Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
Int J Cancer. 2010 Feb 15;126(4):852-63. doi: 10.1002/ijc.24766.
The synergistic actions of atorvastatin (ATST) with gamma-tocotrienol (gamma-TT) and celecoxib (CXIB) were studied in human colon cancer cell lines HT29 and HCT116. The synergistic inhibition of cell growth by ATST and gamma-TT was demonstrated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and isobologram analysis. delta-TT exhibited a similar inhibitory action when combined with ATST. Mevalonate and geranylgeranyl pyrophosphate eliminated most of the growth inhibitory effect of ATST, but only marginally decreased that of gamma-TT; whereas farnesyl pyrophosphate and squalene exhibited little effect on the inhibitory action of ATST and gamma-TT, indicating protein geranylgeranylation, but not farnesylation are involved in the inhibition of colon cancer cell growth. Both mevalonate and squalene restored the cellular cholesterol level that was reduced by ATST treatment, but only mevalonate eliminated the cell growth inhibitory effect, suggesting that the cholesterol level in cells does not play an essential role in inhibiting cancer cell growth. Protein level of HMG-CoA reductase increased after ATST treatment, and the presence of gamma-TT attenuated the elevated level of HMG-CoA reductase. ATST also decreased membrane-bound RhoA, possibly due to a reduced level of protein geranylgeranylation; addition of gamma-TT enhanced this effect. The mediation of HMG-CoA reductase and RhoA provides a possible mechanism for the synergistic action of ATST and gamma-TT. The triple combination of ATST, gamma-TT and CXIB showed a synergistic inhibition of cancer cell growth in MTT assays. The synergistic action of these three compounds was also illustrated by their induction of G(0)/G(1) phase cell cycle arrest and apoptosis.
阿托伐他汀（ATST）与γ-生育三烯酚（γ-TT）和塞来昔布（CXIB）的协同作用在人结肠癌细胞系 HT29 和 HCT116 中进行了研究。3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐（MTT）测定和等效应线分析表明，ATST 和 γ-TT 的协同抑制细胞生长。δ-TT 与 ATST 联合使用时表现出类似的抑制作用。甲羟戊酸和香叶基香叶基焦磷酸酯消除了 ATST 生长抑制作用的大部分，但仅略微降低了 γ-TT 的作用；而法呢基焦磷酸酯和角鲨烯对 ATST 和 γ-TT 的抑制作用影响不大，表明蛋白质香叶基香叶基化，而不是法呢基化参与了结肠癌细胞生长的抑制。甲羟戊酸和角鲨烯都恢复了 ATST 处理降低的细胞胆固醇水平，但只有甲羟戊酸消除了细胞生长抑制作用，表明细胞内胆固醇水平对抑制癌细胞生长不起关键作用。ATST 处理后 HMG-CoA 还原酶蛋白水平升高，γ-TT 的存在减弱了 HMG-CoA 还原酶的升高水平。ATST 还降低了膜结合的 RhoA，可能是由于蛋白质香叶基香叶基化水平降低；添加 γ-TT 增强了这种作用。HMG-CoA 还原酶和 RhoA 的介导为 ATST 和 γ-TT 的协同作用提供了一种可能的机制。ATST、γ-TT 和 CXIB 的三联组合在 MTT 测定中显示出对癌细胞生长的协同抑制作用。这三种化合物的协同作用还通过诱导 G0/G1 期细胞周期停滞和细胞凋亡得到了说明。
