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Minireview
Beneficial health effects of lupeol triterpene: A review of preclinical studies
Hifzur Rahman Siddique, Mohammad Saleem ⁎
Section of Molecular Chemoprevention and Therapeutics, The Hormel Institute, University of Minnesota, Austin, MN, USA
abstractarticle info
Article history:
Received 16 September 2010
Accepted 15 November 2010
Available online 28 November 2010
Keywords:
Diseases
Lupeol
Triterpene
Pharmacological
Clinical trial
Since ancient times, natural products have been used as remedies to treat human diseases. Lupeol, a phytosterol
and triterpene, is widely foundin edible fruits, and vegetables. Extensive research over thelast three decades has
revealed several important pharmacological activities of lupeol. Various in vitro and preclinical animal studies
suggest that lupeol has a potential to act as an anti-inflammatory, anti-microbial, anti-protozoal, anti-
proliferative, anti-invasive, anti-angiogenic and cholesterol lowering agent. Employing various in vitro and in
vivo models,lupeol has also been tested for its therapeutic efficiencyagainst conditions including wound healing,
diabetes, cardiovascular disease, kidney disease, and arthritis. Lupeol has been found to be pharmacologically
effective in treating various diseases under preclinical settings (in animal models) irrespective of varying routes
of administration viz; topical, oral, intra-peritoneal and intravenous. It is noteworthy that lupeol has been
reported to selectively target diseased and unhealthy human cells, while sparing normal and healthy cells.
Published studies provide evidence that lupeol modulates the expression or activity of several molecules such as
cytokinesIL-2, IL4, IL5, ILβ,proteases, α-glucosidase, cFLIP, Bcl-2and NFκB. This minireviewdiscusses in detail the
preclinical studies conducted with lupeol and provides an insight into its mechanisms of action.
© 2010 Elsevier Inc. All rights reserved.
Contents
Introduction ................................................................ 286
Triterpenes .............................................................. 286
Source of lupeol ............................................................ 286
Physical properties and biosynthesis of lupeol .............................................. 286
An overview of therapeutic and preventive potential of lupeol ...................................... 286
Lupeol as an anti-arthritic agent ................................................. 286
Lupeol as an anti-microbial agent ................................................ 286
Lupeol as an antiprotozoal agent ................................................. 288
Lupeol as anti-cancerous agent .................................................. 288
Lupeol as anti-diabetic agent ................................................... 288
Lupeol as cardioprotective agent ................................................. 288
Lupeol as anti-inflammatory agent ................................................ 289
Lupeol as skin protective agent.................................................. 290
Lupeol as hepatoprotective agent ................................................. 290
Lupeol as nephroprotective agent ................................................ 290
Perspectives for clinical trials ........................................................ 291
Perspectives for improvement of activity ................................................... 291
Conflict of interest statement ........................................................ 291
Acknowledgements ............................................................. 291
References ................................................................. 291
Life Sciences 88 (2011) 285–293
⁎Corresponding author. Section of Molecular Chemoprevention and Therapeutics, The Hormel Institute, University of Minnesota, 801, 16th Ave. NE, Austin, MN, 55912 USA.
Tel.: +1 507 437 9662; fax: +1 507 437 9606.
E-mail address: msbhat@umn.edu (M. Saleem).
0024-3205/$ –see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.lfs.2010.11.020
Contents lists available at ScienceDirect
Life Sciences
journal homepage: www.elsevier.com/locate/lifescie
Author's personal copy
Introduction
Triterpenes
Triterpenes (members of phytosterol family) are natural compo-
nents of human diet (Moreau et al., 2002). Triterpenes are largely
derived from vegetable oils, cereals, and fruits. Although human
consumption of triterpenes is estimated to be approximately 250 mg
per day in the Western world, it is noteworthy that in Mediterranean
countrieswhere mostof the diets are olive oil based, the average intake
of triterpenes consumed by a person could reach 400 mg/kg/day
(Moreau et al., 2002). During the last decade, there has been an
unprecedented escalation of interest in triterpenes. Although much of
the research is focused on the cholesterol-lowering properties of
triterpenes, there are enormous amounts of published data suggesting
the utility of triterpenes for the treatment of a wide variety of disease
conditions (Ovesná et al., 2004;Liby et al., 2007; Jang et al., 2009). These
studieshave culminated intoseveral clinical studies, patents and a boom
in the marketing of triterpene-based products (ranging from supple-
mental to cosmetics) frequently found in theshelves of pharmaceutical
stores (Ovesná et al., 2004; Alander and Andersson, 2005; Liby et al.,
2007; Jang et al., 2009). A recent clinical study comprising 2500 subjects
taking different types of triterpenes with (N25 g/day) reported no
adverse effects in humans (Moreau et al., 2002, and references therein).
Lupeol is a triterpene that has gained the attention of medical
professionals, researchers and pharmaceutical marketers for its wide
ranging pharmacological activities.
