International Journal of Cancer Research and Treatment
ANTICANCER RESEARCH 35: 3137-3146 (2015)
Anticancer Effects of Sandalwood (Santalum album)
and CHANDRADHAR DWIVEDI
Department of Pharmaceutical Sciences, South Dakota State University, Brookings, SD, U.S.A.
.A. ABRAHAMSSON, Malm
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. AKIMOTO, Kashiwa, Chiba, Japan
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. S. BRULAND, Oslo, Norway
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. R. F. KRUEGER, K
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Abstract. Effective management of tumorigenesis requires
development of better anticancer agents with greater efficacy
and fewer side-effects. Natural products are important
sources for the development of chemotherapeutic agents and
almost 60% of anticancer drugs are of natural origin. α-
Santlol, a sesquiterpene isolated from Sandalwood, is known
for a variety of therapeutic properties including anti-
inflammatory, anti-oxidant, anti-viral and anti-bacterial
activities. Cell line and animal studies reported
chemopreventive effects of sandalwood oil and α-santalol
without causing toxic side-effects. Our laboratory identified
its anticancer effects in chemically-induced skin
carcinogenesis in CD-1 and SENCAR mice, ultraviolet-B-
induced skin carcinogenesis in SKH-1 mice and in vitro
models of melanoma, non-melanoma, breast and prostate
cancer. Its ability to induce cell-cycle arrest and apoptosis
in cancer cells is its most reported anticancer mechanism of
action. The present review discusses studies that support the
anticancer effect and the mode of action of sandalwood oil
and α-santalol in carcinogenesis.
Plants are important natural sources of anticancer compounds
and many anticancer agents in current use have been isolated
from various plant sources (1). A majority of
chemotherapeutic agents, including those isolated from plants
such as taxol and vincristine, induce cancer cell apoptosis. At
the same time, they also severely damage normal cells of the
host (2). The sandalwood tree and its products have been
known for their medicinal properties since ancient times. A
number of studies including those from our laboratory have
shown anticancer effects of sandalwood oil and its major
chemical constituent α-santalol, without causing any visible
side-effects (3-14). It is non-mutagenic and has low acute oral
and dermal toxicity in laboratory animals (15).
Sandalwood is a root hemiparasitic tree belonging to the
family Santalaceae and depends on host trees to obtain
nutrients for its growth. The wood is highly aromatic and is
the second most expensive type of wood in the world, after
African Blackwood, Dalbergia melanoxylon (16).
Sandalwood grows in tropical Asia, Australia, Pacific islands
and Hawaii. There are many species of sandalwood, one of
which the Indian sandalwood (Santalum album Linn.)
(Figure 1A), called the ‘Royal Tree’ in India (17), is a well-
known and economically important species, having the most
fragrant wood and highest oil content. It has been
categorized as ‘vulnerable’ by the International Union for
Conservation of Nature (IUCN) in 1997 (16). Historically,
sandalwood is considered as one of the most sacred trees and
an important part of devotional and spiritual rituals of certain
religions. Statues of gods and parts of many ancient temples
have been made of this wood. The Egyptians used it in
embalming the dead and in ritual burning to venerate the god
(16). The products of sandalwood have been widely used for
incense, wood carving, funeral pyres; in the food industry as
a flavor ingredient, and in insect repellents, perfumes, soaps,
detergents and cosmetics to add fragrance.
The essential oil of sandalwood develops in the heartwood
and root of the trees and this process requires about 15 to 20
years. Fully matured trees of 60-80 years develop the
greatest oil content with high quality and a high level of
fragrance. The average yield of the essential oil is 4.5-6.25%
with Santalum album, the highest being in the roots (up to
10% in weight) (18). More than 230 constituents that belong
to different chemical classes have been identified in the
heartwood. These are mainly terpenoids (18). Phytochemical
evaluation of sandalwood extracts revealed that the tree is
rich in saponin, phenolics and tannins in addition to
Current Address: Department of Medicine, Division of
Gastroenterology and Nutrition, Loyola University Chicago,
Maywood, IL, U.S.A.
Correspondence to: Dr. Chandradhar Dwiwedi, Department of
Pharmaceutical Sciences, South Dakota State University, Brookings,
SD, U.S.A. E-mail: firstname.lastname@example.org
Key Words: Sandalwood, santalol, cancer, apoptosis, cell cycle,
carcinogenesis, angiogenesis, review.
