Terpenoids: Natural products for cancer therapy

Abstract

Introduction:
Terpenoids constitute the largest class of natural products and are a rich reservoir of candidate compounds for drug discovery. Recent efforts into the research and development of anti-cancer drugs derived from natural products have led to the identification of a variety of terpenoids that inhibit cancer cell proliferation and metastasis via various mechanisms. Despite the increasing number of research reports, there lacks a comprehensive review of anti-cancer activity of terpenoids.

Areas covered:
The present article provides an overview of the recent progress in the anti-cancer studies on terpenoids. Over a dozen naturally originated terpenoid compounds, in particular those derived from traditional Chinese medicine, were classified into five categories according to the structures, namely monoterpenoids, sesquiterpenoids, diterpenoids, triterpenoids and tetraterpenoids. The anti-cancer activities and relevant mechanistic insights of these compounds are discussed in this review.

Expert opinion:
The anti-cancer activity of terpenoids appears promising and will potentially open more opportunities for cancer therapy. However, current studies are restricted to descriptive findings and lack mechanistic insights and systematic structure-activity relationship (SAR) studies. Future efforts into the systematic identification of the targets of terpenoids are believed to increase chances of gaining breakthrough insights in the field.

Full text

1. Introduction
2. Monoterpenoids
3. Sesquiterpenoid
4. Diterpenoids
5. Triterpenoids
6. Tetraterpenoids
7. Expert opinion
Review
Terpenoids: natural products for
cancer therapy
Min Huang*, Jin-Jian Lu*, Ming-Qing Huang, Jiao-Lin Bao, Xiu-Ping Chen
& Yi-Tao Wang
†
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical
Sciences, University of Macau, Macao, China
Introduction: Terpenoids constitute the largest class of natural products and
are a rich reservoir of candidate compounds for drug discovery. Recent efforts
into the research and development of anti-cancer drugs derived from natural
products have led to the identification of a variety of terpenoids that inhibit
cancer cell proliferation and metastasis via various mechanisms. Despite the
increasing number of research reports, there lacks a comprehensive review
of anti-cancer activity of terpenoids.
Areas covered: The present article provides an overview of the recent
progress in the anti-cancer studies on terpenoids. Over a dozen naturally
originated terpenoid compounds, in particular those derived from traditional
Chinese medicine, were classified into five categories according to the struc-
tures, namely monoterpenoids, sesquiterpenoids, diterpenoids, triterpenoids
and tetraterpenoids. The anti-cancer activities and relevant mechanistic
insights of these compounds are discussed in this review.
Expert opinion: The anti-cancer activity of terpenoids appears promising and
will potentially open more opportunities for cancer therapy. However,
current studies are restricted to descriptive findings and lack mechanistic
insights and systematic structure-- activity relationship (SAR) studies. Future
efforts into the systematic identification of the targets of terpenoids are
believed to increase chances of gaining breakthrough insights in the field.
Keywords: cancer, mechanisms, natural products, terpenoids, traditional Chinese medicine
Expert Opin. Investig. Drugs (2012) 21(12):1801-1818
1. Introduction
In spite of the tremendous progress in the past decades, anti-cancer drug develop-
ment has been considerably hampered by the limited sources of chemical scaffolds.
Specifically, the rapid growth in the number of potential therapeutic targets is
placing an ever-increasing demand on the access to novel and diverse chemical
libraries. Natural products, which are a rich source of compounds with enormous
structural diversity, have been extensively explored in the field of drug discovery
and have led to remarkable successes. This is particularly evident in the field of
cancer therapeutics, where over 50% of the approved drugs discovered in the last
two decades of the 20
th
century were of natural origin [1]. Many widely applied
anti-cancer agents such as vincristine, irinotecan, etoposide, and paclitaxel, which
represent a range of structurally diverse anti-cancer drugs, are all naturally derived
and play a dominant role in chemotherapy.
As the largest class of natural products, terpenoids consist of approximately
25,000 chemical structures thus far with potential practical applications in the
fragrance and flavor industries, and in the pharmaceutical and chemical industries
in particular [2]. Based on structures, terpenoids are composed of several subclasses,
including monoterpenoids, sesquiterpenoids, diterpenoids, triterpenoids, and
tetraterpenoids. This review will focus on naturally derived terpenoids that have
10.1517/13543784.2012.727395 ©2012 Informa UK, Ltd. ISSN 1354-3784 1801
All rights reserved: reproduction in whole or in part not permitted