Source of lupeol
Lupeol has been reported to be present in diverse species of the plant
kingdom. Lupeol is found in edible vegetables and fruits such as white
cabbage, pepper, cucumber, tomato, carrot, pea, bitter root, soy bean, ivy
gourd, black tea, figs, strawberries red grapes, mulberries, date palm and
guava. Lupeol is also found in abundance in medicinal plants such as, Shea
butter plant, licorice, Tamarindus indica,Celastrus paniculatus,Zanthoxylum
riedelianum,Allanblackia monticola,Himatanthus sucuuba,Leptadenia
hastata,Crataeva nurvala,Bombax ceiba,Sebastiania adenophora,Aegle
marmelos and Emblica officinalis (Erazo et al., 2008; Saleem, 2009 and
references therein). The quantification studies have shown that lupeol is
present in Olive fruit (3 μg/g), Mango fruit (1.80 μg/g pulp), Aloe leaf
(280 μg/g dry leaf), Elm plant (800 μg/g bark), Japanese Pear (175 μg/g
twig bark) and Ginseng oil (15.2 mg/100 g of oil).
Physical properties and biosynthesis of lupeol
The chemical formula of lupeol is C
30
H
50
O and its structure is
presented in Fig. 1a. The infra-red spectrum of lupeol shows the
presence of a hydroxyl function and an olefinic moiety at a spectrum of
3235 and 1640 cm
−1
and HPLC–MS studies of lupeolconfirmed a parent
ion peak at m/z 409 (M+ H-18)(+) (Saleem, 2009). The melting point
of lupeol is 215–216 °C and the structural analysis shows that it
possesses the exact mass of 426.386166 (Saleem, 2009).
Lupeol biosynthesis in plants is orchestrated by the triterpene
synthases and is considered as one of the most complex reactions
occurring in nature (Phillips et al., 2006). The biosynthesis of lupeol is
briefly presented in Fig. 1b.Lupeol biosynthesis occurs in the cytosol and
occurs through the stepwise formation of the mevalonate (MVA), the
isopentenyl pyrophosphate (IPP), and dimethylallyl pyrophosphate
(DMAPP) and farnesyl pyrophosphate (FPP) from acetyl CoA. This
reaction is catalyzed by farnesyl pyrophosphate synthase (FPS). Next,
Squalene synthase (SQS) converts FPP into squalene. Squalene
epoxidase (SQE) oxidizes squalene to 2, 3-oxidosqualene, which is
then cyclized by lupeol synthases (LUS), to form the lupenyl cation.
Finally, lupenyl cation is converted into lupeol by deprotonation of the
29-methyl group (Phillips et al., 2006).
An overview of therapeutic and preventive potential of lupeol
Lupeol isreported to exhibita spectrum of pharmacological activities
against various disease conditions (Fig. 2). These include conditions
such as inflammation, arthritis, diabetes, cardiovascular ailments, renal
disorder, hepatic toxicity, microbial infections and cancer (Al-Rehaily
et al., 2001; Fernández et al., 2001a,b; Chaturvedi et al., 2008; Sudhahar
et al., 2008a,b). The available literature suggests that lupeol is a non-
toxic agent and does not cause any systemic toxicity in animals at doses
ranging from 30 to 2000 mg/kg (Geetha et al., 1998; Al-Rehaily et al.,
2001; Saleem et al., 2004, 2005, 2008; Bani et al., 2006; Preetha et al.,
2006; Prasad et al., 2008; Sudhahar et al., 2008a,b; Murtaza et al., 2009).
The doses of lupeol which have been tested in animal models
(representing various human diseases) are summarized in Table 1.
Lupeol has been shown to target molecules which are known to play a
key role in the development of various human ailments. A summary of
molecular targets of lupeol is presented in Fig. 3. The summary of
preclinical studies conducted to test the pharmacological action of
lupeol for various ailments is discussed as following:
Lupeol as an anti-arthritic agent
The potential of lupeol as an anti-arthritic agent has been tested in
various in vitro and in vivo models of arthritis (Geetha et al., 1998; Geetha
and Varalakshmi, 1999a,b, 2001; Bani et al., 2006; Azebaze et al., 2009;
Blain et al., 2009). Arthritis is a systemic disease and causes alteration in
lysosomal integrity and metabolism of connective tissue (Geetha and
Varalakshmi, 1999a). Alteration of lysosomal integrity results in signifi-
cantly increased destruction of connective tissue and cartilage by
lysosomal enzymes (Geetha and Varalakshmi, 1999a). A study conducted
by Geetha and Varalakshmi (1999a) established the role of lupeol in
treating the arthritic condition in a rat model. In this study, arthritis was
induced by the intradermal injection of 0.1 ml of Complete Freund's
Adjuvant (CFA; 10 mg heat killed Mycobacterium tuberculosis in 1 ml
paraffin oil) in the right hind paw. Arthritic rats treated with lupeol
(50 mg/kg for 7 days) showed significantly reduced levels of lysosomal
enzymes and increased collagen levels (Geetha and Varalakshmi, 1999a).
Chronic inflammation, bone degradation and swelling at joints are the
markers of human arthritis (Blain et al., 2009). Arthritic animals exhibit
similar features as are observed in human disease (Geetha et al., 1998;
Geetha and Varalakshmi, 1999a; Azebaze et al., 2009). As evident from
several published reports, lupeol treatment decreases inflammation and
paw swelling in animals suffering from arthritis (Geetha et al., 1998;
Azebaze et al., 2009; Geetha and Varalakshmi, 1999a,b, 2001)lupeol
treatment also improved the overall condition of arthritic animals by
affording protection from pain and improving their mobility (Geetha et al.,
1998; Azebaze et al., 2009; Geetha and Varalakshmi, 1999a,b, 2001).
