Induction of apoptosis by hydroxydibenzoylmethane through coordinative modulation of cyclin D3, Bcl-XL, and Bax, release of cytochrome c, and sequential activation of caspases in human colorectal carcinoma cells
Induction of apoptosis by hydroxydibenzoylmethane through coordinative modulation of cyclin D3, Bcl-XL, and Bax, release of cytochrome c, and sequential activation of caspases in human colorectal carcinoma cells
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DOI：
10.1021/jf034094i
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发表时间：
2003-07-02
影响因子：
6.1
通讯作者：
Lin, CH
中科院分区：
文献类型：
--
作者：
Pan, MH;Huang, MC;Lin, CH
DBM（二苯甲酰甲烷）是甘草的一种次要成分，具有抗诱变活性。然而，它的其他生物活性尚不清楚。结构相关的β -二酮羟基二苯甲酰甲烷（HDB）和羟甲基二苯甲酰甲烷（HMDB）能够诱导结肠直肠癌COLO 205细胞凋亡。因此，我们评估了结构相关的β -二酮对细胞活力、DNA断裂和半胱天冬酶活性的影响。这些化合物对结肠直肠癌COLO 205细胞凋亡的影响顺序为HDB > HMDB > DBM。我们发现，HDB诱导的凋亡细胞死亡伴随着cyclin D3、Bax和p21的上调和Bcl-X-L的下调，而HDB对Bcl-2和Bad蛋白的水平没有影响。这些结果表明，HDB允许caspase激活的脱氧核糖核酸酶进入细胞核并降解染色体DNA，诱导DFF-45降解。提示hdb诱导的细胞凋亡是由细胞色素c释放到细胞质中、procaspase-9加工、caspase-3和caspase-2的激活、PARP的降解以及caspase激活的脱氧核糖核酸酶通过消化DFF-45引起的DNA片段化等触发的。HDB诱导细胞凋亡可能是其癌症化学预防作用的关键机制。
DBM (dibenzoylmethane) is a minor constituent of licorice that has antimutagenic activity. However, its other biological activities are not well-known. The structurally related beta-diketones hydroxydibenzoylmethane (HDB) and hydroxymethyldibenzoylmethane (HMDB) were able to induce apoptosis in colorectal carcinoma COLO 205 cells. Thus, the effect of structurally related beta-diketones on cell viability, DNA fragmentation, and caspase activity was assessed. The potency of these compounds on these features of apoptosis were in the order of HDB > HMDB > DBM in colorectal carcinoma COLO 205 cells. Here, we found that HDB-induced apoptotic cell death was accompanied by upregulation of cyclin D3, Bax, and p21 and down-regulation of Bcl-X-L, while HDB had no effect on the levels of Bcl-2 and Bad protein. These results indicate that HDB allows caspase-activated deoxyribonuclease to enter the nucleus and degrade chromosomal DNA and induces DFF-45 degradation. It is suggested that HDB-induced apoptosis is triggered by the release of cytochrome c into cytosol, procaspase-9 processing, activation of caspase-3 and caspase-2, degradation of PARP, and DNA fragmentation caused by the caspase-activated deoxyribonuclease through the digestion of DFF-45. The induction of apoptosis by HDB may provide a pivotal mechanism for its cancer chemopreventive action.