exhibited anti-cancer activities, particularly those that func-
tion as major bioactive constituents of traditional Chinese
medicine, whose therapeutic efficacy has long been proved
by thousands of years of clinical usage. Insights into this sub-
set of compounds have a better chance to give rise to anti-
cancer drugs that have clinical benefit. Some derivatives with
prominent anti-cancer activity will also be discussed (Table 1).
This review is intended to summarize the recent progress in
the investigation of anti-cancer activities and the underlying
mechanism of these terpenoids (Figure 1), which have not
been extensively discussed previously except for a few reviews
focused on different aspects of terpenoids [3,4]. Hopefully, this
article will provide a comprehensive review of this class of
compounds and their potential in cancer therapy. In addition,
we have to mention that due to the lack of SAR studies for
most of the terpenoids included in this review, we chose to
focus on the generalities of the compound categories and the
impacts of chemical modifications on activities alteration is
beyond the scope of this review.
2. Monoterpenoids
2.1 Limonene
Limonene is a monocyclic monoterpene belonging to ter-
penes, a class of terpenoid derivatives. Limonene is found in
the essential oils of citrus fruits and many other plant species.
Industrial uses of limonene include use in cleaning products
and as additives for aroma or flavoring of a product. Limo-
nene occurs in two optically active forms, L-limonene and
D-limonene, which are mirror images of one another chemi-
cally. D-limonene is a major constituent of several citrus oils
(e.g., lemon, orange, mandarin, lime, and grapefruit) and
has been the focus of anti-cancer research.
D-limonene has well-validated chemopreventive activity
against many types of cancer. It is believed to prevent
carcinogen-induced mammary cancer at both the initiation
and the promotion/progression stages. It prevents liver cancer
by increasing the levels of hepatic enzymes that can detoxify
carcinogens [5]. The therapeutic effects of D-limonene have
been recognized for more than two decades. It has been
demonstrated to suppress the growth of pancreas, stomach,
colon, skin, and liver cancers in animal models. In an ortho-
topic mouse model for human gastric cancer, D-limonene
inhibits tumor growth and metastasis, probably via its anti-
angiogenic, proapoptotic, and anti-oxidant effects. In particu-
lar, the combination of D-limonene and cytotoxic agents,
such as fluorouracil (5-FU) and docetaxel, appeared to be
more effective than either single treatment via a mechanism
involving reactive oxygen species (ROS) generation [6]. Fur-
ther evidence from a Phase I clinical trial demonstrated partial
response in a patient with breast cancer and stable disease for
more than six months in three patients with colorectal
cancer [7].
Mechanistically, the molecular target(s) of D-limonene in
cancer cells remains unclear. D-limonene has been shown to
inhibit 3-hydroxy-3-methylglutanyl coenzyme A (HMG-
CoA) reductase [8], which leads to the inhibition of protein
isoprenylation of small G proteins, including p21, and its
membrane localization [9]. This mechanism is believed to con-
tribute to the efficacy of D-limonene in chemoprevention and
cancer therapy, but such an explanation does not appear to be
applicable to all cancer types [10]. Other studies that focused
on apoptosis reported that D-limonene up-regulated Bax
protein expression, the release of cytochrome cfrom mito-
chondria, and the cleavage of caspase-3, 9 but not caspase-8.
These findings suggest that the mitochondrial death pathway
is primarily involved in D-limonene-induced apoptosis [11].
2.2 Cantharidin
As one of the few non-plant derivative terpenoids, the medi-
cinal understanding of cantharidin from the dried body of
the Chinese blister beetles Mylabris phalerata or Mylabris
cichorii can be traced back to more than 2,000 years in tradi-
tional Chinese medicine. It has been used as an anti-cancer
agent for the treatment of hepatoma and esophageal carci-
noma [12]. Cantharidin is a natural defensive toxin produced
by as much as 1,500 species of blister beetles, with the Spanish
fly Cantharis vesicatoria probably being the best-known
source [13]. It shares structural similarity with highly toxic
commercial herbicides such as endothall, endothall anhydride,
and endothall thioanhydride. Notably, all these herbicides are
known to be environmental carcinogens. Such a structural
similarity may imply the carcinogenic activities of canthari-
din. Indeed, a study performed in early 1970s has revealed
that cantharidin produced an increased incidence of skin
papillomas in mice [14].
The anti-cancer properties of cantharidin have been exper-
imentally demonstrated. It exhibited strong in vitro anti-
cancer activity against a broad spectrum of cancer cells,
including leukemia, colorectal carcinoma, hepatoma, bladder
carcinoma, and breast cancer [15-17]. In spite of its well-
documented anti-cancer activities, the clinical application of
cantharidin is limited due to its severe side-effects and extreme
Article highlights.
.Terpenoids are the largest class of natural products and
represent a rich reservoir of candidate compounds for
drug discovery.
.Terpenoids are structure-wise composed of
monoterpenoids, sesquiterpenoids, diterpenoids,
triterpenoids and tetraterpenoids, where triterpenoids
are most extensively studied in anti-cancer research.
.Increasing number of terpenoids has exhibited
anti-cancer activities both in vitro and in vivo.
.The molecular mechanism of most terpenoids remains
unclear, in spite of the accumulated evidence provided
by previous studies.
.Further studies gaining mechanistic insights into
terpenoids will be critical for a better understanding
of the anti-cancer activity of this class of compounds.
M. Huang et al.
1802 Expert Opin. Investig. Drugs (2012) 21(12)

Table 1. The chemical structures and resources of representative terpenoids with anti-cancer activities.
Subclasses Compounds Structures Resources
Monoterpenoid Limonene
CH
3
H
2
C
H
3
C
Citrus limon L.
Cantharidin
CH
3
O
O
OO
CH
3
Mylabris phalerata Pallas
or Mylabris
cichorii Linnaeus
Sesquiterpenoid Artemisinin O
CH3
O
O
O
H3CO
H
H
CH3
Artemisia annua L
Diterpenoid Tanshinone IIA
O
OCH3
O
H3C CH3
Salvia miltiorrhiza Bge
Triptolide H3C
O
O
O
O
OCH3
OH
CH3
Tripterygium wilfordii Hook.f
Pseudolaric acid B
HO
CH3
O
CH3
H3C
H3C
O
O
O
OH
O
OPseudolarix amabilis (Nelson)Rehd
Terpenoids: natural products for cancer therapy
Expert Opin. Investig. Drugs (2012) 21(12) 1803

Table 1. The chemical structures and resources of representative terpenoids with anti-cancer activities (continued).
Subclasses Compounds Structures Resources
Andrographolide
HO
CH2
H3C
CH3
O
HO
HO
O
H
Andrographis paniculata (Burm. f.) Nees
Oridonin
OH
H
H3C
OH
H
O
OH
CH3
CH2
OH
O
Rabdosia rubescens(Hemsl.)Hara
Triterpenoid
Celastrol
O
OH
HO
CH3
HCH3
CH3
H3C
O
H3C
CH3
Tripterygium wilfordii Hook.f
Cucurbitacin
(The basic skeleton of cucurbitacin)
H3C
H
OH
CH3
CH3
H3C
O
CH3
CH3
H
Cucumis melo L
M. Huang et al.
1804 Expert Opin. Investig. Drugs (2012) 21(12)