Arthritic animals exhibit decreased collagen levels and increased
excretion of urinary hydroxyproline, hexosamine, hexuronic acid and
glycosaminoglycans (Geetha and Varalakshmi, 2001). Lupeol treatment is
reported to restore altered levels of hydroxyproline, hexosamine,
hexuronic acid and glycosaminoglycans to the normal (Geetha and
Varalakshmi, 1999a, 2001). Notably, when compared to well known
anti-inflammatory agents indomethacin and aspirin (Geetha and
Varalakshmi, 2001; Bani et al., 2006), lupeol does not exhibit any
antinociceptive and ulcerogenic actions in arthritic animals, suggesting
that the mechanism of action of lupeol is different from the non-steroidal
anti-inflammatory drugs (Geetha and Varalakshmi, 2001; Bani et al.,
2006; Preetha et al., 2006).
Lupeol as an anti-microbial agent
Lupeol has been found to exhibit antimicrobial activity against a wide
range of commonly encountered microbes (Hernández-Pérez et al., 1994;
Ajaiyeoba et al., 2003; Tanaka et al., 2004; Erazo et al., 2008; Shai et al.,
2008; Abd-Alla et al., 2009; Ahmed et al., 2010). Lupeol is reported to
inhibit the growth of a several types of bacteria, fungi and viral species
(Hernández-Pérez et al., 1994; Ajaiyeoba et al., 2003; Tanaka et al., 2004;
286 H.R. Siddique, M. Saleem / Life Sciences 88 (2011) 285–293
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Erazo et al., 2008; Shai et al., 2008; Abd-Alla et al., 2009; Ahmed et al.,
2010). Lupeol has been found to act as an effective anti-bacterial agent
when tested against both gram positive and gram negative bacteria (Erazo
et al., 2008; Ahmed et al., 2010). These include B. cereus,B. megaterium,
B. subtilis,S. aureus,S. lutea,S. paratyphi,S. typhi,S. boydi,S. dysenteriae,
V. mimicus,V. parahemolyticus,E. coli,D. spinosa,K. pneumoniae,S. aviatum,
P. aeruginosa,andM. flavus (Erazo et al., 2008; Ahmed et al., 2010). Most of
these bacteria cause diseases in humans such as pneumonia, urinary tract
infection and sepsis (K. pneumoniae), typhoid and paratyphoid fever
(S. typhi and S. paratyphi), shigellosis (S. dysenteriae), meningitis,
osteomyelitis, endocarditis and toxic shock syndrome (S. aureus).
Similarly, lupeol (12–250 μg/ml) has been shown to inhibit the growth
of a variety of fungal species such as S. schenckii;M. canis;A. fumigatus;
C. albicans;C. neoformans;C. guilliermondi and C. spicata (Shai et al., 2008).
AstudybyAjaiyeoba et al. (2003) showed that lupeol-rich extract of
Buchholzia coriacea exhibits a dose-dependent antibacterial and antifungal
activity. In this study, the antimicrobial effect of lupeol was shown to be
more than well-known antibiotics such as ampicillin and tioconazole
(Ajaiyeoba et al., 2003). Hernández-Pérez et al. (1994) has reported
the antimicrobial activity of lupeol-containing Visnea mocanera leaf
extract. Further, lupeol has been reported to exhibit anti-viral activity
(Hernández-Pérez et al., 1994). Lupeol exhibited significantly high anti-
viral activity when tested against Herpes simplex virus 1 (HSV1) virus.
Lupeol (EC
50
: 11.7 μM) caused a 100% inhibition of virus plaque formation
at 58.7 μM(Tanaka et al., 2004). Lupeol is also reported to inhibit the
growth of influenza A virus (Hernández-Pérez et al., 1994).
HO
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
C
H2C
SCoA
O+
PPO
OPP
H
OPP
O
Squalene
2,3-Oxidosqualene
HO
Lupenyl cation
FPP
DMAPP
HO
Lupeol
2
2
LUS
SQS
SQE
OSC
FPS
O
O
OH
O
HO
Mevalonate (MVA)
3 ATP
H+
b
a
IPP
Fig. 1. (a) Chemical structure of lupeol and (b) schematic representation of the critical steps of the biosynthesis of lupeol in plants; DMAPP represents dimethylallyl pyrophosphate;
IPP represents isopentenyl pyrophosphate; FPS represents farnesyldiphosphate synthase; FPP represents farnesyl pyrophosphate; SQS represents squalene synthase; SQE represents
squalene epoxidase; OSC represents oxidosqualene cyclase; LUS represents lupeol synthase.
287H.R. Siddique, M. Saleem / Life Sciences 88 (2011) 285–293
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Lupeol as an antiprotozoal agent
Lupeol is reported to be effective against several types of pathogenic
protozoa. These include those which cause malaria, leishmaniasis and
trypanosomiasis. Lupeol is reported to inhibit the proliferation of
malarial parasite (Plasmodium falciparum). Lupeol was shown to block
the invasion of Plasmodium falciparum merozoites into erythrocytes at
IC
50
1.5 μg/ml (Suksamrarn et al., 2003; Ziegler et al., 2004, 2006).
Structure–activity relationship between lupeol and Plasmodium
falciparum showed that lupeol incorporates into the erythrocyte
membrane. The anti-plasmodial effect of lupeol seems to be related to
alterations in the membraneshape of the host cell rather than a targeted
toxic effect on the parasiteorganelles or metabolic pathways(Rodrigues
and de Souza, 2008). Lupeol treatment was shown to significantly
inhibit the growth of Trypanosoma cruzi and Leishmania with an IC
90
at
the dose of 100 μg/ml (Fournet et al., 1992).
