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Sesquiterpene Alcohol Cedrol Chemosensitizes Human Cancer Cells and Suppresses Cell Proliferation by Destabilizing Plasma Membrane Lipid Rafts
Frontiers in Cell and Developmental Biology ( IF 4.6 ) Pub Date : 2020-12-16 , DOI: 10.3389/fcell.2020.571676
Siddhartha Kumar Mishra , Yun Soo Bae , Yong-Moon Lee , Jae-Sung Kim , Seung Hyun Oh , Hwan Mook Kim

Chemosensitization of cancer cells with small molecules may improve the therapeutic index of antitumoral agents by making tumor cells sensitive to the drug regimen and thus overcome the treatment resistance and side effects of single therapy. Cell membrane lipid rafts are known to transduce various signaling events in cell proliferation. Sensitizing cancer cells may cause modulation of membrane lipid rafts which may potentially be used in improving anticancer drug response. Cedrol, a natural sesquiterpene alcohol, was used to treat human leukemia K562 and colon cancer HT-29 cell lines, and effects were observed. Cedrol decreased the cell viability by inducing apoptosis in both cell lines by activation of pro-apoptosis protein BID and inhibition of anti-apoptosis proteins Bcl-XL, Bcl-2, and XIAP. Cedrol activated the caspase-9-dependent mitochondrial intrinsic pathway of apoptosis. Furthermore, cedrol inhibited the levels of pAKT, pERK, and pmTOR proteins as well as nuclear and cytoplasmic levels of the p65 subunit of NF-κB. Cedrol caused redistribution of cholesterol and sphingomyelin contents from membrane lipid raft, which was confirmed by a combined additive effect with methyl-β-cyclodextrin (lipid raft-disrupting agent). Lipid raft destabilization by cedrol led to the increased production of ceramides and inhibition of membrane-bound NADPH oxidase 2 enzyme activity. Cholesterol/sphingomyelin-redistributing abilities of cedrol appear as a novel mechanism of growth inhibition of cancer cells. Cedrol can be classified as a natural lipid raft-disrupting agent with possibilities to be used in general studies involving membrane lipid raft modifications.



中文翻译:

倍半萜烯醇雪松醇对人癌细胞具有化学敏感性,并通过使血浆膜脂筏不稳定来抑制细胞增殖。

用小分子对癌细胞进行化学增敏可以通过使肿瘤细胞对药物方案敏感来改善抗肿瘤剂的治疗指数,从而克服单一疗法的治疗抗性和副作用。已知细胞膜脂质筏可转导细胞增殖中的各种信号事件。致敏的癌细胞可能引起膜脂筏的调节,其可能潜在地用于改善抗癌药物反应。天然倍半萜烯醇Cedrol被用于治疗人白血病K562和结肠癌HT-29细胞系,并观察到效果。Cedrol通过激活促凋亡蛋白BID和抑制抗凋亡蛋白Bcl-X诱导两种细胞系的凋亡来降低细胞活力大号,Bcl-2和XIAP。Cedrol激活caspase-9依赖的线粒体内在凋亡途径。此外,西多洛尔抑制pAKT,pERK和pmTOR蛋白的水平以及NF-κBp65亚基的核和细胞质水平。鲸蜡酚引起膜脂筏中胆固醇和鞘磷脂含量的重新分布,这通过与甲基-β-环糊精(脂质筏破坏剂)的相加作用得以证实。赛多尔对脂筏的去稳定作用导致神经酰胺产量的增加和膜结合NADPH氧化酶2酶活性的抑制。乙醛的胆固醇/鞘磷脂的再分配能力似乎是癌细胞生长抑制的新机制。

更新日期:2021-01-21
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