Table 1. The chemical structures and resources of representative terpenoids with anti-cancer activities (continued).
Subclasses Compounds Structures Resources
Alisol B
O
CH3
CH3
CH3
H
HO
CH
H
CH3
CH3
H
H3C
H3C
O
H
HO Alisma orientalis (Sam.)Juzep
Pachymic acid
OH
CH3
CH3
O
OH
H3C
CH3
OO
CH3
CH3
H3C
CH3
CH3
Poria cocos
(Schw.)Wolf
Tetraterpenoid Lycopene CH3
CH3
H3C
CH3
CH3
CH3
CH3
CH3
CH3
CH3Lycopersicon esculentum Miller
Terpenoids: natural products for cancer therapy
Expert Opin. Investig. Drugs (2012) 21(12) 1805

toxicity. In this regard, the most promising venue for
anti-cancer drug development probably involves chemical
modifications of cantharidin to create analogs with compara-
ble anti-cancer property and less toxic effect on non-
cancer cells compared with the mother compound.
Thus far, serine/threonine protein phosphatase 1 (PP1) and
2A (PP2A) have been the best-documented targets of cantha-
ridin. Cantharidin has long been known to be a potent and
selective inhibitor of these two phosphatases, which play
important roles in the control of cell cycle, apoptosis, and
cell-fate determination. Cantharidin inhibits the activity
of purified catalytic subunits of PP1 and PP2A at a sub-
micromolar level [18]. In recent years, there has been intense
interest in developing potent and selective inhibitors of
PP1 and PP2A based on the structure of cantharidin [19-22].
Advances in mechanistic studies have extended our knowledge
of cantharidin and its analogs. PP2A inhibition by canthari-
din triggers cancer cell apoptosis in an IKKa/IkBa/
p65 NF-kB pathway-dependent manner, leading to
subsequent activation of TNF-a, TRAILR1, and
TRAILR2 extrinsic apoptotic signaling [23]. Moreover, the
mitogen-activated protein kinases (MAPKs)/ERK/JNK/
p38 signaling axis was also found to be involved in
cantharidin-triggered apoptosis in cancer cells [24].
3. Sesquiterpenoid
3.1 Artemisinin and its derivatives
Artemisinin is an active terpenoid isolated from the Chinese
medicinal herb Artemisia annua L., which has been used in
China for thousands of years for treating malaria. Therapy
based on artemisinin has saved millions of lives worldwide,
especially in the developing countries. In addition to malaria
control, artemisinin and its derivatives (ARTs) have been
implicated in schistosomiasis control, immunosuppression,
and cancer treatment [25-30]. Chemically, artemisinin is a
sesquiterpene trioxane lactone containing a peroxide bridge,
which is essential for its activity. The anti-cancer activities of
D-limonene
Cantharidin
Artemisinin and its derivatives
Tanshinone IIA
Triptolide
Pseudolaric acid B
Andrographolide
Oridonin
Celastrol
Cucurbitacins
Alisol
Pachymic acid
Lycopene
Inhibition of HMG-CoA reductase and CoA synthesis, etc.
Inhibition of serine/threonine PP1 and PP2A, etc.
Cleavage of iron- or heme-mediated peroxide bridge, etc.
DNA minor groove binder, etc.
Inhibition of XPB ATPase and transcription factors, etc.
Blockage of microtubule and degradation of HIF-1α, etc.
Inhibition of NF-κB, JAK-STAT, PI3K, HSP90 and MMPs, etc.
Downregulation of AP-1 and inhibition of NF-κB signaling, etc.
Inhibition of the IKK α, β kinases and proteasomes, etc.
Interfere with F-actin and inhibition of STAT3, etc.
Inhibition of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase, etc.
Inhibition of DNA topoisomerase I and II, MMP9 and NF-κB, etc.
Scavengers of ROS, inhibition of MMP2 and u-PA, etc.
Terpenoids
Terpenoids
Mechanisms
Mechanisms
Cell cycle arrest
Apoptosis
Autophagy
Differentiation
Anti-angiogenesis
Anti-metastasis
Anti-MDR
Chemoprevention
Figure 1. The schematic diagram of the anti-cancer properties and molecular mechanisms for the terpenoids included in this
review. The highlighted color boxes in the left panel indicate the impacts of each compound on the cellular events listed in
the headings based on Pubmed database. The molecular targets of most terpenoids are unclear. The listed mechanisms in the
right panel are confirmed direct molecular targets or mediators contributing to their anticancer activities.
HIF-1a: Hypoxia-inducible factor 1a; HMG-CoA: 3-Hydroxy-3-methylglutanyl coenzyme A; MMP9: Matrix metalloproteinase 9; NF-kB: Nuclear factor k-light-chain-
enhancer of activated B cells; JAK-STAT: The Janus kinase-signal transducer and activator of transcription; PI3K: Phosphoinositide 3-kinase; PP1: Protein phospha-
tase 1; PP2A: Protein phosphatase 2A; STAT-3: Signal transducer and activator of transcription 3; u-PA: Urokinase-type plasminogen-activator.
M. Huang et al.
1806 Expert Opin. Investig. Drugs (2012) 21(12)

dihydroartemisinin (DHA, one of the main metabolites of
ARTs) and artesunate (a semi-synthesized derivative of arte-
misinin) have been extensively studied. A review by
Chaturvedi et al., has provided detailed insights into the
SAR of ARTs, which therefore will not be the focus of the
current review [31].
ARTs inhibit the proliferation of various types of cancer
cells, including leukemia, breast cancer, ovarian cancer, pros-
tate cancer, colon cancer, hepatoma, gastric cancer, mela-
noma, and lung cancer [32-42]. They seem to be able to
bypass the multi-drug resistant (MDR) cancer cells and pres-
ent similar anti-cancer potency in the parent and the MDR
cancer cells [43,44]. An established DHA-resistant HCT116
colon cancer cell line also does not present MDR characte-
ristics [45]. The in vivo anti-cancer potentials of ARTs
have been demonstrated in numerous xenograft animal
models [35,46,47]. The addition of ARTs to carboplatin or
gemcitabine sensitized chemotherapy in xenograft tumor
models [33,47], indicating that ARTs have a potential role in
combination chemotherapy.
The anti-cancer mechanisms of ARTs appear to be related
to the cleavage of iron- or heme-mediated peroxide
bridge [34,48]. Improved intracellular heme synthesis increases
the cytotoxicity of DHA [48] and CCRF-CEM and U373
cells are sensitive to combined artesunate and iron (II)-glycine
sulfate or holotransferring [49]. Pretreatment with deferox-
amine mesylate salt, an iron chelator, restored DHA-induced
apoptosis or proliferative inhibition [34,37]. Tumor suppressor
p16 and the anti-oxidant protein catalase render cells resistant
to ARTs, whereas the onco-protein c-MYC sensitizes cancer
cells toward ARTs [38,50]. Besides, evidence has suggested
that the anti-cancer activities of ARTs are likely to be medi-
ated by the intervention of multiple cellular events. ARTs
mediate G1 cell cycle arrest by affecting cyclin D, cyclin E,
CDK2, CDK4, p21, p27, NF-kBetc. [33,35,40,51,52] and induce
apoptosis in various cancer cell types via activation of
p38 MAPK, enhancement of Fas expression and activation
of caspases etc. [33-35,39,43,47,53,54]. ARTs also regulate the levels
of urokinase plasminogen activator (u-PA), matrix metallo-
proteinase (MMP)2, MMP7, and MMP9, avb3 integrins
and vascular endothelial growth factor (VEGF), thus
inhibiting angiogenesis, metastasis, and invasion [55-58].
4. Diterpenoids
4.1 Tanshinone IIA
Tanshinones are the major diterpenoid compounds of Salvia
miltiorrhiza Bunge, which are commonly used in China
for the treatment of cardiovascular diseases [59].Asthe
most abundant and extensively studied diterpenoid deri-
vative from Salvia miltiorrhiza Bunge, the in vitro and
in vivo anti-cancer effects of tanshinone IIA has been
demonstrated in various human carcinoma cells, including
leukemia, breast cancer, colon cancer, and hepatocellular
carcinoma [60-67]. It also exhibits synergetic effects when
combined with other anti-cancer agents such as doxorubicin
and cisplatin [68,69].
Tanshinone IIA is a DNA minor groove binder, leading to
the DNA structure damage and in turn the inhibition of
RNAPII binding to DNA and the initiation of RNAPII phos-
phorylation. Such a mechanism has been demonstrated to be
the molecular basis of the anti-cancer property of tanshinone
IIA. The transcription defect likely leads to the down-
regulation of erythroblastosis oncogene B, upregulation of
TNF-a, inhibition of the PI3K/AKT pathway, ROS genera-
tion, activation of calcium-dependent signaling pathway,
increase of Bax/Bcl-2 protein ratio etc., which are all believed
to contribute to the anti-cancer mechanisms of tanshinone
IIA [61-64,67,70-74]. Tanshinone IIA also induces differentiation
in several cancer cell types [75,76] and inhibits invasion and
metastasis of cancer cells via reducing the levels of u-PA,
MMP2, MMP9, and NF-kB, and increasing the levels of
tissue inhibitor of matrix metalloproteinase protein (TIMP)
1 and TIMP2 [77,78]. In addition, tanshinone IIA exhibits
in vitro and in vivo anti-angiogenic effects in HUVEC by
decreasing MMP2 and increasing TIMP2 secretion [79]. Other
tanshinones such as tanshinone I, cryptotanshinon, and
dihydrotanshinone also have anti-cancer activities and similar
mechanisms as tanshinone IIA [80-86].
4.2 Triptolide
Triptolide is a structurally unique diterpene triepoxide isolated
from Tripterygium wilfordii Hook.f. The extracts of this
medicinal plant have been used in traditional Chinese medicine
for a wide variety of diseases from inflammation to autoim-
mune diseases for centuries. In addition to its well-established
immunosuppressive and anti-inflammatory activities, triptolide
has also been shown to exhibit potent anti-proliferative
effects [87]. Triptolide inhibits the proliferation of all 60 US
National Cancer Institute cancer cell lines, with IC
50
values
at nanomolar levels. In vivo anti-cancer activity of triptolide
has been confirmed in xenograft animal models in multiple
preclinical studies. In fact, triptolide and its derivatives
have entered clinical trials for cancer treatment. However, the
molecular mechanism underlying the anti-cancer activity of
triptolide remains unclear.
Compelling evidence has suggested that triptolide has a sig-
nificant impact on the transcriptional machinery of cancer cells,
which may partially, if not completely, account for the anti-
cancer activities of triptolide. Triptolide interferes with a num-
ber of transcription factors, including NF-kB, p53, NF-AT,
and HSF-1 [88-90]. Triptolide seems to block the transactivation
activity of all these transcriptionfactors without affecting DNA-
binding affinity. Intriguingly, triptolide was also observed to
inhibit de novo RNA synthesis, probably due to the indirect
inhibition of transcription mediated by RNA polymerases I
and II [91,92]. A more recent study by Wang et al. [93] demon-
strated that triptolide inhibits global gene transcription
by inducing proteasome-dependent degradation of the largest
subunit of RNA polymerase II (Rpb1) in cancer cells.
Terpenoids: natural products for cancer therapy
Expert Opin. Investig. Drugs (2012) 21(12) 1807

In spite of all these advances, the specific target(s) that trip-
tolide interferes with in cancer cells remains unclear. A series
of attempts to identify the molecular targets of triptolide
have led to the identification of several potential molecular
targets; including calcium channel polycystin-2 [94],an
unknown 90-kDa nuclear protein [91] and the recently defined
human XPB, a subunit of the transcription factor TFIIH [95].
Polycystin-2 cannot account for most of the aforementioned
biological activities of triptolide and the identity of the
putative nuclear triptolide-binding protein has remained
unknown. The covalent binding of triptolide to XPB and
the consequent inhibition of XPB ATPase activity impor-
tantly explain majority of the known cellular and physio-
logical activities of triptolide to date. This strongly suggests
that XPB is a primary molecular target of triptolide. In addi-
tion, triptolide has been observed to induce DNA damages in
cancer cells, probably due to impaired nucleotide excision
repair from XPB inhibition, also known as ERCC3. More-
over, hypoxia-inducible factor-1a(HIF-1a) accumulates
with triptolide treatment but reduces transcriptional activity,
which also has a role in mediating the anti-cancer effects of
triptolide [96]. Together, the relative roles of these proteins
in mediating the anti-cancer effects of triptolide need
further investigation.
4.3 Pseudolaric acid B
Pseudolaric acids are diterpenoids isolated from Pseudolarix
kaempferi, an indigenous plant of eastern China. The root
bark of the plant, described as ‘‘tujingpi’’ in traditional Chinese
medicine, has been used for the treatment of dermatologic
fungal infections since the 17
th
century [97].Analysisofthe
‘‘tujingpi’’ extracts led to the isolation and identification of
pseudolaric acids as the main bioactive constituents. Pseu-
dolaric acids A and B (PAA and PAB) stand out as the most
important natural diterpenoids and constitute the major
anti-fungal and anti-angiogenic congeners of this family
of compounds.
The anti-cancer activities of PAB and the underlying
mechanism have been intensively studied. Considerable cyto-
toxicity of PAB toward a broad-spectrum cancer cell lines
(IC
50
~1µM), including those of lung, colon, breast, brain,
and renal origins, were first observed over 20 years ago [98].
Later investigations revealed that such potent cytotoxic
effect is achieved largely through targeting and destabilization
of microtubules [99]. Tumors are notorious for having
MDR against most naturally derived anti-cancer drugs,
including the existing microtubule-targeting agents, through
P-glycoprotein (P-gp). PAB circumvents P-gp, indicating
that PAB has potential advantages in the treatment of cancer
types resistant to anti-cancer drugs, which are known to be
the substrates of P-gp protein.
Increasing evidence has revealed the intrinsic connection
between anti-angiogenic effect and microtubule blockage [100].
Microtubule functions are believed to contribute to cell
shape, polarization, migration, and other processes, so that
microtubule blockage is responsible for tumor-cytostatic and
specific anti-angiogenic effects [101]. PAB was observed to
inhibit angiogenesis at a non-cytotoxic dosage. Further inves-
tigations revealed that PAB displays dual anti-angiogenic
activities by directly inhibiting endothelial cell growth and
antagonizing VEGF-stimulated cellular events. The latter
involves abrogation of VEGF paracrine stimulation from
tumor cells by promotion of proteasome-mediated HIF-1a
degradation [102,103].
Interference with cancer cell signaling of PAB treatment
extends far beyond microtubule blockage. JNK and ERK
appear to be involved in PAB-induced apoptosis [104], whereas
the Bcl-2 protein family contributes to PAB-induced auto-
phagy in murine fibrosarcoma cells [105]. More studies
are needed to elucidate the mechanisms involved in the
anti-cancer activities of PAB.
4.4 Andrographolide
Andrographolide is a labdane diterpenoid that is the primary
bioactive component of Andrographis paniculata, a traditional
Chinese plant used in many Asian countries for the treatment
of colds, fever, laryngitis, and diarrhea. The bioactive mole-
cules of Andrographis paniculata, including andrographolide,
have displayed varying degrees of anti-inflammatory and
anti-cancer activities in both in vitro and in vivo experimental
models of inflammation and cancer [106]. Andrographolide
also has therapeutic effects for diabetes, since it can reduce
plasma glucose by increasing glucose utilization [107].
Thus far, NF-kB signaling blockage has been suggested to
account for most therapeutic effects of andrographolide.
NF-kB inhibitory activity is partially attributed to its covalent
modification of reduced cysteine in the oligonucleotide-
binding pocket of p50, the transcription factor of
NF-kB[108]. Andrographolide has been shown to reduce the
production of cytokines, chemokines, adhesion molecules,
nitric oxide, and lipid mediators via inhibition of the
NF-kB signaling pathway [106]. Inhibition of NF-kB causes
attenuated neointimal hyperplasia in arterial restenosis
through modulation of the expression of NF-kB target genes,
including tissue factor, E-selectin, and vascular cell adhesion
molecule-1 [109]. Andrographolide also exhibits protective
effects on the beta cell through a mechanism associated with
its NF-kB inhibitory and anti-oxidant activity. Regarding its
anti-cancer activities, andrographolide reduces phosphoryla-
tion of p65 at Ser536 and IkBaat Ser32/36, which leads to
inhibition of aberrant NF-kB activation, attenuation of
neoplastic cell proliferation, and promotion of apoptosis of
human tongue squamous cell carcinoma cells, with concomi-
tant reduction of the expression of NF-kB targeting molecules
in vitro [110].
In addition to NF-kB signaling intervention, a broad range
of signaling pathways and factors are affected by andrographo-
lide treatment, including inhibition of JAK-STAT and PI3K,
suppression of HSP90, cyclins, and cyclin-dependent kinases,
metalloproteinases and growth factors, and induction of tumor
M. Huang et al.
1808 Expert Opin. Investig. Drugs (2012) 21(12)

