Interferon-alpha enhances sensitivity of human osteosarcoma U2OS cells to doxorubicin by p53-dependent apoptosis.

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Yuan XW, Zhu XF, Huang XF, Sheng PY, He AS, Yang ZB, Deng R, Feng GK, Liao WM

Interferon-alpha enhances sensitivity of human osteosarcoma U2OS cells to doxorubicin by p53-dependent apoptosis.

Acta Pharmacol Sin. 2007 Nov;28(11):1835-41.

PubMed ID

17959036 [ View in PubMed

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Abstract

AIM: To determine whether interferon-alpha(IFNalpha) 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: IFNalpha increased doxorubicin-induced cytotoxicity to a much greater degree through apoptosis in human osteosarcoma p53-wild U2OS cells, but not p53-mutant MG63 cells. IFNalpha 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 IFNalpha/doxorubicin combination-induced cytotoxicity and PARP cleavage. CONCLUSION: IFNalpha enhances the sensitivity of human osteosarcoma U2OS cells to doxorubicin by p53-dependent apoptosis. The proper combination with IFNalpha and conventional chemotherapeutic agents may be a rational strategy for improving the treatment of osteosarcoma with functional p53.