Lupeol as anti-cancerous agent
Lupeol is reported to exhibit strong anti-mutagenic activity when
tested underin vitro and in vivo conditions (Sunitha et al., 2001; Sultana
et al., 2003; You et al., 2003; Lee et al., 2007; Lira Wde et al., 2008.
A recently published review article from our laboratory provides a
comprehensive account of the chemotherapeutic and chemopreventive
potential of lupeol against a variety of cancers (Saleem, 2009 and
references therein). Lupeol has been reported to inhibit the growth of
several tumor types by modulatingkey molecular pathways,involved in
proliferation, survival and apoptosis. The most striking observation is
that lupeoldoes not exhibitany toxic effect on normal human cellsat the
dose at which it kills cancerous cells (Saleem et al., 2004, 2005, 2008;
Murtaza et al., 2 009). A summarized account of the mechanism of action
of lupeol against tumor cells is presented in Fig. 4.
Lupeol as anti-diabetic agent
Lupeol has been reported to exhibit anti-diabetic activity in in vitro
and in vivo models(Ali et al., 2006; Narvaez-Mastacheet al., 2006;Ortiz-
Andrade et al., 2007; Na et al., 2009). Several studies showed that lupeol
exhibits antihyperglycemic activity and its administration lowers the
risk of development of diabetes in animal models (Ali et al., 2006;
Narvaez-Mastache et al., 2006Ortiz-Andrade et al., 2007; Na et al., 2009).
Protein tyrosine phosphatase 1B (PTP1B) plays a major role in the
inhibition of insulin action, development of type 2 diabetes and obesity
(Na et al., 2009). Recently, Na et al. (2009) showed that lupeol
(IC
50
=5.6μM) inhibits the activity of PTP1B. This study suggested the
therapeutic potential of lupeol to counter other insulin resistance
related diseases. Efficiency of lupeol against diabetes development has
been investigated by several investigator employing animal models of
diabetes (Narvaez-Mastache et al., 2006; Ortiz-Andrade et al., 2007.
In one study, diabetes was induced by streptozotocin administration in
experimental rats (Narvaez-Mastache et al., 2006). However, lupeol-
rich plant extract treatment inhibited the development of diabetes in
streptozotocin-induced diabetic rats (Narvaez-Mastache et al., 2006).
Lupeol is reported to be a principal constituent in medicinal plants such
as Tournefortia hartwegiana, used by country doctors in treating diabetes
Ortiz-Andrade et al. (2007).Ortiz-Andrade et al. (2007) demonstrated
that lupeol-rich extract of Tournefortia hartwegiana (310 mg/kg)
inhibits the α-glucosidase activity suggesting that anti-diabetic effect
of lupeol is through the suppression of carbohydrate absorption in the
intestine. Lupeol is reported to inhibit the alpha-amylase, an enzyme,
which is known to contribute in the development of diabetes (Ali et al.,
2006). The complete mechanism of lupeol in inhibiting diabetes in
experimental animals is not fully understood. However, targeting of
PTP1B, alpha-amylase and α-glucosidase activities (which are directly
linked with sugar metabolism) could be a potential mechanism. Further
studies are warranted in this direction (Ali et al., 2006; Ortiz-Andrade
et al., 2007; Na et al., 2009).
Lupeol as cardioprotective agent
Plant sterols have been investigated as one of the safe and potential
alternative methods in lowering plasma cholesterol levels (Rong et al.,
1997; Uusitupa et al., 1997; Frye and Leonard, 1999; Moreau et al., 2002).
Several human clinical studies have shown that plant sterols significantly
reduce total and LDL cholesterol levels (Rudkowska et al., 2008a, b;
Microbial
activities
Arthritis
Liver
Toxicity
Cardiovascula
r
diseases
Renal
Diseases
Cancer
Lupeol
Inflammation
Diabetes
Fig. 2. Diagram represents the effect of lupeol against different types of human diseases.
Lupeol has been shown to have valuable medicinal properties for the treatment of
several chronic diseases. Studies have also shown that lupeol has no effect on normal
cells and kills only diseased cells.
Table 1
Studies with lupeol in animal models.
Animal
species
Disease
model
Route of
administration
Highest dose
(mg/kg body Wt).