suppressor proteins p53 and p21. These mechanisms are
associated with inhibition of cancer cell proliferation, survival,
metastasis, and angiogenesis [111].
4.5 Oridonin
Oridonin is a biologically active ingredient isolated from the
Chinese herb Rabdosia rubescens, which has been used for
cleaning the throat. Oridonin has been recently demonstrated
to have a therapeutic effect on various solid tumors, including
liver cancer, skin carcinoma, osteoma, and colorectal cancers.
Oridonin inhibits growth of primary adult T-cell leukemia,
acute lymphoblastic leukemia, chronic lymphocytic leukemia,
non-Hodgkin’s lymphoma, and multiple myeloma cells as
well [112].In vivo anti-cancer activity has been demonstrated
in a colorectal cancer colostomy implantation model [113].
Apoptosis is considered to primarily account for oridonin-
caused cancer cell death, which is associated with blockade of
the NF-kB signal pathways via inhibition of the DNA-
binding activity of NF-kB[112]. Further studies in a colorectal
tumor model revealed that activator protein-1 (AP-1) is
decreased after oridonin treatment, followed by downregula-
tion of the NF-kB and p38 pathways. These findings suggest
that AP-1 downregulation may be the initial response to
oridonin treatment. Expression of the NF-kB and mitogen-
activated protein kinase pathways are later affected, thereby
inhibiting tumor growth [113]. Oridonin treatment down-
regulates PI3K/Akt signaling and the expression of forkhead
box class O (FOXO) transcription factor and glycogen
synthase kinase 3 (GSK3). These effects also contribute to
oridonin-induced cancer cell apoptosis [114].
Investigations discovered that oridonin-treated cancer cells
also undergo autophagy in addition to apoptosis. However,
the association between these two events upon oridonin treat-
ment has been controversial. Inhibition of autophagy was
found to decrease oridonin-induced apoptosis in human sar-
coma HT1080 cells in a p53-dependent manner, suggesting
that oridonin-induced apoptosis and autophagy act in synergy
to mediate cell death [115]. However, inhibition of autophagy
by 3-MA or siRNA against LC3 and beclin 1 in murine fibro-
sarcoma L929 cells promoted oridonin-induced apoptosis [116],
which concurs with another finding that autophagy enhances
p38 MAPK-NF-kB signaling-mediated cell survival and
inhibits ROS-mediated apoptosis induced by oridonin treat-
ment [117]. A more recent study found that N-acetylcysteine, a
ROS scavenger, significantly reduces both apoptosis and
autophagy induced by oridonin in human cervical carcinoma
HeLa cells [118]. The reasons for these discrepancies remain
unknown and are possibly due to difference in species or
heterogeneity of cancer cells.
5. Triterpenoids
5.1 Celastrol
Celastrol, also known as tripterine, is another bioactive terpe-
noid from Tripterygium wilfordii Hook. f that possesses various
biological activities, including anti-oxidant, anti-cancer, and
anti-inflammatory activities [119].
Celastrol has attracted tremendous interest, particularly in
the field of anti-inflammation. In vivo anti-inflammatory
effects of celastrol have been demonstrated in animal models
of collagen-induced arthritis, Alzheimer’s disease, asthma,
and lupus [120,121]. Several studies have suggested that the
relevant activity resides in the inhibition of the synthesis and
secretion of proinflammatory cytokines and the expression
of adhesion molecules [122,123]. Celastrol also attenuates
hypertension-induced inflammation and oxidative stress in
vascular smooth muscle cells. An increasing number of studies
have identified heme oxygenase-1 as a key factor mediating
the anti-inflammatory effects of celastrol [124,125].
While the anti-cancer activity of celastrol in increasingly
recognized, the molecular basis of the anti-cancer effect of celas-
trol remains unclear. Various signaling pathways appear to be
affected by celastrol treatment and may contribute to their
anti-cancer effects. Celastrol i) directly inhibits the IKKA
˜and
bkinases, ii) inhibits thefunction of proteasomes, iii)inactivates
the Cdc37 and p23 proteins which are co-chaperones of
HSP90, iv) activates the HSF1 and subsequently triggers the
heat shock response, and v) inhibits AKT/mTOR/P70S6K
signaling to mediate the tumor growth suppression and angio-
genesis. It seems that the quinone methide structure present in
celastrol can react with the thiol groups of cysteine residues,
forming covalent protein adducts. [126-129].
5.2 Cucurbitacins
Cucurbitacin and its derivatives comprise a class of highly
oxidized cucurbitane-type tetracyclic triterpenoids widely
distributed in the plants. To date, more than 100 cucurbita-
cins have been reported. Cucurbitacins are specific insect
attractants and are thus widely used as bait in insecticides [130].
Studies have demonstrated that cucurbitacins possess strong
pharmacological activities in humans, including anti-cancer,
anti-inflammatory, and hepatoprotective effects [131,132].In
the past ten years, their anti-cancer activities have regained
attention after more than 40 years of negligence [132]. Accu-
mulated reports showed that most cucurbitacins significantly
inhibit the proliferation of multiple tumor line cells to IC
50
at nanomolar levels in vitro.
Cucurbitacins induce cell cycle arrest, mainly G2/M [133,134] S
phase arrest [135,136] depending on the cell types and the tested
cucurbitacins. Furthermore, some reports suggested that cucur-
bitacins might induce differentiation in several tumor cell
lines [135,137]. A more recent study showed that cucurbitacin B
induces autophagy but is interpreted as a pro-survival compen-
satory response [138]. Although current data have already
suggested their potential activities, the anti-angiogenesis effects
of cucurbitacins have not been well established. Cucurbitacins
have potent effects on tumor line cell invasion and in vitro
migration, and dramatically inhibit tumor invasion and
metastasis in vivo [134,139-142]. Back to 1965, the combination
of cucurbitacin D or E with X-rays irradiation has been found
Terpenoids: natural products for cancer therapy
Expert Opin. Investig. Drugs (2012) 21(12) 1809