ANTICANCER RESEARCH 35: 3137-3146 (2015)
Anticancer Effects of Sandalwood (Santalum album)
and CHANDRADHAR DWIVEDI
Department of Pharmaceutical Sciences, South Dakota State University, Brookings, SD, U.S.A.
Properties of Sandalwood Oil
The chipped heartwood is used for extraction of
commercially valuable sandalwood oil by steam distillation.
The oil is colorless to yellowish and viscous (5). In addition
to the Indian sandalwood, the Australian sandalwood
(Santalum spicatum) and Hawaiian Sandalwood (Santalum
ellipticum) are two major species used for the production of
sandalwood oil. The compositions of the oils are different
and the quality of Indian sandalwood is considered superior.
The major constituent of sandalwood oil is santalol, a
mixture of two isomers, α-santalol and β-santalol (C
(Figure 1B and C). These are the two molecules mainly
associated with sandalwood’s fragrance (18, 20), while α-
santalol is mainly reported for its anticancer properties (5-
14). α-Santalol is a sesquiterpene with a molecular weight
of 220.35 g mol
, boiling point of 166˚C and density of
. Nikiforov et al. identified α-santalene, α-
santalal, β-santalal, epi-β-santalal, α-santalol, β-santalol, (E)-
β-santalol, α-bergamotol and spirosantalol as the odorant
components in sandalwood oil (21). α-Santalol has a slightly
woody fragrance, while β-santalol is responsible for the
highly prized typical warm-woody, milky, musky, urinous,
animal aspects of sandalwood (18).
Isolation of α-Santalol from Sandalwood Oil
Our laboratory isolated α-santalol from sandalwood oil by
column chromatography with n-hexane:ethyl acetate (3:1) as
a solvent system (13). Different fractions were analyzed by
thin-layer chromatography and the purity was assessed by
gas chromatography–mass spectrometry (22). Studies
indicated that the major component of sandalwood oil is α-
santalol, constituting 61%, followed by β-santalol at 28%
(5). Other constituents include cisnuciferol, α-bisabalol,
cisbergamatol, epi-β-santalol, γ-curcumen-12-ol, β-
curcumen-12-ol, cis-lanceol and trans-farnesol (23).
The products of Santalum album have been used for the
treatment of various diseases since ancient times. It is non-
toxic and exhibits a wide variety of medicinal properties
including anti-microbial, anti-oxidant, anti-inflammatory,
anti-spasmodic, diuretic, expectorant and antiseptic activities.
In Chinese medicine, sandalwood products are used to treat
dysentery, stomach ache, gonorrhea, skin diseases, and
anxiety (24). Emulsion, paste and essential oil of sandalwood
have been used for centuries in India for the treatment of
inflammatory and eruptive skin diseases (25-27). It is used
in the traditional Unani system of medicine to treat gastric
ulcers and various cardiac, brain, liver, stomach and skin
disorders (28, 29). Anti-ulcer potential of hydro-alcoholic
extract of Santalum album stem at 500 mg/kg was reported
in gastric ulceration models of albino Wistar rats (28).
Sandalwood oil is widely used in aromatherapy to relieve
anxiety, stress, and depression (30). It has neuroleptic,
relaxing, soothing, bronchial dilating and astringent effects.
α-Santalol has been reported to have central nervous system
depressant effects, such as sedation (31). It promotes restful
sleep and helps to ease an anxious mind. In sleep-disturbed
rats, inhalation of α-santalol affected the sleep-wake cycle,
and caused a significant decrease in total waking time and
an increase in total non-rapid eye movement sleep time.
Results also suggest the action of α-santalol via the
circulatory system by absorption into the blood through the
respiratory mucosa rather than the olfactory system (31). The
results of a pilot study in patients receiving palliative care to
ANTICANCER RESEARCH 35: 3137-3146 (2015)
Figure 1. A: Sandalwood tree (Santalum album). Structure of α-santalol (B) and β-santalol (C).
evaluate the effectiveness of aromatherapy support the notion
that sandalwood oil is effective in reducing anxiety (32).
Antimicrobial activity of leaf and stem aqueous extracts
of Santalum album were observed against Escherichia coli,
Staphylococcus aureus and Pseudomonas, in which leaves
extract showed significantly higher inhibition when
compared to stem extract (33). In another study, the
antibacterial activity of the aqueous extract was evaluated
against two strains of Escherichia coli, one each of
Klebsiella pneumoniae, Klebsiella oxytoca, Pseudomonas
aeruginosa, Staphylococcus aureus, Bacillus subtilis and
Aeromonas species. It showed strongest inhibitory activity
of 87% against Staphylococcus aureus whereas there was no
inhibition of Escherichia coli and Bacillus subtilis. For the
other strains, the inhibition was between 66% and 78% (34).
Sandalwood oil had in vitro antiviral activity against Herpes
simplex virus (HSV)-1 and HSV-2. It inhibits viral
replication in a dose-dependent manner and is more effective
against HSV-1 (35).
Anticancer Effects of Sandalwood Oil
Chemoprevention is a means of cancer control by the use of
natural or synthetic agents allowing suppression, retardation
or reversion of carcinogenesis (36). Chemopreventive agents
can be broadly classified as blocking and suppressive agents.
The blocking agents inhibit the initiation step by preventing
carcinogenic agents from reaching or acting on critical target
sites, whereas suppressive agents inhibit malignant cell
proliferation during the promotion and progression steps of
carcinogenesis (37). The available experimental evidence
suggests that sandalwood oil could function as an inhibitor
of tumor initiation and promotion stages of carcinogenesis.
Studies in male Swiss albino mice indicate the
anticarcinogenic potential of sandalwood oil via enhancing
the excretion of carcinogens. In that study, oral gavage
feeding of sandalwood oil induced a time- and dose-
responsive increase in the activity of glutathione-S-
transferase (GST) and acid soluble sulfhydryl levels in the
liver (38). GSTs are a family of phase II detoxification
enzymes that function to protect cellular macromolecules
from attack by reactive electrophiles. They catalyze the
conjugation of glutathione to a wide variety of endogenous
and exogenous electrophilic compounds, leading to the
elimination of toxic compounds (39). Enhancement of GST
activity and acid-soluble sulfhydryl levels indicate a possible
chemopreventive action of sandalwood oil on carcinogenesis
through a blocking mechanism.
Studies from our laboratory have shown skin cancer
chemopreventive effects of sandalwood oil in chemically
induced skin carcinogenesis in CD-1 mice. Topical
application of sandalwood oil (5% in acetone, w/v) prevented
skin tumor development initiated by 7,12-dimethylbenz
[a]anthracene (DMBA) and promoted by 12-O-tetradecanoyl
phorbol-13-acetate (TPA) and TPA-induced ornithine
decarboxylase (ODC) activity in CD-1 mice. It significantly
reduced papilloma incidence by 67%, multiplicity by 96%,
and TPA-induced ODC activity by 70% (3). Sandalwood oil
pre-treatment reduced papilloma incidence and multiplicity
in a concentration- and time-dependent manner in CD-1
mice. Pre-treatment with 5% sandalwood oil 1 hour before
DMBA and TPA treatments produced the most effective
chemopreventive effects (4).
A recent study on HaCat keratinocytes reported the
induction of autophagic cell death with Indian sandalwood
oil treatment (40). A number of autophagy-modulating
agents have been proposed as potential anticancer
therapeutics when used as either single or combinatorial
treatments (41). Autophagy is a self-degradative process
which involves the engulfment and degradation of
cytoplasmic components within lysosomes. It is designated
as type II programmed cell death, while the process of
apoptosis is referred to as programmed cell death type I (41).
Treatment of HaCat cells with sandalwood oil up to a
concentration of 0.0005% resulted in a concentration-
dependent reduction of UV-induced activator protein-1
activity and inhibition of cellular proliferation. UV-induced
activator protein-1 activity has been linked to cellular
proliferation and survival and is a major causative factor in
UV-induced skin cancer. Study showed an induction of
microtubule-associated protein light chain 3-II (LC3-II)
formation and poly (ADP-ribose) polymerase (PARP)
cleavage by UV-irradiation. However, sandalwood oil
treatment blocked PARP cleavage and UV-induced apoptosis
but increased the level of LC3-II formation, which is marker
of active autophagosome formation (40).
