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.
Cao
Wei
W
Laboratory of Medical Molecular Virology, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
Ma
Sheng Lin
SL
Tang
Juanjuan
J
Shi
Jingquan
J
Lu
Yanjun
Y
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology* / Q000633:toxicity; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004359:Drug Therapy, Combination; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D011233:Precipitin Tests; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000633:toxicity
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases