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- Title
Nutlin-3 cooperates with doxorubicin to induce apoptosis of human hepatocellular carcinoma cells through p53 or p73 signaling pathways.
- Authors
Tongsen Zheng; Jiabei Wang; Xuan Song; Xianzhi Meng; Shangha Pan; Hongchi Jiang; Lianxin Liu
- Abstract
Despite recent advances in chemotherapeutic agents for Hepatocellular carcinoma (HCC) treatment, the results of chemotherapy remain unsatisfactory. Doxorubicin (DOX) still represents the cornerstone in HCC chemotherapy, but resistance and toxicity to normal cells are major obstacles to successful chemotherapy. Therefore, new active agents in HCC chemotherapy and agents that increase the chemosensitivity of HCC cells to DOX are still urgently required. Nutlin-3 is a small-molecule inhibitor that acts to inhibit murine double minute-2 (MDM2) binding to p53 or p73, and subsequently activates p53- or p73-dependent apoptosis signaling pathway. This study was designed to investigate whether Nutlin-3 alters cell toxicity to HCC cells following DNA damage and to assess the suitability of DOX/Nutlin-3 as a chemotherapeutic combination in HCC chemotherapy. Four human HCC cells were analyzed using cell proliferation assay, apoptosis assay, western blotting, co-immunoprecipitation and siRNA experiments. Anti-tumoral effects of Nutlin-3/DOX targeting the p53/MDM2 and p73/MDM2 pathways were evaluated in HCC cell lines. Nutlin-3 enhances the growth inhibition by DOX and potentates the apoptotic effect in all HCC cell lines with different p53 types. Nutlin-3 acts through the disruption of p53–MDM2 binding in HepG2, and the disruption of p73–MDM2 in Huh-7 and Hep3B cell lines with subsequent activation of the apoptotic pathway, which leads to the increase in chemosensitivity to DOX in HCC cells. Taken together, our findings suggest that Nutlin-3 will be active in the treatment of HCC and offers new prospects for overcoming DOX resistance.
- Subjects
LIVER cancer; DRUG therapy; DOXORUBICIN; CELLS; APOPTOSIS
- Publication
Journal of Cancer Research & Clinical Oncology, 2010, Vol 136, Issue 10, p1597
- ISSN
0171-5216
- Publication type
Article
- DOI
10.1007/s00432-010-0817-8