Time period
(days)
Mortality Systematic
toxicity
References
Albino rats Inflammation Oral 100 7 No No Al-Rehaily et al. (2001)
Albino rats Inflammation Gavage 40 7 No No Al-Rehaily et al. (2001)
Wister albino rats Liver Oral 100 7 No No Preetha et al. (2006)
Wister rats Arthritis Oral 50 8–10 No No Geetha et al. (1998) and Latha et al. (2001)
Wister rats Renal damage Oral 50 15 No No Sudhahar et al. (2008a,b)
Cd-1 mice Skin cancer Topical 80 180 No No Saleem et al. (2004)
Athymic
nude mice
Prostate, Pancreatic and
Melanoma, Head and Neck
Intraperitoneal 40. 42–56 No No Murtaza et al. (2009),Saleem et al. (2005, 2008),
Lee et al. (2007)
Balb/c Mice Inflammation Oral 2000 14 No No Bani et al. (2006)
Wister rats Inflammation Intra-dermal 50 8 No No Geetha and Varalakshmi (2001)
Wister rats Liver Oral 150 3 No No Sunitha et al. (2001)
Swiss albino mice Liver Gavage 25 7 No No You et al. (2003)
Wister rats Heart Intra-peritoneal 200 10 No No Frye and Leonard (1999)
Swiss albino mice Skin cancer Topical 75 4 No No Saleem et al. (2001)
Wister rats Liver Oral 50 30 No No Sudhahar et al. (2006a,b)
Wister rats Kidney Oral 35 21 No No Vidya et al. (2002)
Dogs Melanoma Intra-tumoral
injection
0.75–1.5 mg/tumor site 1 No No Hata et al. (2010)
288 H.R. Siddique, M. Saleem / Life Sciences 88 (2011) 285–293
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Jenkins et al., 2008; Weidner et al., 2008). Hypertension is known to cause
stroke, cardiac disorders and renal failure. A study by Saleem et al. (2003)
in experimental mice (exhibiting acetylcholine-induced hypertension)
showed that lupeol treatment (15 mg/kg) restores the blood pressure to
normal levels in these animals. This study implies that lupeol has a
potential to be developed as an agent for treating hypertension.
Hyperlipidemic condition is also reported to increase the incidence of
myocardial ischemia and cardiac arrest Sudhahar et al. (2007a,b).
Hyperlipidemia is a major risk factor for the premature development of
coronary heart disease. Hyperlipidemia is marked by increased levels of
total cholesterol, triglycerides and phospholipids concurrent with
aberrant activities of enzymes including lactate dehydrogenase, aspartate
aminotransferase, alanine aminotransferase and alkaline phosphatase.
These enzymes are associated with proper heart functioning Sudhahar et
al. (2007a,b).Sudhahar et al. (2007a,b) reported the therapeutic efficacy
of lupeol against the hyperlipidemic-induced heart malfunction in
animals. Lupeol treatment (50 mg/kg for 15 days) significantly prevented
the hypertrophic cardiac condition, and restored the normal ultra-
structural architecture in heart tissues of hyperlipidemic animals
Sudhahar et al. (2007a,b). In this study, lupeol was shown to restore the
altered activities of key enzymes needed for proper heart function
(Sudhahar et al., 2007a,b).
Lupeol has also been investigated for its cardioprotective potential in
animal receiving cyclophosphamide, a drug used in the treatment of
cancer and autoimmune disorders Sudharsan et al. (2005a, 2005b).
Cyclophosphamide treatment (200 mg/kg for 10 days) was reported to
significantly decrease the activity of ATPases and alter the levels of urea,
uric acid and creatinine in serum and urine of animals (Sudharsan et al.,
2005a,b). However, lupeol (50 mg/kg for 10 days) treatment was shown
to afford protection against cyclophosphamide-induced cardiotoxicity in
these mice (Sudharsan et al., 2005a). A similar report showed that lupeol
by modulating the activities of TCA cycle enzymes (succinate dehydro-
genase, malate dehydrogenase, and isocitrate dehydrogenase), and
inhibiting the swelling of mitochondria (numerous electron dense
granules and damaged cristae) affords protection against cyclophospha-
mide-induced mitochondrial-cardiomyopathy in animals (Sudharsan
et al., 2005b). Hypercholesterolemia is reported to cause severe
malfunctioning of the cardio-vascular system Sudhahar et al. (2006a,b).
Lupeol was tested for its anti-hypercholesterolemia activity in an
experimental rat model in which hypercholesterolemia was induced by
feeding animals a high cholesterol diet Sudhahar et al. (2006a,b).The
hypercholesterolemia animals exhibited severe myocardiac damages
such as increased lysosomal hydrolase activity in serum and heart,
decreased cellular thiol levels, and swollen myofibres Sudhahar et al.
(2006a,b). Lupeol (50 mg/kg) treatment to hypercholesterolemia animals
(exhibiting myocardiac damages) restored the altered levels of lysosomal
hydrolases and cellular thiol to normal Sudhahar et al. (2006a,b).Lupeol
treatment was also shown to restore the altered levels of lipoproteins and
lipid fractions to normal Sudhahar et al. (2006a,b).Recently,Reddy et al.
(2009) tested lupeol for antidyslipidemic activity in a dyslipidemic
hamster model. In this study, streptozotocin (100 mg/kg) treatment
caused an increase in the levels of triglycerides, glycerol and cholesterol in
hamster. However, when dyslipidemic hamsters were treated with lupeol
(50 mg/kg), a significant reduction in the levels of triglycerides, glycerol
and cholesterol (LDL) was observed. Further lupeol improved the
cholesterol (HDL) levels in dyslipidemic animals' hamster. Taken together,
these studies suggest that lupeol has the potential to be developed as a
therapeutic agent against cardiovascular diseases.