Studies on J82 human bladder cancer cells showed that
sandalwood oil induced cell death via DNA damage and cell-
cycle arrest (42). In this study, sandalwood oil was shown to
up-regulate growth arrest genes [(Growth arrest and DNA-
damage-inducible protein 45 alpha (GADD45A), GADD45B,
and protein phosphatase 1 regulatory subunit 15A
(PPP1R15A)] and proapoptotic genes [(Caspase 9 and
Inhibitor of growth protein 5 (ING5]. Sandalwood oil
treatment led to negative regulation of protein kinase activity
and activation of G-protein-coupled receptors. In addition, the
expression of transcription factors, such as Activating
transcription factor 3 (ATF3), DNA damage-inducible
transcript 3 (DDIT3), Early growth response protein 1
(EGR1), FOSB, JUN, JUNB, MYC, and several inhibitors of
DNA binding (ID1, ID2, and ID3), along with members of the
zinc finger family were also modulated by sandalwood oil.
In another study, five lignans isolated from sandalwood
heartwood were evaluated for their cytotoxic activities
against HL-60 human promyelocytic leukemia cells and
A549 human lung adenocarcinoma cells (43). Two of these
Santha and Dwivedi: Anticancer Effects of Santalum album (Review)
compounds exhibited cytotoxicity against HL-60 cells with
values of 1.5 and 4.3 μM, and against A549 cells with
values of 13.6 and 19.9 μM, respectively. These tumor
cell deaths were shown to be mediated through induction of
apoptosis. The aldehyde group was identifided as a structural
requirement for the appearance of cytotoxicity in this type
Anticancer Effects of α-Santalol
The efficacy of α-santalol as chemopreventive agent appears
to be very promising in skin cancer control. Studies from our
laboratory indicated the chemopreventive potential of α-
santalol similar to that of sandalwood oil in DMBA-initiated
and TPA-promoted skin tumors in CD-1 and SENCAR mice
(5). Chemopreventive effects were determined during the
initiation and promotion phases; α-santalol treatment did not
show any significant effects during initiation phase.
However, it significantly prevented papilloma development
during the promotion phase of the DMBA and TPA
carcinogenesis protocol in both CD-1 and SENCAR mice.
The treatment resulted in a significant inhibition of TPA-
induced ODC activity and incorporation of
DNA in the epidermis of both strains of mice. Since DMBA-
induced initiation was not affected by treatment, the
anticancer effects of α-santalol on TPA-induced promotion
is unlikely to be due to the blocking of TPA absorption.
In chemically-induced skin carcinogenesis, α-santalol
reduced tumor incidence and multiplicity in a time- and
concentration-dependent manner in a dose–response study.
Maximum effect was shown by 5% of α-santalol compared
to 1.25% and 2.5% and it significantly reduced skin tumor
incidence and multiplicity, and inhibitied TPA-induced ODC
activity and DNA synthesis (6). In animal models, topical
application of α-santalol used at concentrations of 2.5 and
5% (w/v in acetone) did not result in any visible side-effects.
Gas chromatography–mass spectrometry studies detected α-
santalol in the serum, skin, and liver of animals which
received topical application of α-santalol and suggested
systematic absorption of α-santalol in its chemopreventive
In addition to chemically-induced skin carcinogenesis, α-
santalol had a strong chemopreventive potential in UVB-
induced skin tumorigenesis of SKH-1 hairless mice under
three different protocols (DMBA-initiated and UVB-
promoted; UVB-initiated and TPA-promoted and UVB-
initiated and UVB promoted) (8). The treatment was most
effective, with 72% reduction in tumor multiplicity on UVB-
induced complete tumorigenesis. In another study on UVB-
induced skin tumor development, α-santalol was shown to
inhibit in vitro lipid peroxidation in skin and liver
microsomes and prevent tumor development possibly by
acting as an anti-peroxidant (9). In dose-response study, 5%
α-santalol led to optimal chemoprevention as compared to
1.5% and 2.5%, and the minimum possible concentration of
α-santalol potentially able to reduce UVB-induced skin
tumor development was identified as 2.5% (9). A study
which used a physiologically relevant dose of UVB (30 mJ
) to induce photocarcinogenesis in SKH-1 mice showed
that α-santalol pretreatment has potential to target various
pathways involved in photocarcinogenesis. This dose of
UVB is in the range of human exposure to sunlight that can
cause skin cancer (14). α-Santalol has been shown to
suppress proliferation of non-melanoma and melanoma skin
cancer cells in culture (7, 11).
