​ ​Molecular Understanding and

Essay Edge
Leading ​

Modern Application of Traditional Medicines:

Triumphs and Trials
Timothy W. Corson​1 ​and Craig M. Crews​1,2,​* ​1​Department of Molecular, Cellular & Developmental Biology, Yale University, New

Haven, CT 06511, USA 2​​ Departments of Chemistry and Pharmacology, Yale University, New Haven, CT 06511, USA
*Correspondence: craig.crews@yale.edu DOI 10.1016/j.cell.2007.08.021
Traditional medicines provide fertile ground for modern drug development, but first they must
pass along a pathway of discovery, isolation, and mechanistic studies before eventual
deployment in the clinic. Here, we highlight the challenges along this route, focusing on the
compounds artemisinin, triptolide, celastrol, capsaicin, and curcumin.
Traditional medicines continue to provide front-line pharmacotherapy for many millions of people world- wide. Although their
application is often viewed with skepticism by the Western medical establishment, medicinal extracts used in ancient
medical traditions such as Ayurveda on the Indian subcontinent and tra- ditional Chinese medicine (TCM) are a rich source
of therapeutic leads for the pharmaceutical industry.
The transformation of traditional medicines into modern drugs has its origins in the archetypal examples of the antimalarial
quinine and the anti- pyretic analgesic aspirin. The alkaloid quinine was isolated in 1820 from the bark of several species of
Cin- chona,​ thought to have been used by
Cell ​130,​ September 7, 2007 ©2007 Elsevier Inc. 769 ​Peruvian Indians to suppress shiver- ing and used since the 17th century
in the treatment of malarial fevers (Greenwood, 1992). Similarly, aspirin was derived from salicylic acid in the bark of the
willow tree (​Salix s​ pecies), used traditionally to treat fever and inflammation in many cultures world- wide for at least four
millennia (Mahdi et al., 2006). The successes of these two early “blockbuster” drugs set the stage for ongoing drug discovery
efforts from traditional medicines.
Compounds derived from medici- nal extracts are appealing for several reasons (Schmidt et al., 2007). They are often
stereochemically complex, multi- or macrocyclic molecules with limited likelihood of prior chemi- cal synthesis, and they tend
to have
interesting biological properties. But perhaps most importantly, parent extracts have been “clinically” tested in their traditional
milieu, in some cases over millennia.
Despite these advantages, the path from traditional medicine to Western pharmaceutical is fraught with chal- lenges. Here,
we discuss the chal- lenges of each of the four steps in this pipeline (see Figure 1): Western “dis- covery” of a traditional
medicine, iso- lation and/or synthesis of the active component, elucidation of the molec- ular mechanism, and development
as a pharmaceutical. We focus on five interesting and timely examples derived from traditional medicines in varied
therapeutic classes, each at a different stage in the development
Figure 1. The Route from Traditional Medicine to Modern Drug ​Shown are five traditional medicines—artemisinin, triptolide, celastrol, capsaicin,
and curcumin—and the points in the pathway from ancient remedy to modern drug where they face the biggest hurdles.
process, highlighting successes and roadblocks on the path to status as a Western drug.
Artemisinin: Production Problems ​The antimalarial artemisinin (and derivatives) represents one of the greatest recent clinical
success sto- ries arising from a traditional medi- cine, echoing the success of quinine two centuries earlier. Artemisinin (see
Figure 1) is derived from ​Arte- misia annua ​L., the sweet wormwood (​qinghao)​ , a shrub first documented in TCM in 168 BCE
as a hemorrhoid treatment (Liu et al., 2006). Since at
least the fourth century CE, it has been used in the treatment of fever attributed to malaria. This long history of use prompted
Chinese researchers to seek the active antimalarial prin- ciple; artemisinin was isolated and its structure determined in the
mid 1970s (Liu et al., 2006).
Artemisinin, an endoperoxide ses- quiterpene lactone with a complex polycyclic ring structure, is modified by Fe​2+ ​ions to
structures containing carbon-centered free radicals. Given that the intracellular environment of the ​Plasmodium m ​ alaria
parasite is rich in this ion from heme, these
770 Cell ​130​, September 7, 2007 ©2007 Elsevier Inc.
Table 1. Five Traditional Medicines in Clinical Trials
Clinical Trials Compound Disease Number Principal Sponsors Artemisinin Malaria 81 31 charities, institutes, universities, and
companies based in Austra- lia, Austria, Belgium, Colombia, Ethiopia, France, Gambia, Germany, Ghana, Guinea-Bissau, the
Netherlands, Papua New Guinea, South Africa, Sudan, Sweden, Switzerland, the United Kingdom, and the USA; and working in
numerous Asian, African, and South American locations Cytomegalovirus infection
1 Hadassah Medical Organization, Israel
Schistosomiasis 1 Dafra Pharma, Belgium Triptolide & Celastrol (​T. wilfordii ​extract)
Rheumatoid arthritis
1 National Institute of Arthritis and Musculoskeletal and Skin Diseases,
MD, USA Capsaicin Chronic pain 13 NeurogesX, CA, USA; AlgoRx Pharmaceuticals, NJ, USA
Postoperative pain 5 National Institute of Dental and Craniofacial Research, MD, USA;
AlgoRx Pharmaceuticals, NJ, USA Radiation-induced mucositis
1 North Central Cancer Treatment Group, MN, USA
Alopecia areata 1 University of Minnesota, USA Morton’s neuroma 1 AlgoRx Pharmaceuticals, NJ, USA Osteoarthritis 1 Khon Kaen
University, Thailand Interstitial cystitis 1 National Institute of Diabetes and Digestive and Kidney Diseases, MD,
USA Curcumin Colon cancer 6 Chao Family Comprehensive Cancer Center, CA, USA; Tel-Aviv
Sourasky Medical Center, Israel; Johns Hopkins University, MD, USA; University of Michigan Comprehensive Cancer Center, USA;
University of Pennsylvania, USA; University of Medicine and Dentistry, NJ, USA Pancreatic cancer 3 Rambam Medical Center,
Israel; M.D. Anderson Cancer Center, TX,
USA; Tel-Aviv Sourasky Medical Center, Israel Alzheimer’s disease 2 John Douglas French Foundation, CA, USA; Chinese
University of Hong
Kong Chemotherapy- induced mucositis
1 Hadassah Medical Organization, Israel
Multiple myeloma 1 M.D. Anderson Cancer Center, TX, USA Psoriasis 1 University of Pennsylvania, USA Cystic fibrosis 1 Seer
Pharmaceuticals, CT, USA Includes registered, open, closed, terminated, and completed trials of these compounds, parent extracts,
or derivatives. For details see www.clinicaltrials.gov. Data current as of August 21, 2007.
radicals are currently thought to be responsible for artemisinin’s antima- larial activity. The classic method of cell
fractionation after treatment with radiolabeled artemisinin has identi- fied numerous cellular constituents alkylated by
artemisinin (Asawamaha- sakda et al., 1994); the strongest vali- dated target for artemisinin is PfATP6, the ​Plasmodium
sarco-endoplas- mic reticulum Ca​2+ ​ATPase (SERCA), which is inhibited by artemisinin (Eck- stein-Ludwig et al., 2003).
Clinical studies, initiated in the 1970s prior to any mechanistic insights into artemisinin function,
complex and low yielding, rendering them
eco- nomically unfeasible (Liu et al., 2006).
demonstrated that artemisinin and its Synthetic chemistry has, however, offered
derivatives are powerful antima- larials. They semi-synthetic artemisinin derivatives with
have proved particularly effective for treating improved solubil- ity (such as sodium
severe malaria and, in combination with artesunate) and stability (such as artemether)
traditional antimalarials, for combatting ​Plas- (Efferth, 2007). Even a totally synthetic
modium d ​ rug resistance. Combina- tion trioxo- lane compound RBX11160 (OZ277),
therapies containing artemisinin are now inspired by the trioxane endoperox- ide
considered the treatment of choice for moiety of artemisinin, has shown promise as
malaria in Asia, with growing adoption in an antimalarial (Venner- strom et al., 2004).
Africa (see Table 1 for information on clinical Artemisinin for clinical use is pre-
trials). Artemisinin may also have efficacy dominantly produced naturally in ​A. annua
against other parasites and as an anticancer plants. Despite efforts to maximize
compound, possibly act- ing via agricultural production, the artemisinin
antiangiogenic and proapop- totic content in plant extracts varies widely due to
mechanisms in the latter case (Efferth, environmental conditions: 0.01%–0.8% dry
2007). weight (Efferth, 2007). This in turn makes the
Despite these dramatic findings, drug itself expensive—particularly
widespread deployment of artemis- inin has problematic for an antimalarial, which is
been hindered by produc- tion difficulties. needed in large quantities in many poorer
Although a dozen synthetic routes to countries. Cell and plantlet cultures are an
artemisinin have been described, all are appealing alterna- tive source of this
 compound as they can be grown under much
more closely controlled conditions than whole
plants. Indeed, useful yields of the compound
can be produced by feeding cultures
artemisinin precur- sors (Liu et al., 2006). An
alternative approach is the genetic
engineering of
nua i​ tself. The plant has proven
ally tractable: Several of the
oid biosynthetic enzymes necessary
emisinin produc- tion have been
and ​A. annua c​ an be successfully
med with ​Agrobacterium tumefaciens
- express key biosynthetic genes (Liu
006).
Perhaps the
promising strat- egy is the use of
es to produce artemisinin. In a triumph
etic engineering, Ro et al. combined
activation of the endoge- nous
nate isoprenoid synthe- sis pathway
troduction of ​A. annua g ​ enes to
e artemisinic acid in the budding yeast
- romyces cerevisiae (​ Ro et al.,
This precursor compound, which can
dily converted to artemisinin in the
ory, is secreted in large quantities
e yeast. Such cre- ative strategies,
ng the power of genetics and in vivo
mistry, can provide a valuable
part to synthetic chemistry and
sources in the production of natural
medicines.
de and Celastrol: Harnessing the
of the Thunder God Vine
ygium wilfordii H ​ ook F., the “thunder
e” (​lei gong teng)​ , is another TCM.
e has been used traditionally for the
nt of arthritis and other diseases, and
source of several biologically active
ary metabolites (Tao and Lipsky,
Some of its TCM uses might rely on
sence of multiple active components,
- ical studies have been performed
acts of the plant (Table 1), rather than
gle compound (Tao and Lipsky,
However, substantial work has
on two major bio- active constituent
unds: trip- tolide and celastrol (Figure
Triptolide is a
noid epoxide with a staggering variety
ular effects. Along with
activity, it shows
nosuppressive, and
Qiu and Kao, 2003). It
, and several synthetic
cribed
Cell ​130
since then (Yang et al., 1998 and ref-
erences therein). Like artemisinin, however,
triptolide is currently derived from its plant of
origin with low yield: 6–16 ng/g in one study
(Brinker and Raskin, 2005). Little work has
been done to investigate biotechnological
routes to triptolide production, which are
important to reduce reliance on the natural
source. Moreover, contin- ued development
of derivatives of trip- tolide such as the
succinyl sodium salt PG490-88 will be
valuable to improv- ing the solubility and
side-effect pro- file of this compound (Tao
and Lipsky, 2000).
since then (Yang et al., 1998 and ref-
erences therein). Like artemisinin, however,
triptolide is currently derived from its plant of
origin with low yield: 6–16 ng/g in one study
(Brinker and Raskin, 2005). Little work has
been done to investigate biotechnological
routes to triptolide production, which are
important to reduce reliance on the natural
source. Moreover, contin- ued development
of derivatives of trip- tolide such as the
succinyl sodium salt PG490-88 will be
valuable to improv- ing the solubility and
side-effect pro- file of this compound (Tao
and Lipsky, 2000).
since then (Yang et al., 1998 and ref-
erences therein). Like artemisinin, however,
triptolide is currently derived from its plant of
origin with low yield: 6–16 ng/g in one study
(Brinker and Raskin, 2005). Little work has
been done to investigate biotechnological
routes to triptolide production, which are
important to reduce reliance on the natural
source. Moreover, contin- ued development
of derivatives of trip- tolide such as the
succinyl sodium salt PG490-88 will be
valuable to improv- ing the solubility and
side-effect pro- file of this compound (Tao
and Lipsky, 2000).
Determination of triptolide’s cellu- lar target has proven to
be an even greater challenge. This is not
unusual: Many a promising therapeutic
 natural product has faltered when no clear-
cut mechanism of action could be identified.
Although progression into the clinic without
such knowledge is possible, as was the case
with arte- misinin, a solid knowledge of
molec- ular mechanism (ideally at the struc-
tural, not just the molecular, level) allows
medicinal chemists to perform rational
derivatization to improve affinity, specificity,
pharmacoki- netics, and stability. Knowledge
of mechanism can also potentially lead to
more specific clinical trials and, in cases like
triptolide, completely new insights.
Determination of triptolide’s cellu- lar target has proven to
be an even greater challenge. This is not
unusual: Many a promising therapeutic
natural product has faltered when no clear-
cut mechanism of action could be identified.
Although progression into the clinic without
such knowledge is possible, as was the case
with arte- misinin, a solid knowledge of
molec- ular mechanism (ideally at the struc-
tural, not just the molecular, level) allows
medicinal chemists to perform rational
derivatization to improve affinity, specificity,
pharmacoki- netics, and stability. Knowledge
of mechanism can also potentially lead to
more specific clinical trials and, in cases like
triptolide, completely new insights.
Determination of triptolide’s cellu- lar target has proven to
be an even greater challenge. This is not
unusual: Many a promising therapeutic
natural product has faltered when no clear-
cut mechanism of action could be identified.
Although progression into the clinic without
such knowledge is possible, as was the case
with arte- misinin, a solid knowledge of
molec- ular mechanism (ideally at the struc-
tural, not just the molecular, level) allows
medicinal chemists to perform rational
derivatization to improve affinity, specificity,
pharmacoki- netics, and stability. Knowledge
of mechanism can also potentially lead to
more specific clinical trials and, in cases like
triptolide, completely new insights.
Determination of triptolide’s cellu- lar target has proven to
be an even greater challenge. This is not
unusual: Many a promising therapeutic
natural product has faltered when no clear-
cut mechanism of action could be identified.
Although progression into the clinic without
such knowledge is possible, as was the case
with arte- misinin, a solid knowledge of
molec- ular mechanism (ideally at the struc-
tural, not just the molecular, level) allows
medicinal chemists to perform rational
derivatization to improve affinity, specificity,
pharmacoki- netics, and stability. Knowledge
of mechanism can also potentially lead to
more specific clinical trials and, in cases like
triptolide, completely new insights.
A large body of work describes triptolide’s inhibitory
effects on tran- scription mediated through
NF-​κ​B and NFAT (Qiu and Kao, 2003), but
until recently, direct cellular targets were
elusive. Nonetheless, careful cell
fractionation with [​3​H]-triptolide enabled
identification of the Ca​2+ ​channel polycystin-2
(encoded by the ​PKD2 ​gene) as a possible
triptolide- binding protein (others also likely
exist) (Leuenroth et al., 2007). ​PKD2 ​or the
gene encoding its activator, ​PKD1,​ causes
polycystic kidney dis- ease (PKD) when
mutated because entry of Ca​2+ ​ions is
essential for growth arrest of epithelial cells
form- ing the kidney tubule. Because trip-
tolide activates opening of the poly- cystin-2
channel, it could potentially complement loss
of ​PKD1​. This is the case in a mouse model
of polycys-
A large body of work describes triptolide’s inhibitory
effects on tran- scription mediated through
NF-​κ​B and NFAT (Qiu and Kao, 2003), but
until recently, direct cellular targets were
elusive. Nonetheless, careful cell
fractionation with [​3​H]-triptolide enabled
identification of the Ca​2+ ​channel polycystin-2
(encoded by the ​PKD2 ​gene) as a possible
triptolide- binding protein (others also likely
exist) (Leuenroth et al., 2007). ​PKD2 ​or the
gene encoding its activator, ​PKD1,​ causes
polycystic kidney dis- ease (PKD) when
mutated because entry of Ca​2+ ​ions is
essential for growth arrest of epithelial cells
form- ing the kidney tubule. Because trip-
tolide activates opening of the poly- cystin-2
channel, it could potentially complement loss
of ​PKD1​. This is the case in a mouse model
of polycys-
A large body of work describes triptolide’s inhibitory
effects on tran- scription mediated through
NF-​κ​B and NFAT (Qiu and Kao, 2003), but
until recently, direct cellular targets were
elusive. Nonetheless, careful cell
fractionation with [​3​H]-triptolide enabled
identification of the Ca​2+ ​channel polycystin-2
(encoded by the ​PKD2 ​gene) as a possible
 triptolide- binding protein (others also likely shown promise as an anti-inflam- matory
exist) (Leuenroth et al., 2007). ​PKD2 ​or the compound in animal models of arthritis,
gene encoding its activator, ​PKD1,​ causes lupus, amyotrophic lateral sclerosis, and
polycystic kidney dis- ease (PKD) when Alzheimer’s disease (Sethi et al., 2007 and
mutated because entry of Ca​2+ ​ions is references therein). It also has
essential for growth arrest of epithelial cells antiproliferative effects against numerous
form- ing the kidney tubule. Because trip- cancer cell lines. Several molecular
tolide activates opening of the poly- cystin-2 mechanisms have been identified for these
channel, it could potentially complement loss effects, including gene expression
of ​PKD1.​ This is the case in a mouse model modulation likely mediated through inhibition
of polycys- of NF-​κ​B via TAK1 and I​κ​B​α ​kinase (Sethi et
A large body of work describes triptolide’s inhibitory al., 2007 and references therein),
effects on tran- scription mediated through proteasome inhibition, topoisomerase II
NF-​κ​B and NFAT (Qiu and Kao, 2003), but inhibition, and heat shock response
until recently, direct cellular targets were activation (Hieronymus et al., 2006 and
elusive. Nonetheless, careful cell references therein). Nonethe- less, direct
fractionation with [​3​H]-triptolide enabled targets remain elusive. As celastrol and
identification of the Ca​2+ ​channel polycystin-2 triptolide move into human studies, it will be
(encoded by the ​PKD2 ​gene) as a possible vital not only to better understand their
triptolide- binding protein (others also likely mecha- nisms of action but also to
exist) (Leuenroth et al., 2007). ​PKD2 ​or the investigate any potential synergistic effects of
gene encoding its activator, ​PKD1,​ causes the two compounds, both at the cellular and
polycystic kidney dis- ease (PKD) when organismal levels.
