Gamma-tocotrienol reverses multidrug resistance of breast cancer cells with a mechanism distinct from that of atorvastatin
Gamma-tocotrienol reverses multidrug resistance of breast cancer cells with a mechanism distinct from that of atorvastatin
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γ-生育三烯酚通过调节γ-生育三烯酚-NF-γB-P-gp 轴逆转乳腺癌细胞的多药耐药性
DOI：
10.1016/j.jsbmb.2016.11.009
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发表时间：
2017-03-01
影响因子：
4.1
通讯作者：
Huang, Biao
中科院分区：
文献类型：
--
作者：
Ding, Yuedi;Peng, Ying;Huang, Biao
除了其抗氧化特性外，γ-生育三烯酚还具有抑制HMG-CoA还原酶的能力，HMG-CoA还原酶是胆固醇生物合成的甲羟戊酸途径中的关键酶。他汀类药物是HMG-CoA还原酶的竞争性抑制剂，其抑制HMG-CoA还原酶的活性被认为是其抗肿瘤活性和逆转肿瘤细胞多药耐药的重要机制之一。在这里，我们确定了甲羟戊酸途径在γ-生育三烯酚介导的癌细胞多药耐药逆转中的作用。我们发现γ-生育三烯酚和阿托伐他汀都能有效逆转MCF-7/Adr的多药耐药，并显著抑制细胞内FPP和GGPP的水平。外源性添加甲羟戊酸或FPP和GGPP几乎完全阻止阿托伐他汀的逆转能力，但仅部分减弱γ-生育三烯酚对阿霉素耐药性的逆转作用。此外，γ-生育酚还能抑制P-gp的表达，增加阿霉素在细胞内的蓄积，从而导致G2/M期阻滞和细胞凋亡。总之，γ-生育三烯酚逆转MCF-7/Adr的多药耐药的机制与阿托伐他汀不同。而不是甲羟戊酸途径，P-gp表达的抑制是一个潜在的机制，γ-生育三烯酚逆转MCF-7/Adr的多药耐药。(C)2016爱思唯尔有限公司版权所有。
In addition to its antioxidant properties, gamma-tocotrienol also has the ability to inhibit HMG-CoA reductase, which is the key enzyme in the mevalonate pathway for cholesterol biosynthesis. Statins, the competitive inhibitors of HMG-CoA reductase, display potent anticancer activity and reversal ability of multidrug resistance in a variety of tumor cells, which is believed to be due to their inhibition of HMG-CoA reductase. Here, we determined the role of the mevalonate pathway in gamma-tocotrienol-mediated reversal of multidrug resistance in cancer cells. We found both gamma-tocotrienol and atorvastatin effectively reversed multidrug resistance of MCF-7/Adr and markedly inhibited the intracellular levels of FPP and GGPP. Exogenous addition of mevalonate or FPP and GGPP almost completely prevented the reversal ability of atorvastatin but only partly attenuated the reversal effect of gamma-tocotrienol on doxorubicin resistance. In addition, gamma-tocottienol actively inhibited the expression of P-gp and increased the accumulation of doxorubicin in cells, which led to the enhanced G2/M arrest and cell apoptosis. Taken together, gamma-tocotrienol reversed the multidrug resistance of MCF-7/Adr with a mechanism distinct from that of atorvastatin. Instead of the mevalonate pathway, the inhibition of P-gp expression is a potential mechanism by which gamma-tocotrienol reverses multidrug resistance in MCF-7/Adr. (C) 2016 Elsevier Ltd. All rights reserved.