Recent studies demonstrated the anticancer effects of α-
santalol in non-skin cancer models including breast and
prostate cancer. Studies on PC-3 and LNCaP human prostate
cancer cell lines, as well as in PC-3 tumor xenograft models,
demonstrated the efficacy of α-santalol against androgen-
dependent and -independent prostate cancer (12, 45). In both
studies, α-santalol produced less toxic effects on normal
cells. In PC-3 tumor xenograft models, α-santalol had a
chemopreventive effect at the level of tumor promotion by
inhibiting angiogenesis and growth of prostate tumor. We
reported the anti-neoplastic effects of α-santalol on estrogen
receptor-positive and -negative breast cancer cells (13). A
strong time and concentration-dependent reduction in cell
viability and proliferation was observed in MCF-7 and
MDA-MB-231 cells treated with 10-100 μM concentrations
of α-santalol. At the same time, normal breast epithelial cell
line, MCF-10A was more resistant to α-santalol treatment.
Our laboratory is investigating the transdermal and
transmammary application of α-santalol for the prevention
and treatment of breast cancer in animal models. Tumor-
selective cytotoxicity of santalol derivatives were shown in
a study on HL-60 human promyelocytic leukemia cells (46).
Mechanisms of Action of α-Santalol
Induction of cell-cycle arrest. Various in vitro and in vivo
studies have shown strong anticancer activities of α-santalol
mediated by different modes of action. The most published
anticancer mechanism of action of α-santalol is its ability to
induce cell-cycle arrest and apoptosis in cancer cells.
Cellular growth and proliferation is a highly regulated event,
in which complex series of signaling pathways control the
growth and division of DNA. Disorders in the regulation of
the cell cycle can lead to uncontrolled proliferation and
contribute to a malignant phenotype. The cell cycle consists
, S, G
and M phases in which G
phases between the processes of DNA synthesis (S phase)
and mitosis (M phase), respectively (47). Progression of the
cell cycle through each phase is regulated by specific cyclin
and cyclin-dependent kinase (CDK) complexes. Bindings of
ANTICANCER RESEARCH 35: 3137-3146 (2015)
CDK inhibitory proteins such as p21 and p27 negatively
regulate the cell cycle (48, 49).
Previous studies from our laboratory on non-melanoma
and melanoma skin cancer cells indicated G
/M phase cell-
cycle arrest upon α-santalol treatment in p53-mutated A431
human epidermoid carcinoma cells and p53 wild-type
UACC-62 human melanoma cells (11). α-Santalol up-
regulated the expression of wild-type p53 in UACC-62 cells
and suppressed the expressions of mutated p53, along with
up-regulation level of CDK-inhibitor p21 in A431 cells.
Further studies indicated a p53- and p21-independent G
phase arrest in these cells. Knockdown of p21 in A431 cells
or knockdown of both p21 and p53 in UACC-62 cells did not
/M phase arrest caused by α-santalol treatment.
Furthermore, in UACC-62 cells, α-santalol treatment caused
microtubule depolymerization similar to the positive control
vinblastine used in the study.
Consistent with the studies on skin cancer cells, our
studies on MCF-7 (p53 wild-type) and MDA-MB-231 (p53-
mutated) breast cancer cells also showed α-santalol induced
/M phase cell-cycle arrest regardless of their estrogen
receptor or p53 status (13). Up-regulation of p21 along with
suppressed expression of mutated p53 was observed in
MDA-MB-231 cells. On the contrary, α-santalol did not
increase the expression of wild-type p53 and p21 in MCF-7
cells. α-Santalol-induced cell-cycle arrest was associated
with a decrease in the protein levels of G
cyclins (cyclins A and B), CDKs (CDK2 and CDC2),
CDC25B and CDC25C accompanied by strong increase of
phospho-CDC25C (Ser216) in both cell lines (13). Cyclin A
is able to bind CDK2 and CDC2 and promote the cell-cycle
progression through S and G2 phases. Entry into mitosis is
regulated by the activation of cyclin B–CDC2 complex (47).