to be more potent than either cucurbitacin or irradiation
alone [143]. The combination therapy of cucurbitacins with other
commonly prescribed chemotherapeutic agent has become the
focus of research. Cucurbitacins demonstrated synergistic effects
when combined with gemcitabine [144,145], cisplatin, doxorubi-
cin, 5-flouroracil, paclitaxel [146], and docetaxel [147] in both
in vitro and in vivo models.
The mechanisms underlying the anti-tumor effects of
cucurbitacins need to be further investigated. Potential mole-
cular targets identified include F-actin and signal transduction
and activators of transcription-3 (STAT3). Cucurbitacins
strongly interfere with the disruption, aggregation, and
assembly of actin cytoskeleton (mainly F-actin), resulting in
morphological changes and cellular dysfunction [135,148-152].
Cucurbitacins are small-molecule inhibitors of STAT3; inhi-
bition of the phosphorylation of STAT3 result in dysfunction
of the JAK2/STAT3 pathway [152-157].In vitro, cucurbitacins
also inhibits cyclooxygenase-2 (COX-2) [158-160] and tyrosine
kinase [161].
5.3 Alisol
Alisol derivatives are unique protostane-type triterpenoid
compounds isolated from the rhizome Alisma orientalis
(Sam.) Juzep, which is a well-known traditional medicine in
East Asia for the treatment of hypertension, hyperlipidemia
and urological diseases [162]. In recent years, these compounds
have received increasing attention due to their potential anti-
cancer activities [163]. Alisol B induces endoplasmic reticulum
stress, autophagy, and apoptosis in several cancer cell lines,
with the sarcoplasmic/endoplasmic reticulum Ca
2+
ATPase
as its potential molecular target [164]. Alisol B 23-acetate medi-
ates G2/M cell cycle arrest and induces apoptosis in cancer
cells and the inhibition of PI3K/Akt signaling pathway, upre-
gulation of Bax/Bcl-2 ratio, and activation of caspases which
contribute to its anti-cancer effect [165,166]. In addition, alisol
B 23-acetate is suggested to be a potential MDR-reversing
agent that restores the sensitivity of MDR cell lines [167].
5.4 Pachymic acid
Pachymic acid, is a lanostane-type triterpenoid derived from
Poria cocos and known to possess anti-inflammatory [168,169]
and anti-cancer activities [170-174]. Reports on the anti-cancer
activities and underlined mechanism of actions of pachymic
acid are limited. It exhibits cytotoxicity against human lung
cancer A549 cells, human prostate cancer DU145 cells,
and colon carcinoma HT29 cells [172,174] and induces apopto-
sis in DU145, LNCaP prostate cancer cells, and A549
cells [171,173]. Pachymic acid-treatment activates PARP,
caspases-9, and caspases-3 [173]. It also shows inhibitory acti-
vities on both DNA topoisomerase I and II [174]. Invasion of
MDA-MB-231 and MCF-7 breast carcinoma cells is sup-
pressed by pachymic acid at non-lethal concentrations, and
is associated with decreased MMP9 secretion [170]. Pachymic
acid also reduces the PMA-induced transcriptional activity
of NF-kB[170].
5.5 Others
A few other triterpenoid-derived acids (e.g., ursolic acid, betu-
linic acid, and asiatic acid) with evident anti-cancer efficacy
were not covered in this review. In fact, triterpenoids consti-
tute the largest sub-group of bioactive terpenoids among those
tested in anti-cancer studies. Although the reason for this
observation remains elusive at this moment, we speculate
that exploration of triterpenoids could potentially increase
the success of anti-cancer drug development.
6. Tetraterpenoids
The most common tetraterpenoids are the carotenoids, contai-
ning more than 600 known natural structural variants. Carote-
noids are natural fat-soluble pigments that provide bright
coloration to plants and animals [175]. Structurally, carotenoids
feature three aspects: i) most widely known carotenoids are
either simple unsaturated hydrocarbons having the basic lyco-
pene structure or their corresponding oxygenated analogs,
usually termed as Xanthophylls; ii) eight isoprene units are
found to be joined head to tailin lycopene to give it a conjugated
system that eventually is responsible for attributing the chro-
mophoric character to the molecule, i.e., producing color, and
iii) cyclization of lycopene at both terminals of the molecule
yields a bicyclic hydrocarbon commonly known as b-carotene,
which occur most abundantly in the higher plants.
It has been noted that dietary intake of carotenoids reduces
the risk of a variety of cancers, suggesting preventive roles of
carotenoids in cancer. Preclinical studies have also revealed the
therapeutic roles of carotenoids, such as b-carotene, a-carotene,
lycopene, lutein, zeaxanthin, b-cryptoxanthin, fucoxanthin,
canthaxanthin and astaxanthin have all been proven to exhibit
anti-carcinogenic activity [176].
6.1 Lycopene
Lycopene is an open-chain hydrocarbon containing 11 conju-
gated and 2 non-conjugated double bonds arranged in a linear
array. It is derived predominantly from tomatoes. With the
interest in anti-cancer activity of natural compounds derived
from the regular human diet growing lately, the potential of
tomato-derived carotenoid lycopene has been tested in clinical
studies. In a Phase II clinical trial, the efficacy of lycopene
alone or in combination with soy isoflavones on serum PSA
levels in men with prostate cancer was investigated. Lycopene
and soy isoflavones delayed progression of both hormone-
refractory and hormone-sensitive prostate cancer [177]. More-
over, a small, randomized clinical trial showed that lycopene
supplementation may increase prostate tissue levels of lyco-
pene, modulate biomarkers of growth and differentiation,
and decrease clinical parameters of disease aggressiveness of
clinically localized prostate cancer [178,179].
Lines of evidence have revealed the molecular basis responsi-
ble for the remarkable chemopreventive and anti-proliferative
activity of lycopene. Lycopene has been shown to exhibit
anti-oxidant effects via scavenging ROS, which allows lycopene
M. Huang et al.
1810 Expert Opin. Investig. Drugs (2012) 21(12)

