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

Abstract

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.

Cedrol restricts the growth of colorectal cancer in vitro and in vivo by inducing cell cycle arrest and caspase-dependent apoptotic cell death

“…It also exerts inhibitory effects in human lung cancer A549 cells (IC 50 values were 31.88, 14.53, and 5.04 µM at 24, 48, and 72 h) and mediates apoptosis and autophagy through the regulation the PI3K/Akt signaling pathway, generation of reactive oxygen species, and loss of mitochondrial transmembrane potential [29]. In addition, cedrol activates intrinsic apoptosis, suppresses the AKT/ERK/mTOR and NF-κB signaling pathways, and chemosensitizes cancer cells through lipid raft destabilization in human leukemia K562 and colon cancer HT-29 cells, with an IC50 of 179.52 and 185.50 µM at 48 h, respectively [32]. More recently, cedrol was reported to suppress the growth of glioblastoma and triggered apoptosis by the induction of DNA damage and targeting the androgen receptor (IC 50 values of glioblastoma cells were 77.17-141.88 µM at 48 h) [30].…”

“…Our data showed that the combination of cedrol and 5-FU had synergistic effects, which enhanced the reduction in the proliferation of HT-29 cells. Cedrol combined with the clinical drug temozolomide also exhibits synergistic suppression in glioblastoma by downregulation of AKT/mTOR signaling and chemosensitizes human leukemia K562 and CRC HT-29 cells by destabilizing plasma membrane lipid rafts [30][31][32]. Therefore, the combination of cedrol and 5-FU may be a promising strategy for overcoming the limitations of 5-FU in CRC treatment.…”

“…In previous studies, cedrol has been reported to exhibit various biological activities, such as antimicrobial, anti-inflammatory, hair growth-promoting, analgesic, and anxiolytic activities [24][25][26][27][28]. Cedrol-induced autophagy and apoptosis in non-small cell lung cancer cells suppressed the growth of glioblastoma by enhancing DNA damage and attenuating drug resistance and chemosensitized cancer cells through the destabilization of plasma membrane lipid raft [29][30][31][32]. However, little is known about the mechanisms underlying the growth inhibition and apoptosis associated with the anticancer effect of cedrol in CRC.…”

Reprogrammed Lipid Metabolism and the Lipid-Associated Hallmarks of Colorectal Cancer

“…Reprogramming of lipid metabolism that leads to the imbalance of ceramides and S1P also contribute to the dysregulation of lipid raft dynamics. A recent study demonstrated the efficacy of Cedrol in inhibiting HT29 CRC cell growth by destabilising lipid rafts through the redistribution of cholesterol from the plasma membrane, blocking Akt/mTOR signalling and inducing mitochondrial intrinsic apoptosis, thereby resisting cell death [ 171 ]. In a study of colonic cancer stem cell (CSC), impairment of cholesterol biosynthesis by deletion of key synthetic enzymes HMGCR or FDPS lead to reduced spheroid tumorigenic potential via activated TGF-β signalling [ 78 ], a key growth evasion pathway in cancer [ 7 ].…”

Innate Immunomodulatory Activity of Cedrol, a Component of Essential Oils Isolated from Juniperus Species

“…Cedrol has been reported to exhibit a number of biological activities, including anticancer [92][93][94] and anti-inflammatory. For example, cedrol was shown to have analgesic and anti-inflammatory effects in complete Freund's adjuvant (CFA)-induced arthritis in rats [95] and in mice with collagen-induced arthritis (CIA) [96].…”