Down-regulation of CDK activity involves phosphorylation
at Thr 14 and Tyr 15; dephosphorylation of these residues
and activation of CDKs for cell-cycle progression is
controlled by members of the CDC25 phosphatase family
(50, 51). CDC25B and CDC25C play an important role in
/M transition. CDC25B dephosphorylates and activates
CDK2–cyclin A and CDC2–cyclin B, whereas CDC25C
dephosphorylates and activates CDC2–cyclin B mitotic
kinase complex and thereby permits cell entry into mitosis.
Phosphorylation of CDC25C at Ser-216 block the cells from
mitotic entry (52).
In the UVB-induced skin carcinogenesis of SKH1 hairless
mouse, inhibition of cyclins and CDKs of different cell-cycle
phases were observed in a group pretreated with α-santalol
(14). UVB exposure interrupts the cell-cycle checkpoint
controls of epidermal cells and hence the resulting tumors
are associated with an increase in cell-cycle-regulatory
cyclins and CDKs, or decreased expression of CDK
inhibitors. Significant decrease in the expression of cyclins
A, B1, D1 and D2 and CDKs [Cdk1 (CDC2), CDK2, CDK4
and CDK6] and up-regulation of p21 were found in α-
santalol-pretreated group. α-Santalol treament before UVB
radiation strongly inhibited UVB-induced epidermal
hyperplasia and the thickness of the epidermis and
significantly reduced the expression of proliferation markers,
proliferating cell nuclear antigen and Ki-67 (14).
Induction of apoptosis by α-santalol. Most anticancer drugs
in current use primarily act by inducing apoptosis in target
cells. Studies from our laboratory demonstrated the induction
of apoptosis by α-santalol in various cancer cell lines and in
vivo cancer models (7, 10, 12-14). Apoptosis is programmed
cell death characterized by the activation of a group of
intracellular cysteine proteases called caspases. In apoptotic
pathways, caspase-3 functions as an executioner caspase and
its activation leads to cleavage of various substrates,
including PARP (53). In UVB-induced skin carcinogenesis,
topical application of α-santalol before each UVB exposure
resulted in the activation of caspase-3 and cleavage of PARP
in skin of SKH-1 hairless mice, indicating its photoprotective
effect through induction of apoptosis (14). In another study,
α-santalol prevented skin cancer development in UVB-
irradiated mouse skin by inducing pro-apoptotic proteins via
an extrinsic pathway (10). In vitro studies using A431 skin
cancer cells indicated the involvement of both caspase-
dependent and -independent pathways of apoptosis in
response to α-santalol treatment (7). In this study, apoptosis
was found to be primarily through the intrinsic pathway with
loss of mitochondrial membrane potential, release of
cytochrome c, and subsequent activation of caspase-9 and
caspase-3 in response to α-santalol treatment.
α-Santalol induced apoptotic cell death through extrinsic
and intrinsic pathways in MCF-7 and MDA-MB 231 human
breast cancer cell lines (13). Treatment with α-santalol
induced activation of both caspase-8 and caspase-9. The
executioner caspases involved in α-santalol-mediated
apoptosis in MDA-MB-231 cells are caspase-3 and caspase-
6, and in MCF-7 cells, α-santalol led to the activation of
caspase-6 and caspase-7, along with strong cleavage of
PARP in both cell lines.
α-Santalol effectively suppressed the growth of androgen-
dependent LNCaP and androgen-independent PC3 human
prostate cancer cells by causing caspase-3 activation, and
inducing apoptosis (12). The LNCaP cell line, which
expresses wild-type p53, was relatively more sensitive to
apoptosis induction by α-santalol compared to p53-deficient
PC-3 cells. The α-santalol-induced apoptotic cell death and
activation of caspase-3 was significantly attenuated in the
presence of pharmacological inhibitors of caspase-8 and
caspase-9. In another study, seven α-santalol derivatives from
the heartwood of Santalum album were evaluated for
cytotoxicity against HL-60 human promyelocytic leukemia
cells and TIG-3 normal human diploid fibroblasts. One of the
Santha and Dwivedi: Anticancer Effects of Santalum album (Review)
derivatives exhibited tumor-selective cytotoxicity through
induction of caspase-dependent apoptosis of HL-60 cells (46).
