Sesquiterpene Alcohol Cedrol Chemosensitizes Human Cancer Cells and Suppresses Cell Proliferation by Destabilizing Plasma Membrane Lipid Rafts

Frontiers in Cell and Developmental Biology

Yun Soo Bae²  Siddhartha Kumar Mishra³  Yong-Moon Lee⁴  Jae-Sung Kim⁵  Seung Hyun Oh⁶  Hwan Mook Kim⁶ 

[1] Cancer Biology Laboratory, Department of Zoology, School of Biological Sciences, Dr. Harisingh Gour Central University, Sagar, India;Department of Life Science, College of Natural Sciences, Ewha Womans University, Seoul, South Korea;Department of Life Sciences, Chhatrapati Shahu Ji Maharaj University, Kanpur, India;Department of Manufacturing Pharmacy, College of Pharmacy, Chungbuk National University, Cheongju, South Korea;Department of Surgery, University of Florida, Gainesville, FL, United States;Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, South Korea;

关键词: cholesterol;    sphingolipid;    membrane transport proteins;    drug combination;    β-cyclodextrins;    cedrol (PubChem CID: 65575);   

DOI  :  10.3389/fcell.2020.571676

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown