient exposure to a minimally cytotoxic dose of chemotherapy on the development of drug resistance of the tumors. Previous studies have shown that upregulation of drug-exporter proteins (ATP-binding-cassette proteins) may be one of the key mechanisms involved in inducible drug resistance. In this study, we demonstrated that upregulation of NF-KB is another possible mechanism. SiHa cells were exposed to low-dose doxorubicin (100 nM; IC30) for 3 hr, and then were continuously cultured in drug-free culture media (designated as SiHa/DR cells). SiHa/DR cells at up to 9 passages showed increased resistance to doxorubicin and cross-resistance to cisplatin. Results of quantitative real-time PCR and flow cytometry assay indicated that the increased drug-resistance in SiHa/DR cells was not due to upregulation of drug-exporter proteins or to the decrease of intracellular concentration of anticancer drugs. Both the basal and drug-induced NF-KB activity were shown to be increased in SiHa/DR cells by EMSA and NF-KB-driven luciferase reporter gene assay. Suppression of NF-KB activation by transfection of a dominant negative IKBalpha prevented the development of drug resistance, indicating that the upregulated NF-KB activity was positively correlated with the low-dose doxorubicin-induced drug resistance. These results suggest that even a transient exposure to a small dose of anticancer drugs may induce drug resistance in some cancer cells via upregulation of NF-KB activity. (C) 2003 Elsevier Science Inc. All rights reserved.