Anti-inflammatory effects of α-santalol. Many scientific
studies have supported the anti-inflammatory activities of
sandalwood oil and α-santalol. Potential anti-inflammatory
action of sandalwood oil was shown in a clinical trial of
sandalwood oil-containing treatment regimen for eight weeks
in 50 patients with mild to moderate facial acne (54).
Treatment was well tolerated by nearly all patients and 89%
of patients showed improvement in their disease, with
notable reductions in lesion counts in patients with more
severe or inflamed lesions. In another study, topical
application of sandalwood oil and turmeric-based cream
effectively prevented radiation-induced dermatitis in patients
with head and neck cancer who were undergoing
radiotherapy (55). In male Sprague–Dawley rats, inclusion
of sandalwood seed oil in their diet affected the levels of
several inflammatory factors. Sandalwood seed oil inhibited
the generation of pro-inflammatory factors such as
prostaglandin F2α , prostaglandin E
, thromboxane B
leukotriene B4, tumor necrosis factor-α and interleukin-1β
(IL1β) in both liver and plasma of rats (56). Sharma et al.
reported the anti-inflammatory effect of sandalwood oil,
purified α-santalol and β-santalol in lipopolysaccharide
(LPS)-stimulated human epidermal keratinocyte/dermal
fibroblast models through the suppression of LPS-induced
secretion of proinflammatory cytokines and chemokines,
including IL6, IL8, Monocyte Chemoattractant Protein-1, C-
X-C motif chemokine 5 and Granulocyte-macrophage
colony-stimulating factor (57). Purified α-santalol and β-
santalol also suppressed LPS-induced production of the
arachidonic acid metabolites, prostaglandin E2 and
thromboxane B2 by skin cell co-cultures. In this study, β-
santalol was found to be as effective as α-santalol in
suppressing LPS-induced proinflammatory events. In UVB-
induced photocarcinogenesis, pretreatment with α-santalol
resulted in a marked inhibition of UVB-induced
ANTICANCER RESEARCH 35: 3137-3146 (2015)
Figure 2. Molecular targets for the anticancer effects of α-santalol in skin cancer chemoprevention (44, Reproduced by permission).
cyclooxygenase-2 expression in mice (14). Baylac and
Racine reported the anti-inflammatory activities of
sandalwood oil by inhibiting 5-lipoxygenase activity which
is a key marker of inflammation (58).
Anti-oxidant activity. Santalum album extract exhibited 1,1-
diphenyl-2-picrylhydrazyl radical-scavenging activity in a
concentration-dependent manner, with maximum scavenging
of 64% in presence of 500 μl of aqueous extract (34).
Antioxidant activity of Santalum album along with other six
medicinal plants used in traditional Ayurvedic herbal
preparations was explained by Scartezzini and Speroni (59).
In vivo antihyperglycemic and antioxidant potential of
sandalwood oil (1 g/kg) and α-santalol (100 mg/kg) has been
reported in male Swiss albino mouse models of alloxan-
induced diabetes and D-galactose-mediated oxidative stress,
Anti-angiogenic effect. Antiangiogenic effect of α-santalol
was reported in PC-3 xenograft tumor model in nude mice
in vivo and in human umbilical vein endothelial cells
(HUVECs) in vitro (45). In this study, HUVECs were found
to be more sensitive to α-santalol than PC-3 and LNCap
prostatic cancer cells and α-santalol significantly inhibited
endothelial cell proliferation with an IC
value of 17.8 μM.
α-Santalol inhibited migration of endothelial cells in a dose-
dependent manner, and inhibited the invasion of HUVECs
and capillary tube formation. It inhibited angiogenesis and
growth of human prostate tumor growth by targeting vascular
endothelial growth factor receptor 2-mediated AKT/mTOR/
P70S6K signaling pathway. The antitumor and antiantiangio-
genic activities of α-santalol were identified in human
hepatocellular carcinoma cell lines and hepatocellular
carcinoma induced by diethylnitrosamine in mice (61).
