Sesquiterpene alcohol cedrol chemosensitizes human cancer cells by
destabilizing plasma membrane lipid rafts and inhibits cell
proliferation
Abstract
Background and Purpose: Chemosensitization of cells with small molecules
may improve the therapeutic index of antitumoral agents by making tumor
cells sensitive to the drug regiment and thus overcoming 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.
Experimental Approach: Cedrol, a natural sesquiterpene alcohol, was used
to treat human leukemia K562 and colon cancer HT-29 cell lines and
effects were observed. Key Results: 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 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 p65
subunit of NF-κB. Cedrol caused redistribution of cholesterol and
sphingomyelin contents from membrane lipid raft, which was confirmed by
synergistic inhibition in combination 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. Conclusions and Implications:
Cholesterol/sphingomyelin redistributing abilities of cedrol appear as
novel mechanism of growth inhibition of cancer cells. Cedrol can be
classified as a natural lipid raft disrupting agent with possibilities
to be use in general studies involving membrane lipid raft
modifications.