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- 2014.1
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Vorinostat (VOR) has been reported to enhance the cytotoxic effects of doxorubicin (DOX) with fewer side effects because of the lower DOX dosage in breast cancer cells. In this study, we investigated the novel mechanism underlying the synergistic cytotoxic effects of VOR and DOX co-treatment in cervical cancer cells HeLa, CaSki and SiHa cells. Co-treatment with VOR and DOX at marginal doses led to the induction of apoptosis through caspase-3 activation, poly (ADP-ribose) polymerase cleavage and DNA micronuclei. Notably, the synergistic growth inhibition induced by the co-treatment was attributed to the upregulation of the pro-apoptotic protein Bad, as the silencing of Bad expression using small interfering RNA (siRNA) abolished the phenomenon. As siRNA against p53 did not result in an increase in acetylated p53 and the consequent upregulation of Bad, the observed Bad upregulation was mediated by acetylated p53. Moreover, a chromatin immunoprecipitation analysis showed that the co-treatment of HeLa cells with VOR and DOX increased the recruitment of acetylated p53 to the bad promoter, with consequent bad transactivation. Conversely, C33A cervical cancer cells containing mutant p53 co-treated with VOR and DOX did not exhibit Bad upregulation, acetylated p53 induction or consequent synergistic growth inhibition. Together, the synergistic growth inhibition of cervical cancer cell lines induced by co-treatment with VOR and DOX can be attributed to the upregulation of Bad, which is induced by acetylated p53. These results show for the first time that the acetylation of p53, rather than histones, is a mechanism for the synergistic growth inhibition induced by VOR and DOX co-treatments.
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참고문헌 (25)
참고문헌 신청
Cannings E / 2007 / Bad expression predicts outcome in patients treated with tamoxifen / Breast Cancer Res Treat 102 : 173 ~ 179
Carvalho C / 2009 / Doxorubicin: the good, the bad and the ugly effect / Curr Med Chem 16 : 3267 ~ 3285
Feng L / 2005 / Functional analysis of the roles of posttranslational modifications at the p53 C terminus in regulating p53stability and activity / Mol Cell Biol 25 : 5389 ~
Giannini G / 2012 / Histone deacetylase inhibitors in the treatment of cancer : overview and perspectives / Future Med Chem 4 : 1439 ~ 1460
Gu W / 1997 / Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain / Cell 90 : 595 ~ 606
Carvalho C / 2009 / Doxorubicin: the good, the bad and the ugly effect / Curr Med Chem 16 : 3267 ~ 3285
Feng L / 2005 / Functional analysis of the roles of posttranslational modifications at the p53 C terminus in regulating p53stability and activity / Mol Cell Biol 25 : 5389 ~
Giannini G / 2012 / Histone deacetylase inhibitors in the treatment of cancer : overview and perspectives / Future Med Chem 4 : 1439 ~ 1460
Gu W / 1997 / Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain / Cell 90 : 595 ~ 606
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