Lupeol as anti-inflammatory agent
Theroleoflupeolasananti-inflammatory agent has been discussed in
detail in a recently published review article from our laboratory (Saleem
2009). However, a brief account of lupeol as an anti-inflammatory agent is
presented here. Lupeol has been extensively studied for its ant-
inflammatory potential under in vitro and in vivo conditions (Geetha
and Varalakshmi 1999b, 2001; Lambertini et al., 2005; Sudhahar et al.,
NFkB cFLIP
Tumor
Initiation,
Promotion and
Progression
Lupeol
CyclinD1
Cell
Proliferation
ROS/RNS
Mutation
β
-catenin
Transcription of
TCF/LEF Genes
Lupeol
Bcl2
Anti-Apoptosis
Fig. 4. Flowchart represents the mechanism of action of lupeol in curtailing tumor
initiation, promotion and progression. ROS represents reactive oxygen species; RNS
represents reactive nitrogen species; TCF/LEF represents T-cell factor/lymphoid enhancer
factor; NFκB represents nuclear factor kappa B; cFLIP represents cellular form of FLICE
inhibitory protein and Bcl2 represents B-cell lymphoma 2.
Cancer
NFκB, PI3K/Akt , Wnt/β-
catenin, AR, Proteosome,
Kras, p53, cFLI P, Fas, DR3,
PKCα, MMP2, cMyc, Cyclin-
D1, p21, GST, GR
and CAT
Liver Toxicity
Acyl
-CoA cholesterol
acyltransferase
Diabetes
PTP1B and
α-glucosid ase
Inflammation
PGE2, Cox-2,
ILβ, IL2, IL4, I L5, IL6, IL13
Lox-15, TNFα, arachidonic acid ,
GSK3β, 15-sLO and IFN-γ-Th1
Arthritis
IL2, IFN-γ (Τh1),
ΙL4 (Th2), hyd roxy-
Proline and
glycosaminoglycans
Cardiovascular
Na+/K+/Ca2+-ATPase,
Succinate/malate/
isocit rate -
dehyd rogenase
Fig. 3. Pie diagram represents important molecular targets of lupeol for different human
diseases. NFκB represents nuclear factor kappa B; GST represents glutathione S-
transferase; GR represents Glutathione reductase; Cox-2 represent cyclooxygenase-2;
PGE2 represents prostaglandin E2; 15-sLO represents soybean 15-lipoxygenase; TNFα
represents tumor necrosis factorα,ILβrepresents Interleukin β,ILrepresentsInterleukin;
MMP2 represents matrix metalloproteinase; AR represents androgen receptor; PKCα
represents Protein Kinase C alpha; CAT represents Catalase; cFLIPrepresents cellularform
of FLICE inhibitory protein; DR3 represents death receptor 3; and PTP1B represents
tyrosine phosphatase 1B.
289H.R. Siddique, M. Saleem / Life Sciences 88 (2011) 285–293
Author's personal copy
2008a,b; Ashalatha et al., 2010). Employing inflammation-associated
mouse models, several studies have established the anti-inflammatory
potential of lupeol (Davis et al., 1994; Akihisa et al., 1996; Geetha and
Varalakshmi 1999b; Fernández et al., 2001a,b; Ramirez Apan et al., 2004;
Lima et al., 2007). Lupeol treatment has been shown to reduce the
inflammation in mouse models of arthritis and bronchial asthma (Geetha
and Varalakshmi, 2001; Vasconcelos et al., 2008). Comparative studies
conducted in rodent models of inflammation have shown that the anti-
inflammatory potential of lupeol is higher than indomethacin (a non-
steroidal anti-inflammatory drug), dexamethasone and α-Mangosteen,
(anti-inflammatory phytochemicals) (Latha et al., 2001; Vasconcelos et al.,
2008; Nguemfo et al., 2009). Published studies have provided evidence
that the efficacy of lupeol as an anti-inflammatory agent is due to its
potential to act on multiple molecular targets associated with inflamma-
tion (Vidya et al., 2000; Fernández et al., 2001a,b; Moreira et al., 2001; Bani
et al., 2006; Nguemfo et al., 2009). Lupeol is reported to modulate the
expression level of several inflammation associated molecules such as
soybean 15-lipoxygenase (15-sLO), tumor necrosis factor α(TNFα),
Interleukin β(ILβ), prostaglandin E2 (PGE2), cytokines (IL-2, IL-4, IL-5, IL-
6, IL-13, IFN-γ-Th1), myeloperoxidase, macrophages and T-lymphocytes
(Akihisa et al., 1996; Vidya et al., 2000; Fernández et al., 2001a, 2001b;
Moreira et al., 2001; Bani et al., 2006; Ding et al., 2009; Nguemfo et al.,
2009).
Lupeol as skin protective agent
Earlier, we showed that lupeol pretreatment alleviates the toxicity
induced by benzoyl peroxide (a chemical widely used in skin care
products) in skin tissues of Swiss Albino mice (Saleem et al., 2001). The
skin protective effects of lupeol were observed to be associated with its
potential to enhance the skin anti-oxidant system (Saleem et al., 2001).
A study employing an in vitro model of human skin keratinocytes
(epidermal explants) cultured at an air–liquid interface on a de-
epidermized human dermis was conducted to investigate the skin
repairing potential of lupeol (Nikiéma et al., 2001). Lupeol treatment
was observed to significantly repair the damaged skin by inducing
differentiation of keratinocytes with a well-formed stratum corneum
(Nikiéma et al., 2001). Chronic inflammation is known to delay healing
of worn or damaged tissues (Harish et al., 2008). Chronic inflammation
renders damaged tissues to ulceration and irregular tissue growth
(Harish et al., 2008). An excision,incision and dead space wound animal
model is a well tested model to study wound healing and associated
mechanisms (Harish et al., 2008). Utilizing this wound healing model,
Harish et al. (2008) showed that topical application of lupeol (8 mg/ml
0.2% sodium alginate gel) enhances significant wound healing activity.