to prevent lipid peroxidation and DNA damage. Simulta-
neously, lycopene induces enzymes of the cellular anti-oxidant
defense systems by activating the anti-oxidant response element
transcription system [180]. Lycopene has also been shown to
exhibit anti-angiogenic effects, which is probably attributed
to the attenuated activities of MMP2 and u-PA via enhancing
protein expression of tissue inhibitors of MMP2 and plasmino-
gen activator inhibitor-1 [181-183]. In spite of the increasingly
accumulating evidence, the molecular mechanism accounting
for the anti-cancer activity of lycopene remains elusive. Indeed,
a recent study using proteomic analysis has revealed that lyco-
pene modulates the expression of a broad range of proteins,
including cell cycle proteins and heat shock proteins [184].This
approach may represent a powerful strategy to gain mechanistic
insights into the mode of actions of lycopene.
6.2 Others
Although the anti-cancer activity of other carotenoids has
been reported occasionally, the mechanistic insights into these
carotenoids are relatively limited. It has been shown that
b-carotene-induced apoptosis in breast cancer cells by upregu-
lating the expression of peroxisome proliferator-activated
receptor gamma (PPARg). Moreover, b-carotene induced
ROS generation, resulting in mitochondrial dysfunction and
cytochrome crelease, which may also contribute to its induced
apoptosis [185].b-carotenes and oxygenated carotenoids
showed anti-oxidant and anti-inflammatory activities [186].
More studies are needed for a better understanding of
these carotenoids.
Notably, a selection of carotenoids have been shown to
modulate drug resistance [187]. Lutein, antheraxanthin, viola-
xanthin, fucoxanthin, and canthaxanthin all showed moderate
effects on the reversal of MDR in the tumor cells [188]. The
combination of carotenoids with eight structurally different
cytotoxic agents synergistically enhanced their cytotoxicity in
Caco-2 cells [187]. For example, fucoxanthin synergistically
enhanced the cytotoxicity of 5-FU 53.37-fold, of vinblastine
51.01-fold, and of etoposide 12.47-fold. The molecular basis
behind is probably due to the suppressed function of the ABC
transporters, but detailed mechanism appeared to be distinct.
Carotenoids are believed to function as P-gp substrates and
enhance the effectiveness of chemotherapy by competing
with anti-cancer drugs being P-gp substrates, which results
in the increased cellular accumulation of these drugs.
Meanwhile, fucoxanthin and canthaxanthin were found to
significantly decrease the level of P-gp.
7. Expert opinion
Though the anti-cancer efficacy of a large number of terpe-
noids, particularly those included in this review, is encoura-
ging, the insightful anti-cancer studies in this field remain
very limited. Most of the anti-cancer studies involving this
class of compounds mainly presents descriptive findings and
lack insights into the underlying mechanisms. For example,
celastrol has been shown to inhibit IkBakinase [189], protea-
some [190], topoisomerase [191], heat shock protein [192-195],
b1 integrin ligand affinity [196],and VEGFR expression [197],
but none of the studies has provided insights into its mole-
cular targets. Moreover, the lack of systematic SAR studies
for terpenoids, which is indeed common for naturally derived
compounds, has restricted the current understanding to the
generalities of the compound class. As a result, the under-
standing about the chemical modifications rendered activities
alteration is very limited. Potential challenges and future
directions include systematic SAR studies, the identification
of their molecular targets, and molecular mechanisms of
action. In this regard, previous efforts on the identification
of the molecular target of triptolide [91] using isotope-
based measurement of triptolide uptake or binding in cancer
cells could provide a powerful approach and could serve as a
successful model.
Despite the broad spectrum of therapeutic effects of these
terpenoids, all the terpenoids (except for cantharidin, tripto-
lide and cucurbitacin) exhibit relatively modest effects. This
feature is observed in most bioactive compounds derived
from traditional Chinese medicine. Bearing this fact in
mind, combinational therapy probably provides an optimal
venue for the clinic application of these compounds. For
instance, oridonin has been found to sensitize hepatocellular
carcinoma cells to arsenic trioxide (As
2
O
3
) treatment, which
has been successfully employed in the treatment of patients
with acute promyelocytic leukemia [198].
In addition, some of the terpenoids described in this
review largely exhibit their anti-cancer effects via modulation
of the immune system, such as NF-kB signaling. This obser-
vation could be purely coincidental. More likely, all these
compounds are bioactive constituents of traditional Chinese
medicine, which were used for other symptoms thousands of
years ago, when the concept of cancer had not been estab-
lished. Therefore, the anti-cancer effects of these herbs can
be attributed to their effective modulation of multiple
aspects of the patients, with the immune system being
a major factor.
Acknowledgements
We thank D-D Chen for the great assistance in drawing
chemical structures.
Declaration of interest
The authors state no conflict of interest. This study was sup-
ported by the Macao Science and Technology Development
Fund (029/2007/A2, 077/2011/A3), the Research Fund of
University of Macau (UL016/09Y4/CMS/WYT01/ICMS
and MYRG208(Y2-L4)-ICMS11-WYT) and the National
Natural Science Foundation of China (No.81001450).
Terpenoids: natural products for cancer therapy
Expert Opin. Investig. Drugs (2012) 21(12) 1811

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Affiliation
Min Huang*, Jin-Jian Lu*, Ming-Qing Huang,
Jiao-Lin Bao, Xiu-Ping Chen & Yi-Tao Wang
†
†
Author for correspondence
*Co-first authors
State Key Laboratory of Quality
Research in Chinese Medicine,
Institute of Chinese Medical Sciences,
University of Macau,
Macao, China
E-mail: ytwang@umac.mo
M. Huang et al.
1818 Expert Opin. Investig. Drugs (2012) 21(12)