A combined treatment TNF-alpha/doxorubicin alleviates the resistance of MCF-7/Adr cells to cytotoxic treatment.

The efficiency of anticancer therapy is often restricted by the development of drug resistance. Here, we report that the doxorubicin (DOX)-resistant MCF-7/Adr cells were more resistant to DOX-treatment than MCF-7 cells. However, an alternative treatment of DOX/TNF-alpha enhanced the cytotoxic effect in multidrug resistant MCF-7/Adr cell line. Treatment of cells ...
with TNF-alpha following doxorubicin (DOX) resulted in a decrease of the activated Rel A/p65 in nuclei. Histone deacetylase 1 (HDAC1) was found to interact with Rel A/p65 in the complex, suggesting that HDAC1 is involved in mediating nuclear export of Rel A/p65. The combined treatment of TNF-alpha/DOX also resulted in a significant decrease of mRNA levels of anti-apoptotic genes, such as the cellular inhibitor of apoptosis-1 (c-IAP1), and the long isoform of B cell leukemia/lymphoma x gene (Bcl-xL), leading to efficient induction of caspase-8 cleavage and cell death. In previous work, we demonstrated that TNF-alpha promotes DOX-induced cell death and anti-cancer effect through downregulation of p21 in p53-deficient tumor cells. Thus, we proposed that alternative administration of TNF-alpha and DOX may be a new and efficient therapeutic strategy for patients that develop resistance to cytotoxic treatment.
Mesh Terms:
Antibiotics, Antineoplastic, Antineoplastic Agents, Apoptosis, Blotting, Western, Breast Neoplasms, Cell Line, Tumor, Cell Nucleus, Cell Survival, Doxorubicin, Drug Resistance, Neoplasm, Drug Therapy, Combination, Electrophoretic Mobility Shift Assay, Female, Histone Deacetylase 1, Histone Deacetylases, Humans, Precipitin Tests, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factor RelA, Tumor Necrosis Factor-alpha
Biochim. Biophys. Acta
Date: Feb. 01, 2006
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