The wound healing activity of lupeol was found to be higher than
nitrofurazone, a well known skin ointment used for wound healing
(Harish et al., 2008). Aleo vera herb is well known for its skin care
properties and is widely used in skin care products (Davis et al., 1994;
Majeed and Prakash, 2005). The anti-inflammatory and soothing
properties of the Aloe plant have been associated with presence of
two major compounds i.e. Salicylic acid and lupeol (Davis et al., 1994).
Shea butter and its derivatives have been known to the cosmetics
industry for a long time and are excellent emollients for both skin and
hair care applications. It is to be noted that Shea butter possesses a
significant amount (20%) of lupeol (Alander and Andersson, 2005).
Since lupeol is reported to be useful in maintaining skin texture and
integrity, several lupeol-based anti-aging skin creams have been
reported to be under development (Davis et al., 1994; Harish et al.,
2008; Alander and Andersson, 2005; Majeed and Prakash, 2005). These
reports suggest the use of lupeol in anti-aging creams, lotions, gels and
lip balms, with use levels ranging from 0.2 to 3% w/w in formulations
(Davis et al., 1994; Harish et al., 2008; Alander and Andersson, 2005;
Majeed and Prakash, 2005). Recent reports suggest that several lupeol
based anti-aging and anti-fungal skin creams are under development
(Majeed and Prakash, 2005).
Lupeol as hepatoprotective agent
Lupeol has been investigated for its hepatoprotective potential
(Al-Rehaily et al., 2001 and references therein). A recent study showed
that lupeol affords protection against aflatoxin B1, a potent hepatotoxic
agent when tested under in vivo conditions (Al-Rehaily et al., 2001).
Aflatoxin feeding causes peroxidative damage in liver tissue and
increases serum levels of liver function enzymes viz; lactate dehydro-
genase, alkaline phosphatase, alanine and aspartate aminotransferases
(Al-Rehaily et al., 2001). However, oral administration of lupeol
(100 mg/kg) for 7 days caused a reversal in the altered levels of
biomarker enzymes to their normal levels in aflatoxin-treated mice
(Al-Rehaily et al., 2001). Interestingly, the hepato-protective effect of
lupeol was shown to be more than silymarin, a well-known natural
hepatoprotective agent (Al-Rehaily et al., 2001). Recently, Prasad et al.
(2007) showed that lupeol and lupeol-rich mango pulp extract inhibits
7, 12-dimethylbenz(a) anthracene (DMBA)-induced liver damage in a
mouse model. Lupeol supplementation (25 mg/kg/day) for 7 days
effectively inhibited oxidative stress and restored mitochondrial
transmembrane potential in liver tissues of DMBA-treated mice (Prasad
et al., 2007). Several studies have been conducted to examine the
beneficial role of lupeol against other possible conditions which cause
hepatic ailments. One of the important discoveries in this direction was
astudybySudhahar et al. (2006a,b) which showed that lupeol could
ameliorate hypercholesterolemia-induced liver damage in experimen-
tal animals. Lupeol (50 mg/kg) treatment for 15 days significantly
alleviated the liver function abnormalities and increased fecal excretion
of cholesterol in hypercholesterolemic rats (Sudhahar et al., 2006a,b).
Importantly, lupeol was reported to significantly induce the levels of
vitamin C and E in hypercholesterolemic animals (Sudhahar et al.,
2006a,b). Increased hepatic lipid profile along with abnormalities in
lipid-metabolizing enzyme activities (marked by increased expression
of acyl-CoAcholesterol acyltransferase mRNA) and altered liver function
enzymes were observed in hypercholesterolemic rats (Sudhahar et al.,
2006a,b). Lupeol significantly alleviated altered liver function by
restoring normal activities of lipid metabolizing enzymes (Sudhahar
et al., 2006a,b). Another report where oral administration of lupeol
(150 mg/kg/day) alleviated the metal-induced hepatotoxicity in a rat
model validated the hepatoprotective potential of lupeol (Sunitha et al.,
2001).
Lupeol as nephroprotective agent
Lupeol has been tested in several studies for its protective efficacy
against renal ailments. Multiple reports have established the protective
role of lupeol in animal models of urolithiasis (stone formation in
kidney) (Malini et al., 1995; Vidya et al., 2000, 2002; Shirwaikar et al.,
2004; Sudhahar et al., 2008). Animals treated with 2% solution of
ammonium oxalate for 15 days induced hyperoxaluric condition in rats
(Malini et al., 1995; Vidya et al., 2000, 2002; Sudhahar et al., 2008).
These animals exhibited kidney malfunction, renal tissue damage and
renal stones as validated by increased urinary excretion of oxalate;
reduced citrate and glycosaminoglycans and increased levels of lactate
dehydrogenase, inorganic pyrophosphatase, alkaline phosphatase,
gamma glutamyl transferase, β-glucuronidase and N-acetyl β-D
glucosaminidase (Malini et al., 1995; Vidya et al., 2000, 2002;Sudhahar
et al., 2008). Lupeol treatment restored the altered levels of renal
function enzymes in these animals. Lupeol treatment was observed to
decrease the deposition of stone forming constituents in the kidney of
urolithiatic animals (Malini et al., 1995; Vidya et al., 2000, 2002;
Sudhaharet al., 2008a,b). In a study, stone formation was induced in rats
(by administration of a pyridoxine deficient diet containing 3% glycollic
acid for 21 days) thus leading to increased excretion of stone forming
constituents such as calcium, oxalate and uric acid (Vidya et al., 2002).