mutated because entry of Ca​2+ ​ions is
essential for growth arrest of epithelial cells Capsaicin: Painless for Some? ​Used
form- ing the kidney tubule. Because trip- worldwide, the alkaloid cap- saicin is the
tolide activates opening of the poly- cystin-2 main cause of the “hot” sensation associated
channel, it could potentially complement loss with chili pep- pers, members of the genus
of ​PKD1.​ This is the case in a mouse model Capsi- cum​. Beyond their widespread use as
of polycys- a spice, chili peppers were used in the
Americas by the Aztecs and
a remedy for coughs
tic kidney disease in which the mice lack milar uses plus
Pkd1 (​ Leuenroth et al., 2007). Thus, this gastroin- testinal
calcium-dependent activ- ity of triptolide, ted in India after the
which is unrelated to its transcriptional hili peppers in the late
repression activity (Leuenroth and Crews, they are traditionally
2005), opens a new therapeutic avenue for ernally as antisep- tics
pursu- ing triptolide, in addition to its effects er, 1997). However,
on the immune and reproductive sys- tems icin is focused on the
and in cancer. types of pain (see
Highlighting the complexity of plant treatment of detrusor
extracts, the pentacyclic triter- pene celastrol m of urinary inconti-
(Figure 1) is structur- ally a very different nd Fowler, 1997).
component of ​T. wilfordii ​with a divergent n also has anticancer
therapeu- tic profile. Celastrol (also known as mal model studies but
tripterine) is extracted in small quan- tities promoter in others.
from ​T. wilfordii ​or other mem- bers of the Compared
Celastraceae ​(bittersweet) family. To our tolide, and celastrol,
knowledge, no total synthesis or alternative quite simple (Figure
production routes have been reported. named in the 19th
Although not yet tested as a single esized in the 1920s
agent in humans (Table 1), celastrol has er, 1997). But the
 ​ akes
ad cultivation of ​Capsicum m
unneces- sary, as large quantities
cin can easily be extracted from
ailable peppers.
The
m of capsaicin in pain induction has
topic of much neurophysiological
(Cor- tright et al., 2007). Capsaicin,
h thermal heat, directly activates
rs in the skin, the sensory neurons
e for the sensation of pain, with the
nt release of the neurotransmitter
e P. Capsaicin’s therapeutic effect
s due to the desensitization and
destruction of nociceptors following
capsaicin expo- sure. In a classic
of expres- sion cloning, Caterina et
ed the capsaicin receptor (Caterina
97). Capsaicin was known to cause
influx into nociceptors, so these
ransfected a noci- ceptor cDNA
o nonexcit- able HEK293 cells and
for capsaicin-dependent Ca​2+ ​ion
e receptor they cloned, now known
1, is a Ca​2+ ​ion channel that also
to, and integrates, sig- nals from
(the irritant in black pepper),
and other noxious stimuli (Caterina
7).
The cloning of ​TRPV1 ​kick started the field of pain
receptor pharmacol- ogy. Numerous
pharmaceutical com- panies are developing
both TRPV1 antagonists (to block
nociception directly) and agonists (to
desensitize nociceptors, as with capsaicin)
(Immke and Gavva, 2006). Resiniferatoxin,
another traditional medicine from the latex of
Euphorbia resinifera​, is one such agonist with
higher potency than capsaicin (Immke and
Gavva, 2006). Efforts continue to create
TRPV1 ago- nists with better skin permeation
and lacking the distinctive side effect of a
burning sensation on application.
The cloning of ​TRPV1 ​kick started the field of pain
receptor pharmacol- ogy. Numerous
pharmaceutical com- panies are developing
both TRPV1 antagonists (to block
nociception directly) and agonists (to
desensitize nociceptors, as with capsaicin)
(Immke and Gavva, 2006). Resiniferatoxin,
another traditional medicine from the latex of
Euphorbia resinifera​, is one such agonist with
higher potency than capsaicin (Immke and
Gavva, 2006). Efforts continue to create
TRPV1 ago- nists with better skin permeation
and lacking the distinctive side effect of a
burning sensation on application.
