Han J W, Ahn S H, Park S H, Wang S Y, Bae G U, Seo D W, Kwon H K, Hong S, Lee H Y, Lee Y W, Lee H W
Department of Biochemistry and Molecular Biology, College of Pharmacy, Sungkyunkwan University, Suwon, Korea.
Cancer Res. 2000 Nov 1;60(21):6068-74.
Apicidin [cyclo(N-O-methyl-L-tryptophanyl-L-isoleucinyl-D-pipecolinyl -L-2-amino-8-oxodecanoyl)] is a fungal metabolite shown to exhibit antiparasitic activity by the inhibition of histone deacetylase (HDAC). In this study, we evaluated apicidin as a potential antiproliferative agent. Apicidin showed a broad spectrum of antiproliferative activity against various cancer cell lines, although with differential sensitivity. The antiproliferative activity of apicidin on HeLa cells was accompanied by morphological changes, cell cycle arrest at G1 phase, and accumulation of hyperacetylated histone H4 in vivo as well as inhibition of partially purified HDAC in vitro. In addition, apicidin induced selective changes in the expression of p21WAF1/Cip1 and gelsolin, which control the cell cycle and cell morphology, respectively. Consistent with increased induction of p21WAF1/Cip1, phosphorylation of Rb protein was markedly decreased, indicating the inhibition of cyclin-dependent kinases, which became bound to p21WAF1/Cip1. The effects of apicidin on cell morphology, expression of gelsolin, and HDAC1 activity in vivo and in vitro appeared to be irreversible, because withdrawal of apicidin did not reverse those effects, whereas the induction of p21WAF1/Cip1 by apicidin was reversible. Taken together, the results suggest that induction of histone hyperacetylation by apicidin is responsible for the antiproliferative activity through selective induction of genes that play important roles in the cell cycle and cell morphology.
阿皮西丁[环（N - O - 甲基 - L - 色氨酰 - L - 异亮氨酰 - D - 哌啶基 - L - 2 - 氨基 - 8 - 氧代癸酰）]是一种真菌代谢产物，已证明其通过抑制组蛋白脱乙酰酶（HDAC）表现出抗寄生虫活性。在本研究中，我们评估了阿皮西丁作为一种潜在的抗增殖剂。阿皮西丁对各种癌细胞系表现出广泛的抗增殖活性，尽管敏感性有所不同。阿皮西丁对HeLa细胞的抗增殖活性伴随着形态学变化、细胞周期在G1期停滞、体内高乙酰化组蛋白H4的积累以及体外对部分纯化的HDAC的抑制。此外，阿皮西丁诱导了p21WAF1/Cip1和凝溶胶蛋白表达的选择性变化，它们分别控制细胞周期和细胞形态。与p21WAF1/Cip1诱导增加一致，Rb蛋白的磷酸化明显降低，表明细胞周期蛋白依赖性激酶受到抑制，这些激酶与p21WAF1/Cip1结合。阿皮西丁对细胞形态、凝溶胶蛋白表达以及体内外HDAC1活性的影响似乎是不可逆的，因为撤去阿皮西丁并没有逆转这些影响，而阿皮西丁对p21WAF1/Cip1的诱导是可逆的。综上所述，结果表明阿皮西丁诱导组蛋白高乙酰化通过选择性诱导在细胞周期和细胞形态中起重要作用的基因来负责抗增殖活性。