Conclusion and Future directions
Studies suggest that α-santalol is a safe and promising cancer
chemopreventive/therapeutic agent with potential to target
various pathways involved in carcinogenesis (Figure 2). Based
on available data from cell line and animal studies, the
mechanisms of action through which α-santalol functions as an
anti-carcinogenic agent include proapoptotic, antiproliferative,
antiangiogenic, antioxidant and anti-inflammatory activities
(Table I). α-Santalol is relatively non-toxic to normal tissues,
which minimizes undesirable systemic side-effects and
improves patient compliance. It also has a pleasant fragrance
thus facilitating compliance. However, further experimental
and clinical studies are required to better understand the role
of α-santalol in chemoprevention and treatment of various
types of cancer.
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Received February 23, 2015
Revised April 18, 2015
Accepted April 23, 2015
Santha and Dwivedi: Anticancer Effects of Santalum album (Review)
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abbreviations are preferable. If a new abbreviation is used, it must be defined on first usage.
Clinical Trials. Authors of manuscripts describing clinical trials should provide the appropriate clinical trial number in the correct format
in the text.
For International Standard Randomised Controlled Trials (ISRCTN) Registry (a not-for-profit organization whose registry is administered
by Current Controlled Trials Ltd.) the unique number must be provided in this format: ISRCTNXXXXXXXX (where XXXXXXXX
represents the unique number, always prefixed by “ISRCTN”). Please note that there is no space between the prefix “ISRCTN” and the
number. Example: ISRCTN47956475.
For Clinicaltrials.gov registered trials, the unique number must be provided in this format: NCTXXXXXXXX (where XXXXXXXX
represents the unique number, always prefixed by 'NCT'). Please note that there is no space between the prefix 'NCT' and the number.
Ethical Policies and Standards. ANTICANCER RESEARCH agrees with and follows the "Uniform Requirements for Manuscripts Submitted
to Biomedical Journals" established by the International Committee of Medical Journal Editors in 1978 and updated in October 2001
(www.icmje.org). Microarray data analysis should comply with the "Minimum Information About Microarray Experiments (MIAME) standard".
Specific guidelines are provided at the "Microarray Gene Expression Data Society" (MGED) website. Presentation of genome sequences should
follow the guidelines of the NHGRI Policy on Release of Human Genomic Sequence Data. Research involving human beings must adhere to
the principles of the Declaration of Helsinki and Title 45, U.S. Code of Federal Regulations, Part 46, Protection of Human Subjects, effective
December 13, 2001. Research involving animals must adhere to the Guiding Principles in the Care and Use of Animals approved by the Council
of the American Physiological Society. The use of animals in biomedical research should be under the careful supervision of a person adequately
trained in this field and the animals must be treated humanely at all times. Research involving the use of human foetuses, foetal tissue, embryos
and embryonic cells should adhere to the U.S. Public Law 103-41, effective December 13, 2001.
Submission of Manuscripts. Please follow the Instructions to Authors regarding the format of your manuscript and references. There are 3
ways to submit your article (NOTE: Please use only one of the 3 options. Do not send your article twice.):
1. To submit your article online please visit: IIAR-Submissions (http://www.iiar-anticancer.org/submissions/login.php
2. You can send your article via e-mail to email@example.com. Please remember to always indicate the name of the journal you
wish to submit your paper. The text should be sent as a Word document (*doc) attachment. Tables, figures and cover letter can also be
sent as e-mail attachments.
3. You can send the manuscript of your article via regular mail in a USB stick, DVD, CD or floppy disk (including text, tables and figures)
together with three hard copies to the following address:
John G. Delinasios
International Institute of Anticancer Research (IIAR)
Editorial Office of ANTICANCER RESEARCH,
IN VIVO, CANCER GENOMICS and PROTEOMICS.
1st km Kapandritiou-Kalamou Road
P.O. Box 22, GR-19014 Kapandriti, Attiki
Submitted articles will not be returned to Authors upon rejection.
Galley Proofs. Unless otherwise indicated, galley proofs will be sent to the first-named Author of the submission. Corrections of
galley proofs should be limited to typographical errors. Reprints, PDF files, and/or Open Access may be ordered after the acceptance
of the paper. Requests should be addressed to the Editorial Office.
Copyright© 2015 - International Institute of Anticancer Research (J.G. Delinasios). All rights reserved (including those of translation into
other languages). No part of this journal may be reproduced, stored in a retrieval system, or transmitted in any form or by any means,
electronic, mechanical, photocopying, microfilming, recording or otherwise, without written permission from the Publisher.