More Than Spice: Capsaicin in Hot Chili Peppers Makes
Tumor Cells Commit Suicide
Young-Joon Surh
strated that capsaicin-induced apoptosis in some transformed
Hot red chili peppers, which belong to the plant genus Cap-
cells (9,10,15) and in activated T cells (17) is associated with the
sicum, are among the most heavily and frequently consumed
suppression of plasma membrane NADH-oxidoreductase
spices throughout the world. Their principal pungent ingredient
(PMOR), an enzyme that transfers electrons from cytoplasmic
is the phenolic substance capsaicin (8-methyl-N-vanillyl-6-
NADH via coenzyme Q (ubiquinone) to external electron ac-
nonenamide). Although capsaicin can cause neurogenic inflam-
ceptors such as oxygen. PMOR is thought to be involved in the
mation per se under certain physiologic conditions, it also has
control of cell growth and proliferation (20) by maintaining the
analgesic and anti-inflammatory activities and is used currently
proper NAD+/NADH ratio required for cell viability. However,
in topical creams and gels (e.g., Axsain and Zostrix) to mitigate
PMOR activity in normal tissues and in nontransformed cells is
neurogenic pain. A receptor for capsaicin and other structurally
responsive to growth factors and hormones, whereas PMOR
related substances was identified and cloned (1–3). This recep-
activity in tumor tissues and transformed cells is not (20,21).
tor, vanilloid receptor subtype 1 (VR1), forms a nonselective
Although the capsaicin analogue dihydrocapsaicin and the ul-
cation channel in the plasma membrane that mediates some of
trapotent vanilloid receptor agonist resiniferatoxin also caused
the pleiotropic effects exerted by capsaicin and its analogues,
apoptotic death, the apoptogenic activity of these vanilloids, as
which are collectively named vanilloids.
well as that of capsaicin, does not appear to be mediated by the
The role of capsaicin in carcinogenic processes is quite con-
vanilloid receptor, at least in human blood cell lines, because
troversial. Although some investigators suspect that capsaicin is
treatment with capsazepin, a prototype vanilloid receptor an-
a carcinogen, co-carcinogen, or tumor promoter, others have
tagonist, failed to block the apoptosis induced by those com-
reported that it has chemopreventive and chemotherapeutic ef-
pounds (15,18).
fects [reviewed in (4–8) and references therein]. Interestingly,
Coenzyme Q is a lipophilic and mobile electron carrier of the
capsaicin has been found to preferentially repress the growth of
plasma membrane electron transport system that is essential for
some transformed human and mouse cells (9,10). Although the
cell growth and for the cellular response to redox changes. Pre-
antiproliferative activity of capsaicin has been ascribed to its
incubation of human lymphoblastoid cells with coenzyme Q
ability to induce apoptosis (9–18), relatively little is known
prevents capsaicin-induced apoptosis (15), suggesting that cap-
about the molecular basis for the programmed cell death induced
saicin, a quinone analogue, induces apoptosis by competing with
by this edible phytochemical. In an excellent study published in
coenzyme Q in the plasma membrane redox system. Because
this issue of the Journal, Hail and Lotan (19) have conducted a
capsaicin can also inhibit the NADH:coenzyme Q oxidoreduc-
series of elegant experiments that afford important insights into
tase (i.e., complex I) activity of the mitochondrial electron trans-
mechanisms underlying the apoptogenic action of capsaicin at
port system (22,23), the question remained as to whether cap-
the cellular level. The authors report that capsaicin-induced ap-
optosis in cultured cells derived from human cutaneous squa-
mous cell carcinoma (SCC) occurs through inhibition of mito-
Correspondence to: Young-Joon Surh, Ph.D., College of Pharmacy, Seoul
chondrial respiration.
National University, Shinlim-dong, Kwanak-ku, Seoul 151–742, South Korea
Although the work by Hail and Lotan addresses the impor-
(e-mail: surh@plaza.snu.ac.kr).
tance of the mitochondrial redox system as a primary target for
See “Note” following “References.”
capsaicin in SCC-derived cells, other investigators have demon-
© Oxford University Press
Journal of the National Cancer Institute, Vol. 94, No. 17, September 4, 2002
EDITORIALS 1263

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saicin triggered apoptosis by blocking mitochondrial complex I
treatment with capsaicin or resiniferatoxin, the authors measured
activity, PMOR activity, or both. The biochemical mechanisms
vanilloid-stimulated hydroperoxide generation in ?0 clones de-
that mediate vanilloid-induced apoptosis through PMOR inhibi-
rived from the SCC cells. ?0 cells exposed to either capsaicin or
tion are unclear, but it has been suggested that an enzyme an-
resiniferatoxin released less hydroperoxide than did DMSO-
tagonist, such as capsaicin, may interfere with the coenzyme Q
treated control cells, supporting the notion that the majority of
binding site, which may redirect the normal electron flow in the
hydroperoxide initially produced in the parental SCC cells after
complex and generate excess reactive oxygen species (ROS) and
vanilloid treatment was of mitochondrial origin (19). Moreover,
a pro-oxidant environment in the plasma membrane (15). The
exposure of the ?0 cells to capsaicin or resiniferatoxin failed to
possible involvement of ROS in vanilloid-induced apoptosis has
disrupt ?? or increase the proportion of cells that were under-
m
also been reported by Macho et al. (16–18). They showed that
going apoptosis. The authors’ explanation—that the association
capsaicin- or resiniferatoxin-treated transformed human T cells
between initial generation of ROS and the induction of apoptosis
(i.e., Jurkat cells) displayed a loss of nuclear DNA and a con-
in the vanilloid-treated SCC cells was a consequence of mito-
comitant increase in the proportion of subdiploid (apoptotic)
chondrial electron transport perturbation—is reasonable. How-
cells and that this vanilloid-induced apoptosis was preceded by
ever, their study did not clarify whether such a mechanism oc-
an increase in ROS generation and disruption of the mitochon-
curs preferentially in transformed cells versus nonmalignant
drial transmembrane potential (?? ) (16), both invariant fea-
cells. It would be worthwhile to compare the activities of mito-
m
tures of early programmed cell death. The pro-oxidative envi-
chondrial NADH oxidoreductase in SCC cells and in normal
ronment generated by perturbations in the plasma membrane
skin cells, as well as the relative sensitivities of these cells to
redox system can result in oxidation of thiol groups in mito-
vanilloid-induced cytotoxicity.
