Synergistic growth inhibition by acyclic retinoid and phosphatidylinositol 3-kinase inhibitor in human hepatoma cells.
Synergistic growth inhibition by acyclic retinoid and phosphatidylinositol 3-kinase inhibitor in human hepatoma cells.
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DOI：
10.1186/1471-2407-13-465
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发表时间：
2013-10-08
期刊：
影响因子：
3.8
通讯作者：
Moriwaki H
中科院分区：
文献类型：
--
作者：
Baba A;Shimizu M;Ohno T;Shirakami Y;Kubota M;Kochi T;Terakura D;Tsurumi H;Moriwaki H
RXRα磷酸化导致的功能障碍与肝癌的发生有关，以RXRα为靶点的非环类维生素A（acyclic retinoid，ACR）可预防肝细胞癌（hepatocellular carcinoma，HCC）的发生。PI 3 K/Akt信号通路的激活在肝癌细胞的增殖和存活中起着关键作用。本研究探讨了ACR和LY 294002（一种PI 3 K抑制剂）对人肝癌细胞生长的可能联合作用。本研究检查了ACR与LY 294002的组合对HLF人HCC细胞生长的影响。ACR和LY 294002优先抑制HLF细胞的生长相比，HC正常肝细胞。1 μM ACR和5 μM LY 294002的组合（其中使用的浓度低于这些药物的IC 50值）协同抑制HLF、Hep 3B和Huh 7人HCC细胞的生长。当联合给药时，这些药物协同作用诱导HLF细胞凋亡。ACR与LY 294002联合作用可显著抑制HLF细胞中RXRα、Akt和ERK蛋白的磷酸化。此外，这种组合还增加了RXRE启动子活性和RARβ和p21 CIP 1的细胞水平，同时降低了细胞周期蛋白D1的水平。ACR和LY 294002协同增加RARβ的表达，同时抑制RXRα的磷酸化，这些作用与诱导人HCC细胞凋亡和抑制细胞生长有关。因此，这种组合可能是有效的化学预防和化疗的肝癌。
A malfunction of RXRα due to phosphorylation is associated with liver carcinogenesis, and acyclic retinoid (ACR), which targets RXRα, can prevent the development of hepatocellular carcinoma (HCC). Activation of PI3K/Akt signaling plays a critical role in the proliferation and survival of HCC cells. The present study examined the possible combined effects of ACR and LY294002, a PI3K inhibitor, on the growth of human HCC cells. This study examined the effects of the combination of ACR plus LY294002 on the growth of HLF human HCC cells. ACR and LY294002 preferentially inhibited the growth of HLF cells in comparison with Hc normal hepatocytes. The combination of 1 μM ACR and 5 μM LY294002, in which the concentrations used are less than the IC50 values of these agents, synergistically inhibited the growth of HLF, Hep3B, and Huh7 human HCC cells. These agents when administered in combination acted cooperatively to induce apoptosis in HLF cells. The phosphorylation of RXRα, Akt, and ERK proteins in HLF cells were markedly inhibited by treatment with ACR plus LY294002. Moreover, this combination also increased RXRE promoter activity and the cellular levels of RARβ and p21CIP1, while decreasing the levels of cyclin D1. ACR and LY294002 cooperatively increase the expression of RARβ, while inhibiting the phosphorylation of RXRα, and that these effects are associated with the induction of apoptosis and the inhibition of cell growth in human HCC cells. This combination might therefore be effective for the chemoprevention and chemotherapy of HCC.
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有效使用 PI3K 和 MEK 抑制剂治疗突变型 Kras G12D 和 PIK3CA H1047R 小鼠肺癌。
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
11.5
作者：
Shimizu, M;Suzui, M;Weinstein, IB
通讯作者：
Weinstein, IB
影响因子：
13.5
作者：
Llovet, Josep M.;Bruix, Jordi
通讯作者：
Bruix, Jordi
影响因子：
3.8
作者：
Shimizu M;Yasuda Y;Sakai H;Kubota M;Terakura D;Baba A;Ohno T;Kochi T;Tsurumi H;Tanaka T;Moriwaki H
通讯作者：
Moriwaki H
DOI：
10.1006/bbrc.1996.0188
发表时间：
1996-02-06
影响因子：
3.1
作者：
Nakamura, N;Shidoji, Y;Muto, Y
通讯作者：
Muto, Y