The cloning of ​TRPV1 ​kick started the field of pain
receptor pharmacol- ogy. Numerous
pharmaceutical com- panies are developing
both TRPV1 antagonists (to block
nociception directly) and agonists (to
desensitize nociceptors, as with capsaicin)
(Immke and Gavva, 2006). Resiniferatoxin,
another traditional medicine from the latex of
Euphorbia resinifera​, is one such agonist with
higher potency than capsaicin (Immke and
Gavva, 2006). Efforts continue to create
TRPV1 ago- nists with better skin permeation
and lacking the distinctive side effect of a
burning sensation on application.
Capsaicin itself has been used clinically with moderate
success as a topical treatment for the pain of
rheu- matoid and osteoarthritis, psoriasis,
diabetic neuropathy, and posther- petic
neuralgia (Table 1), but herein lies the
particular challenge with this molecule: The
chronic pain dis- orders are notoriously
idiosyncratic, and not all patients or all pain
syn- dromes respond to capsaicin (Immke
and Gavva, 2006). The somewhat vague and
diffuse traditional uses of this compound offer
little assistance here, unlike artemisinin, for
instance. Thus, testing for capsaicin efficacy
is a matter of clinical trial and error, largely
undermining the “tried and true” advantage of
a traditional medi- cine. The major clinical
advantage that capsaicin holds over other
unre- lated pain drugs under development is
its approved status as a foodstuff.
Capsaicin itself has been used clinically with moderate
success as a topical treatment for the pain of
rheu- matoid and osteoarthritis, psoriasis,
diabetic neuropathy, and posther- petic
neuralgia (Table 1), but herein lies the
particular challenge with this molecule: The
chronic pain dis- orders are notoriously
idiosyncratic, and not all patients or all pain
syn- dromes respond to capsaicin (Immke
and Gavva, 2006). The somewhat vague and
diffuse traditional uses of this compound offer
little assistance here, unlike artemisinin, for
instance. Thus, testing for capsaicin efficacy
is a matter of clinical trial and error, largely
undermining the “tried and true” advantage of
a traditional medi- cine. The major clinical
 advantage that capsaicin holds over other
unre- lated pain drugs under development is
its approved status as a foodstuff.
Capsaicin itself has been used clinically with moderate
success as a topical treatment for the pain of
rheu- matoid and osteoarthritis, psoriasis,
diabetic neuropathy, and posther- petic
neuralgia (Table 1), but herein lies the
particular challenge with this molecule: The
chronic pain dis- orders are notoriously
idiosyncratic, and not all patients or all pain
syn- dromes respond to capsaicin (Immke
and Gavva, 2006). The somewhat vague and
diffuse traditional uses of this compound offer
little assistance here, unlike artemisinin, for
instance. Thus, testing for capsaicin efficacy
is a matter of clinical trial and error, largely
undermining the “tried and true” advantage of
a traditional medi- cine. The major clinical
advantage that capsaicin holds over other
unre- lated pain drugs under development is
its approved status as a foodstuff.
Capsaicin itself has been used clinically with moderate
success as a topical treatment for the pain of
rheu- matoid and osteoarthritis, psoriasis,
diabetic neuropathy, and posther- petic
neuralgia (Table 1), but herein lies the
particular challenge with this molecule: The
chronic pain dis- orders are notoriously
idiosyncratic, and not all patients or all pain
syn- dromes respond to capsaicin (Immke
and Gavva, 2006). The somewhat vague and
diffuse traditional uses of this compound offer
little assistance here, unlike artemisinin, for
instance. Thus, testing for capsaicin efficacy
is a matter of clinical trial and error, largely
undermining the “tried and true” advantage of
a traditional medi- cine. The major clinical
advantage that capsaicin holds over other
unre- lated pain drugs under development is
its approved status as a foodstuff.
Capsaicin itself has been used clinically with moderate
success as a topical treatment for the pain of
rheu- matoid and osteoarthritis, psoriasis,
diabetic neuropathy, and posther- petic
neuralgia (Table 1), but herein lies the
particular challenge with this molecule: The
chronic pain dis- orders are notoriously
idiosyncratic, and not all patients or all pain
syn- dromes respond to capsaicin (Immke
and Gavva, 2006). The somewhat vague and
diffuse traditional uses of this compound offer
little assistance here, unlike artemisinin, for
instance. Thus, testing for capsaicin efficacy
is a matter of clinical trial and error, largely
undermining the “tried and true” advantage of
a traditional medi- cine. The major clinical
advantage that capsaicin holds over other
unre- lated pain drugs under development is
its approved status as a foodstuff.
