Acyclic retinoid synergises with valproic acid to inhibit growth in human hepatocellular carcinoma cells.
Acyclic retinoid synergises with valproic acid to inhibit growth in human hepatocellular carcinoma cells.
复制标题
DOI：
10.1016/j.canlet.2009.05.019
复制
发表时间：
2009-11
期刊：
影响因子：
9.7
通讯作者：
H. Tatebe;M. Shimizu;Y. Shirakami;Hiroyasu Sakai-;Y. Yasuda;H. Tsurumi;H. Moriwaki
中科院分区：
文献类型：
--
作者：
H. Tatebe;M. Shimizu;Y. Shirakami;Hiroyasu Sakai-;Y. Yasuda;H. Tsurumi;H. Moriwaki
维甲酸X受体α(RXRα)磷酸化导致的功能障碍与肝细胞癌的发生发展有关，以RXRα为靶点的无环类维甲酸可阻止第二原发癌的发生。丙戊酸(VPA)是一种组蛋白脱乙酰酶(HDAC)抑制剂，可诱导癌细胞凋亡和细胞周期停滞。VPA还可以增强癌细胞对维甲酸的敏感性。本研究探讨了ACR与VPA联合应用对人肝癌细胞株HepG2的可能联合作用。5-μ-M-ACR和1 mM-VPA联合应用对人肝癌细胞株的生长有协同抑制作用，而对人正常肝细胞的生长无明显影响。ACR与VPA联合应用也能协同诱导HepG2细胞凋亡和G0-G1期停滞。这种结合进一步协同抑制RXRα、ERK、Akt和GSK-3β蛋白的磷酸化，并导致乙酰化组蛋白H3和H4的积累。丙戊酸能提高细胞RARβ和p21CIP1的表达水平。这些药物的组合显著提高了REARE启动子和RXRE启动子在HepG2细胞中的活性。上述结果提示，阿昔洛韦和丙戊酸协同作用可上调RARβ和p21CIP1的表达，抑制RXRα的磷酸化，其作用机制可能与诱导细胞凋亡和抑制细胞生长有关。因此，这种联合疗法可能是一种有效的肝癌化学预防和化疗方案。
A malfunction of retinoid X receptor-α (RXRα) due to phosphorylation is associated with the development of hepatocellular carcinoma (HCC) and acyclic retinoid (ACR), which targets RXRα, can prevent the development of second primary HCC. Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, induces apoptosis and cell cycle arrest in cancer cells. VPA can also enhance the sensitivity of cancer cells to retinoids. The present study examined the possible combined effects of ACR plus VPA in HepG2 human HCC cell line. The combination of 5μM ACR and 1mM VPA, about the IC25value for both compounds, synergistically inhibited the growth of HepG2 cells without affecting the growth of Hc normal human hepatocytes. The combined treatment with ACR plus VPA also acted synergistically to induce apoptosis and G0–G1cell cycle arrest in HepG2 cells. This combination further exerted a synergistic inhibition of the phosphorylation of RXRα, ERK, Akt and GSK-3β proteins and caused an accumulation of acetylated histones H3 and H4 proteins. VPA enhanced the ability of ACR to raise the cellular levels of RARβ and p21CIP1. The combination of these agents markedly increased both the RARE and RXRE promoter activities in HepG2 cells. These results suggest that ACR and VPA cooperatively increase the expression of RARβ and p21CIP1, while inhibiting the phosphorylation of RXRα, and these effects were associated with induction of apoptosis and the inhibition of cell growth in HepG2 cells. This combination might therefore be an effective regimen for the chemoprevention and chemotherapy of HCC.