Abstract
Aim:
To determine whether interferon-α (IFNα) can enhance doxorubicin sensitivity in osteosarcoma cells and its molecular mechanism.
Methods:
Cell viability was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Apoptosis was studied using Flow cytometry analysis, Hoechst33258 staining, DNA fragmentation assay, as well as the activation of caspase-3 and poly (ADP-ribose) polymerase. Protein expression was detected by Western blotting. The dependence of p53 was determined using p53-siRNA transfection.
Results:
IFNα increased doxorubicin-induced cytotoxicity to a much greater degree through apoptosis in human osteosarcoma p53-wild U2OS cells, but not p53-mutant MG63 cells. IFNα markedly upregulated p53, Bax, Mdm2, and p21, downregulated Bcl-2, and activated caspase-3 and PARP cleavage in response to doxorubicin in U2OS cells. Moreover, the siRNA-mediated silencing of p53 significantly reduced the IFNα /doxorubicin combination-induced cytotoxic-ity and PARP cleavage.
Conclusion:
IFNα enhances the sensitivity of human osteosarcoma U2OS cells to doxorubicin by p53-dependent apoptosis. The proper combination with IFNα and conventional chemotherapeutic agents may be a rational strategy for improving the treatment of osteosarcoma with functional p53.
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Project supported by grants from the National Natural Science Foundation of China (No 30070766).
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Yuan, Xw., Zhu, Xf., Huang, Xf. et al. Interferon-α enhances sensitivity of human osteosarcoma U2OS cells to doxorubicin by p53-dependent apoptosis. Acta Pharmacol Sin 28, 1835–1841 (2007). https://doi.org/10.1111/j.1745-7254.2007.00662.x
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DOI: https://doi.org/10.1111/j.1745-7254.2007.00662.x
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