Curcumin: Awaiting Targets and Outcomes
Like capsaicin, the polyphenol cur- cumin
(Figure 1) is best known as a spice
constituent: It is the yellow pig- ment
component of the curry spice turmeric
(​Curcuma longa​, known as h ​ aldi i​ n Hindi). It
is also, however, a drug used in Ayurveda
and TCM in the treatment of diseases as
diverse as rheumatism, fever, intestinal dis-
orders, trauma, and amenorrhea (see the
Analysis by S. Singh on page 765 of this
issue). Modern research has attributed
anti-inflammatory, immuno- modulatory,
antimalarial, and antican- cer effects to this
multitalented com- pound (Aggarwal et al.,
2007).
Curcumin: Awaiting Targets and Outcomes
Like capsaicin, the polyphenol cur- cumin
(Figure 1) is best known as a spice
constituent: It is the yellow pig- ment
component of the curry spice turmeric
(​Curcuma longa​, known as h ​ aldi i​ n Hindi). It
is also, however, a drug used in Ayurveda
and TCM in the treatment of diseases as
diverse as rheumatism, fever, intestinal dis-
orders, trauma, and amenorrhea (see the
Analysis by S. Singh on page 765 of this
issue). Modern research has attributed
anti-inflammatory, immuno- modulatory,
antimalarial, and antican- cer effects to this
multitalented com- pound (Aggarwal et al.,
2007).
Curcumin: Awaiting Targets and Outcomes
Like capsaicin, the polyphenol cur- cumin
(Figure 1) is best known as a spice
constituent: It is the yellow pig- ment
component of the curry spice turmeric
(​Curcuma longa​, known as h ​ aldi i​ n Hindi). It
is also, however, a drug used in Ayurveda
and TCM in the treatment of diseases as
diverse as rheumatism, fever, intestinal dis-
orders, trauma, and amenorrhea (see the
Analysis by S. Singh on page 765 of this
issue). Modern research has attributed
anti-inflammatory, immuno- modulatory,
antimalarial, and antican- cer effects to this
 multitalented com- pound (Aggarwal et al., 2007).

772 Cell ​130,​ September 7, 2007 ©2007 Elsevier Inc.

taking preclinical or pilot studies,
us clinical trials, has
Like capsaicin, synthesis of cur- cumin is validation of curcumin.
trivial and was first reported in 1910, but ded by lim- ited
sufficient quantities of curcumin for pany inter- est because
therapeutic use are available from the spice. ot patentable (although
This is par- ticularly important as low ds, derivatives, and
bioavail- ability of the parent compound cou- ulations are) and by the
pled with rapid intestinal metabolism dictates a foodstuff, curcumin is
large doses for clinical use (Sharma et al., al (perhaps a dietary
2005); derivatization of the natural product is than a traditional drug.
actively being pursued. only be changed by
ing successful disease
Given its pleiotropic clinical effects, it is
cumin. Phase I studies
perhaps not surprising that cur- cumin has
tolerance up to 8000
documented effects on countless intracellular
large dose- response
signaling path- ways. Its anti-inflammatory
in phase II studies,
action can be attributed largely to its inhibi-
re under- way for the
tion of NF-​κ​B activity, COX-2 and 5- LOX
er, pso- riasis, and
expression, and cytokine release (Aggarwal
(Table 1) (Hsu and
et al., 2007). Curcumin may directly target
ust await the outcomes
I​κ​B​α ​kinase to block NF-​κ​B. It also binds to a
efore curcumin can be
num- ber of other proteins, including thio-
aceutical.
redoxin reductase, several kinases, and
several receptors (Aggarwal et al., 2007).
