Open AccessHistone deacetylase inhibitor valproic acid sensitizes B16F10 melanoma cells to cucurbitacin B treatment
Author(s) -
Dong-Yun Ouyang,
Yanting Zhang,
Lihui Xu,
Jingjing Li,
Qing-Bing Zha,
Xian-Hui He
Publication year - 2011
Publication title -
acta biochimica et biophysica sinica
Language(s) - Uncategorized
Resource type - Journals
SCImago Journal Rank - 0.771
H-Index - 57
eISSN - 1745-7270
pISSN - 1672-9145
DOI - 10.1093/abbs/gmr032
Subject(s) - autophagy , histone deacetylase inhibitor , apoptosis , histone deacetylase , pharmacology , chemistry , valproic acid , melanoma , downregulation and upregulation , cytotoxicity , cell culture , cancer research , biology , histone , biochemistry , in vitro , genetics , neuroscience , epilepsy , gene
Cucurbitacin B (CuB) is reported to have anti-proliferation effects on a variety of tumors including melanoma, and more effective regimens by combination of this agent with others are under investigation. In this study, the anti-melanoma effect of CuB as a single agent and in combination with valproic acid (VPA), an inhibitor of histone deacetylase (HDAC), was evaluated in B16F10, a mouse melanoma cell line. The results demonstrated that CuB inhibited the proliferation of the cell line in a dose-dependent manner. However, it was likely that a pro-survival compensatory response, involving the induction of autophagy and upregulation of anti-apoptotic Bcl-2 protein, was induced by CuB treatment, which might greatly decrease the cytotoxicity of this agent. Supporting this, the melanoma cells were found to be more sensitive to the combination of CuB with chloroquine, a well-known autophagy inhibitor. And CuB-induced autophagy was associated with c-Jun N-terminal kinase (JNK) activation, at least partly, since inhibition of JNK activity by SP600125 could alleviate the autophagy. When CuB was combined with VPA, the two drugs showed synergistic cytotoxicity by induction of cell apoptosis. Moreover, the multiploidization effect of CuB was also suppressed in the presence of VPA. In contrast to the transient activation of JNKs by CuB, the combination of CuB and VPA resulted in prolonged JNK activation, although at low level after 4 h. Our results demonstrated that HDAC inhibitor VPA can sensitize B16F10 cells to CuB treatment through induction of apoptotic pathway.