chondrial permeability transition pores, leading to dissipation of
ROS can differentially affect cell growth or survival, depend-
?? , which is a prerequisite for the induction of apoptosis. ing on, among other things, the amounts formed, how long a
m
Therefore, overproduction of extramitochondrial ROS due to the
cell is exposed to them, the availability and efficiency of anti-
inhibition of PMOR could contribute to the apoptosis that is
oxidant capacity, and the cell type. Although excess ROS tran-
induced by capsaicin and related vanilloids. However, one can-
siently produced by PMOR inhibitors such as capsaicin and
not exclude the possibility that some of the ROS generation
resiniferatoxin can be cytotoxic, milder endogenous redox stress
promoted by vanilloid treatment is attributable to a disruption of
that results from ROS spontaneously generated by an NAD(P)H:
the mitochondrial respiratory system.
quinone oxidoreductase activity has recently been shown to play
In this context, Hail and Lotan (19) have made a major con-
a functional role in the constitutive activation of the transcription
tribution to the field by identifying an alternative route that
factor, nuclear factor-?B (NF-?B) in several malignant human
mediates vanilloid-induced apoptosis. The authors used two
melanoma cell lines, which may account for the hyperprolifera-
different human cutaneous SCC cell lines (i.e., COLO 16 and
tive potential of these cells (24). NF-?B is constitutively acti-
SRB-12 cells) and respiration-deficient (?0) clones derived from
vated in diverse malignant tumors and in transformed cells (25–
them to examine their susceptibilities to vanilloid-induced ap-
29). Brar et al. (24) found that capsaicin and dicumarol, a known
optosis. When the COLO 16 cells were treated with either cap-
inhibitor of NAD(P)H:quinone oxidoreductase, reduced super-
saicin or resiniferatoxin, more than half underwent apoptosis,
oxide production and proliferation of M1619 melanoma cells,
which was associated with progressive dissipation of ?? and
suggesting that the redox coupling between NAD(P)H:quinone
m
enhanced superoxide production, reflecting the disintegration of
oxidoreductase and coenzyme Q is a more important source of
mitochondria and subsequent malfunction of mitochondrial elec-
growth-signaling ROS in transformed cells than it is in normally
tron transport (19). Exposure to these vanilloids also promoted a
regulated nonmalignant cells. We have shown that topical ap-
rapid induction of hydroperoxide generation in the SCC cells,
plication of capsaicin onto the dorsal skin of mice strongly sup-
which occurred much earlier than superoxide production. Hail
presses epidermal NF-?B activation induced by phorbol ester
and Lotan speculate that inhibition of mitochondrial electron
(30), which may account for the anti-inflammatory and antitu-
transport by capsaicin and resiniferatoxin, presumably at com-
mor promoting effects of this compound. Despite these findings,
plex I, may promote the production of ROS because of redox
it is not yet clear that NAD(P)H oxidoreductase is crucial for cell
cycling of reduced electron carriers upstream of the site of in-
proliferation. The availability of several different genetically
hibition, which could explain the enhanced hydroperoxide gen-
tractable animal models, in which the gene encoding NAD(P)H
eration induced by these vanilloids in conjunction with induction
oxidoreductase is mutated or deleted, will help us better under-
of mitochondrial permeability transition (19). However, cap-
stand the functional role of this enzyme and possibly facilitate
saicin and resiniferatoxin can interrupt plasma membrane elec-
the discovery of drugs that selectively kill tumor cells by tar-
tron transport as well by functioning as coenzyme Q antagonists,
geting this enzyme.
as addressed previously by other investigators (9,10,15). If the
In summary, the oxidative stress that is stimulated by vanil-
initial pro-oxidant effects of these vanilloids were solely asso-
loid treatment of SCC cells is primarily of mitochondrial origin
ciated with the inhibition of PMOR, the resulting oxidative
and contributes to the death of these cells by apoptosis. The
stress would ultimately lead to disruption of the mitochondrial
exact molecular milieu that characterizes elevated oxidative
structure and function which, in turn, could induce mitochon-
stress caused by vanilloid treatment is not clear and requires
drial permeability transition and, eventually, apoptosis.
further investigation. It is possible that a high metabolic rate or
All of the above findings suggest that vanilloids can target
increased oxygen utilization as a direct or indirect consequence
both mitochondrial and plasma membrane electron transport
of aberrant electron flow in the mitochondrial respiratory system
systems, thereby generating ROS that can mediate apoptosis. To
of malignant cells results in the increased production of oxi-
directly assess the relative contributions of mitochondrial and
dants, which may overwhelm cellular antioxidant protections
plasma membrane redox systems to initial ROS generation after
and lead to apoptosis. However, it can be argued that such in-
1264 EDITORIALS
Journal of the National Cancer Institute, Vol. 94, No. 17, September 4, 2002

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Supported in part by a grant (01-PJ1-PG1–01CH05–0001) from the Ministry
vanilloid compounds does not require de novo gene transcription and
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Center (NORTRC-KOSEF), Republic of Korea.
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