The challenge here, then, as with many other An effective drug should
natural products, is deciphering which of ical to produce and
these targets is mechanistically valid for y favorable absorption,
which bio- logical activity. With such a broad sm, excretion, and
spectrum of potential targets and activities racteristics, and should
described for curcumin, this is no easy task. ease with specificity and
Synthesis of deriva- tives that selectively medicines, as with
ablate certain cellular and/or therapeutic ts, can offer powerful
effects is one possible route to tease apart development because
this mechanism-function conun- drum, ries) they already have
perhaps in concert with radio- labeled n the organism.
fractionation experiments (as described s from plant to product is
above) or affinity chroma- tography with he oft-shared limitations
immobilized curcumin. The very versatility examples of traditional
that makes cur- cumin appealing has also onal in the extent to
limited its rigorous clinical testing: There are studied and the
wide-ranging efficacy reports, but most are hieved in the clinic;
based on preclinical, anec- dotal, or pilot sing compounds wallow
studies rather than on randomized,
placebo-controlled, double-blind trials (Hsu The challenges
and Cheng, 2007). Activity has been reported (Fig- ure 1):
in several inflammatory and autoim- mune s must identify a
diseases and numerous can- cers, both as a and active components.
preventative agent and treatment, alone or in urgent, as traditional
combina- tion (Hsu and Cheng, 2007). The traditional plant
rela- tive ease and rapid payoff of under- ost at an alarming rate.
 ists must then synthesize the com-
using a cost-effective method
Cell ​130,​ September
or develop alternative processes such as cell
culture or transgenesis to enable useful-scale
production. Despite continuing advances in
syn- thetic chemistry, the very complex- ity of
many natural products that is responsible for
their desirable bio- logical function can make
production difficult.
or develop alternative processes such as cell
culture or transgenesis to enable useful-scale
production. Despite continuing advances in
syn- thetic chemistry, the very complex- ity of
many natural products that is responsible for
their desirable bio- logical function can make
production difficult.
With a reliable supply of compound available, biologists
can then iden- tify and validate cellular
targets and mechanisms of action. New tools
are sorely needed for this particularly
daunting challenge, such as meth- ods that
compare the phenotypic or gene expression
profiles induced by a small molecule to those
induced by known compounds (Hieronymus
et al., 2006) or chemical enhancer/sup-
pressor screens. Development of in silico
tools to “dock” small molecules with protein
structures to provide models for testing in
vitro will likely come into their own with
advances in structural genomics, as sufficient
computational power becomes avail- able.
With a reliable supply of compound available, biologists
can then iden- tify and validate cellular
targets and mechanisms of action. New tools
are sorely needed for this particularly
daunting challenge, such as meth- ods that
compare the phenotypic or gene expression
profiles induced by a small molecule to those
induced by known compounds (Hieronymus
et al., 2006) or chemical enhancer/sup-
pressor screens. Development of in silico
tools to “dock” small molecules with protein
structures to provide models for testing in
vitro will likely come into their own with
advances in structural genomics, as sufficient
computational power becomes avail- able.
With a reliable supply of compound available, biologists
can then iden- tify and validate cellular
targets and mechanisms of action. New tools
are sorely needed for this particularly
daunting challenge, such as meth- ods that
compare the phenotypic or gene expression
profiles induced by a small molecule to those
induced by known compounds (Hieronymus
et al.,7, 2006)
or chemical
2007 ©2007 enhancer/sup-
Elsevier Inc. 773
pressor screens. Development of in silico
tools to “dock” small molecules with protein
structures to provide models for testing in
vitro will likely come into their own with
advances in structural genomics, as sufficient
computational power becomes avail- able.
With a reliable supply of compound available, biologists
can then iden- tify and validate cellular
targets and mechanisms of action. New tools
are sorely needed for this particularly
daunting challenge, such as meth- ods that
compare the phenotypic or gene expression
profiles induced by a small molecule to those
induced by known compounds (Hieronymus
et al., 2006) or chemical enhancer/sup-
pressor screens. Development of in silico
tools to “dock” small molecules with protein
structures to provide models for testing in
vitro will likely come into their own with
advances in structural genomics, as sufficient
computational power becomes avail- able.
Ideally with a mechanism in hand, clinicians must then
test the com- pound in the disease of interest
(Table 1) while keeping an open mind for
unexpected therapeutic activities and
working with medicinal chemists to produce
derivatives with improved ADMET properties.
Finally, regulatory approval must be
obtained, as with all drugs. This is particularly
problem- atic if the active principle is an
extract or mixture, rather than an isolated
compound; the U.S. Food and Drug
Administration has been understand- ably
reluctant to approve multiple- agent drugs
until recently (Schmidt et al., 2007). Only in
2006 was the first such drug approved:
Polyphenon E (MediGene), a topical antiviral
pre- pared from catechins extracted from
green tea (​Camellia sinensis​).
Ideally with a mechanism in hand, clinicians must then
test the com- pound in the disease of interest
(Table 1) while keeping an open mind for
unexpected therapeutic activities and
working with medicinal chemists to produce
derivatives with improved ADMET properties.
Finally, regulatory approval must be
obtained, as with all drugs. This is particularly
problem- atic if the active principle is an
extract or mixture, rather than an isolated
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