These animals exhibited increased crystal deposition and renal tubular
damage which was evident from the altered levels of renal function
enzymes (Vidya et al., 2002). Interestingly, when these animals received
lupeol (50 mg/kg) treatment, stone formation and stone deposition
290 H.R. Siddique, M. Saleem / Life Sciences 88 (2011) 285–293
Author's personal copy
activity was highly decreased (Vidya et al., 2002). Oral administration of
lupeol was observed to significantly reverse the abnormal biochemical
and histological aberrations in these animals (Vidya et al., 2002).
Humans are constantly exposed to metals and some patients are
even treatedby metal based drugs. However, metal toxicitymanifests in
the form of renal failure. A study by Nagaraj et al. (2000) showed that
lupeol has the potential to afford protection against metal-induced
nephrotoxicity in rats. Lupeol supplementation (40 mg/kg) concurrent
with cadmium administration inhibited the cadmium-induced oxida-
tive damage in renal tissues of rats (Nagaraj et al., 2000). A similar study
showed thatoral administration of lupeol (40 and 80 mg/kg) for 10 days
decreases the concentration of blood urea nitrogen, creatinine and lipid
peroxidation, and increased glutathione and catalase activities in
cisplatin (5 mg/kg)-induced nephrotoxicity in rats (Nagaraj et al.,
2000). The association between hypercholesterolemia and kidney
damage has been widely reported (Sudhahar et al., 2008a,b). The
oxidative stress and inflammatory responses are involved in renal
injury, which is upregulated in hypercholesterolemic condition. Lupeol
has been shown to afford protection from the development of
hypercholesterolmic condition in animals in which hypercholesterol-
emia was induced by feeding a high cholesterol diet (HCD) to rats for
30 days (Sudhahar et al., 2008a,b). Hypercholesterolemia in HCD-fed
rats is marked by increased levels of renal total cholesterol, triglycerides
and phospholipids, along with altered serum biochemical parameters of
tissue injury indices and elevated activities of renal marker enzymes
(lactate dehydrogenase and alkaline phosphatase) (Sudhahar et al.,
2008a,b).
Renal lysosomal acid hydrolase activities (ACP, β-Glu, β-Gal, NAG
and Cat-D), acute phase proteins like C-reactive protein and fibrinogen
were significantly increased in HCD-fed rats, indicating the increased
inflammation in the tissues (Geetha et al., 1998). Lupeol effectively
restored renal functional enzyme levels to normal in HCD-fed animals.
Lupeol treatment also decreased renal lysosomal acid hydrolase
activities in HCD-fed rats (Geetha et al., 1998). Taken together, these
studies suggest the chemoprotective potential of lupeol against various
types of renal abnormalities.
Perspectives for clinical trials
Data obtained from in vitro and in vivo studies are promising and
further evaluation of lupeol as a candidate therapeutic agent for
different human diseases (including those not mentioned in this mini-
review) appears warranted. To test the clinical utility of lupeol, detailed
investigations are warranted in animal models which develop diseases
spontaneously. Steps are being taken in this direction by our laboratory
and others. Recently, Hata et al. (2010) tested lupeol in dogs suffering
from melanoma. This study involving 7 cases, for the first time provided
information about the clinical utility of lupeol in treating diseases. In this
study, dogs suffering from metastatic melanoma were treated with
lupeol (0.75–1.5 mg). Lupeol administration was reported to result in
the regression of melanomain cases I and II. In case III, lupeol treatment
induced the increase in melanosomes and caused differentiation of
melanoma cells. In cases V–VII, lupeol was tested as an adjuvant to
immunotherapeutic agents to treat melanoma. It is interesting to note
that in case V–VI, melanoma was completely disappeared, however, in
case VII, no beneficial effect of lupeol treatment was observed. This
study concluded that lupeol was successful in 6 out of 7 cases whichis a
promising outcome of treatment, however, fine tuning of interval of
administration, concentration and doses, could enhance the potency of
lupeol under clinical settings. This study opens the window of
opportunity for more preclinical studies and clinical trials to validate
the usefulness of lupeol either alone or in combination with existing
therapies. However, caution is needed in extrapolating the information
obtained from animal studies to humans due to the inter-species
differences.
Perspectives for improvement of activity
Lupeol has high bioavailability (Siddique et al., unpublished data),
however the introduction of synthetic analogs may enhance the potency
and bioavailability of lupeol. This is based on report where synthetic
derivatives of lupeol were observed to exhibit more pharmacological
efficacy than lupeol (Hodges et al., 2003; Sudhahar et al., 2007a,b,
2008a,b). Further, to enhance its pharmacological activity, the effective
dose of lupeol could be fine-tuned after thorough pharmaco-kinetic
studies. Further, factors such as effective dose and the duration of
treatment should be taken into account when lupeol is investigated for its
therapeutic purposes for different diseases under varied conditions.
Conflict of interest statement
None.
Acknowledgements
The referenced work from author'slaboratory is supported by United
States PHS grants (CA133807; CA130064) and AICR grant (09A074) to
the corresponding author.
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