Download Redox-regulated mechanism may account for

Carcinogenesis vol.23 no.11 p.1961, 2002
LETTER TO THE EDITOR
Redox-regulated mechanism may account for zerumbone’s ability
to suppress cancer-cell proliferation.
A.Hoffman1, L.M.Spetner1 and M.Burke2
1Rehovot
Research Associates, Rehovot, Israel and 2Tel Aviv University
Sackler Medical School, Tel Aviv, Israel
Email: [email protected]
Murakami et al. (1) recently reported that zerumbone (ZER)
inhibits the proliferation of colon cancer cells and induces
apoptosis in them, while having less effect on normal-cell
proliferation. Their study pointed to the α,β-unsaturated
carbonyl group in ZER as the likely source of the effect.
They called this finding ‘intriguing’ and suggested that this
group may play an important role in unknown reactions with
unidentified target molecule(s).
We also find their results intriguing, because they corroborate
our recently proposed redox model of cell proliferation (2).
The model is based on a newly discovered role of the
intracellular redox potential E as an important factor in the
control of proliferation of normal cells. E is proportional to
the logarithm of [GSSG]/[GSH]2, where [GSSG] and [GSH],
respectively, are the oxidized and reduced forms of glutathione.
The α,β-unsaturated carbonyl group effectively removes the
intracellular GSH by forming a Michael adduct with it,
thereby raising E, which in turn stops the proliferation of the
cancer cells.
According to our model, if E is above an appropriate
© Oxford University Press
References
1. Murakami,A., Takahashi,D., Kinoshita,T., Koshimizu,K., Kim,H.W.,
Yoshihiro,A., Nakamura,Y., Jiwajinda,S., Terao,J. and Ohigashi,H. (2002)
Zerumbone, a Southeast Asian ginger sesquiterpene, markedly suppresses
free radical generation, proinflammatory protein production and cancer cell
proliferation accompanied by apoptosis: the α,β-unsaturated carbonyl group
is a prerequisite. Carcinogenesis, 23, 795–802.
2. Hoffman,A., Spetner,L.M. and Burke,M. (2001) Cessation of cell proliferation
by adjustment of cell redox potential. J. Theoret. Biol., 211, 403–407.
3. Hutter,D. E., Till,B.G. and Greene,J.J. (1997) Redox state changes in densitydependent regulation of proliferation. Exp. Cell Res., 232, 435–438.
Received July 5, 2002 and accepted August 5, 2002
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A recent report shows that zerumbone (ZER) inhibits the
proliferation of, and induces apoptosis in, colon cancer
cells. We suggest a mechanism for these phenomena, based
on our recently proposed redox model of cell proliferation
which stresses the importance of intracellular redox
potential E in the control of proliferation of normal and
cancer cells.
threshold value θ, the RB protein cannot become, or even
remain, phosphorylated. It is well known that the RB protein
acts as a brake on the cell cycle. When phosphorylated, it
permits the cell to pass the restriction point, R. Unless RB
becomes phosphorylated, a proliferating cell will stop cycling
in mid-G1, before R and this arrested cell may then undergo
apoptosis.
When Murakami et al. (1) administered ZER to the cancer
cells, the α,β-unsaturated carbonyl group on the ZER (partially)
depleted the GSH in the cell, bringing E above θ, dephosphorylating RB and stopping the cell cycle.
Our model also accounts for the weaker effect of ZER
on the proliferation of normal cells. Hutter et al. (3) found
that the average E in proliferating fibroblasts is about –220 mV,
and that in proliferating fibrosarcoma cells it is about –210 mV.
We have induced the threshold value of θ to be about –205 mV.
There is thus a margin of ~10 mV in the adjustability of
E between these normal cells and the cancer cells. It is thus
possible that with an appropriate dose of ZER, E can be made
high enough to stop the proliferation of cancer cells, but not
high enough to stop the proliferation of normal cells.