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Anticancer Effects of Sandalwood (Santalum album)

Article

Anticancer Effects of Sandalwood (Santalum album)

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. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.
ANTICANCER RESEARCH
International Journal of Cancer Research and Treatment
ISSN: 0250-7005
Reprinted from
ANTICANCER RESEARCH 35: 3137-3146 (2015)
Anticancer Effects of Sandalwood (Santalum album)
SREEVIDYA SANTHA
and CHANDRADHAR DWIVEDI
Department of Pharmaceutical Sciences, South Dakota State University, Brookings, SD, U.S.A.
P
.A. ABRAHAMSSON, Malm
ö,
Sweden
B. B. AGGARWAL, Houston, TX, USA
T
. AKIMOTO, Kashiwa, Chiba, Japan
A
. ARGIRIS, San Antonio, TX, USA
J. P. ARMAND, Toulouse, France
V. I. AVRAMIS, Los Angeles, CA, USA
R
. C. BAST, Houston, TX, USA
D
.-T. BAU, Taiwan, ROC
G. BAUER, Freiburg, Germany
E
. E. BAULIEU, Le Kremlin-Bicetre, France
Y. BECKER, Jerusalem, Israel
E. J. BENZ, Jr., Boston, MA, USA
J. BERGH, Stockholm, Sweden
D
. D. BIGNER, Durham, NC, USA
A. B
ÖCKING, Düsseldorf, Germany
G. BONADONNA, Milan, Italy
F. T. BOSMAN, Lausanne, Switzerland
G. BROICH, Monza, Italy
J. M. BROWN, Stanford, CA, USA
Ø
. S. BRULAND, Oslo, Norway
M. M. BURGER, Basel, Switzerland
M. CARBONE, Honolulu, HI, USA
C. CARLBERG, Kuopio, Finland
J. CARLSSON, Uppsala, Sweden
A. F. CHAMBERS, London, ON, Canada
P. CHANDRA, Frankfurt am Main, Germany
L. CHENG, Indianapolis, IN, USA
J.-G. CHUNG, Taichung, Taiwan, ROC
E. DE CLERCQ, Leuven, Belgium
W. DE LOECKER, Leuven, Belgium
W. DEN OTTER, Amsterdam, The Netherlands
E. P. DIAMANDIS, Toronto, ON, Canada
G. TH. DIAMANDOPOULOS, Boston, MA, USA
D. W. FELSHER, Stanford, CA, USA
J. A. FERNANDEZ-POL, Chesterfield, MO, USA
I. J. FIDLER, Houston, TX, USA
A. P. FIELDS, Jacksonville, FL, USA
B. FUCHS, Zurich, Switzerland
G. GABBIANI, Geneva, Switzerland
R. GANAPATHI, Charlotte, NC, USA
A. F. GAZDAR, Dallas, TX, USA
J. H. GESCHWIND, Baltimore, MD, USA
A. GIORDANO, Philadelphia, PA, USA
G. GITSCH, Freiburg, Germany
R. H. GOLDFARB, Saranac Lake, NY, USA
S. HAMMARSTR
ÖM, Umea
°
, Sweden
I. HELLSTR
ÖM, Seattle, WA, USA
L. HELSON, Quakertown, PA, USA
R. M. HOFFMAN, San Diego, CA, USA
K.-S. JEONG, Daegu, South Korea
S. C. JHANWAR, New York, NY, USA
J. V. JOHANNESSEN, Oslo, Norway
B. KAINA, Mainz, Germany
P. -L. KELLOKUMPU-LEHTINEN, Tampere,
Finland
B. K. KEPPLER, Vienna, Austria
D. G. KIEBACK, Marl, Germany
R. KLAPDOR, Hamburg, Germany
U. R. KLEEBERG, Hamburg, Germany
P. KLEIHUES, Z
ürich, Switzerland
E. KLEIN, Stockholm, Sweden
S. D. KOTTARIDIS, Athens, Greece
G
. R. F. KRUEGER, K
öl
n, Germany
D. W. KUFE, Boston, MA, USA
P
at M. KUMAR, Manchester, UK
S
hant KUMAR, Manchester, UK
O. D. LAERUM, Bergen, Norway
F. J. LEJEUNE, Lausanne, Switzerland
L
. F. LIU, Piscataway, NJ, USA
D
. M. LOPEZ, Miami, FL, USA
E. LUNDGREN, Umea
°
, Sweden
H
. T. LYNCH, Omaha, NE, USA
Y. MAEHARA, Fukuoka, Japan
J. MAHER, London, UK
J. MARESCAUX, Strasbourg, France
J
. MARK, Sk
öv
de, Sweden
S. MITRA, Houston, TX, USA
S. MIYAMOTO, Fukuoka, Japan
M. MUELLER, Villingen-Schwenningen,
Germany
F. M. MUGGIA, New York, NY, USA
M. J. MURPHY, Jr., Dayton, OH, USA
M. NAMIKI, Kanazawa, Ishikawa, Japan
R. NARAYANAN, Boca Raton, FL, USA
K. NILSSON, Uppsala, Sweden
S. PATHAK, Houston, TX, USA
J.L. PERSSON, Malm
ö, Sweden
S. PESTKA, Piscataway, NJ, USA
G. J. PILKINGTON, Portsmouth, UK
C. D. PLATSOUCAS, Norfolk, VA, USA
F. PODO, Rome, Italy
A. POLLIACK, Jerusalem, Israel
G. REBEL, Strasbourg, France
M. RIGAUD, Limoges, France
U. RINGBORG, Stockholm, Sweden
M. ROSELLI, Rome, Italy
A. SCHAUER, G
öttingen, Germany
M. SCHNEIDER, Wuppertal, Germany
A. SETH, Toronto, ON, Canada
G. V. SHERBET, Newcastle-upon-Tyne, UK
G.-I. SOMA, Kagawa, Japan
G. S. STEIN, Burlington, VT, USA
T. STIGBRAND, Umea
°
, Sweden
T. M. THEOPHANIDES, Athens, Greece
B. TOTH, Omaha, NE, USA
P. M. UELAND, Bergen, Norway
H. VAN VLIERBERGHE, Ghent, Belgium
R. G. VILE, Rochester, MN, USA
M. WELLER, Zurich, Switzerland
B. WESTERMARK, Uppsala, Sweden
Y. YEN, Duarte, CA, USA
M.R.I. YOUNG, Charleston, SC, USA
B. ZUMOFF, New York, NY, USA
J. G. DELINASIOS, Athens, Greece
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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
terpenoids (19).
3137
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: chandradhar.dwivedi@sdstate.edu
Key Words: Sandalwood, santalol, cancer, apoptosis, cell cycle,
carcinogenesis, angiogenesis, review.
ANTICANCER RESEARCH 35: 3137-3146 (2015)
Review
Anticancer Effects of Sandalwood (Santalum album)
SREEVIDYA SANTHA
and CHANDRADHAR DWIVEDI
Department of Pharmaceutical Sciences, South Dakota State University, Brookings, SD, U.S.A.
0250-7005/2015 $2.00+.40
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
15
H
24
O)
(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
−1
, boiling point of 166˚C and density of
0.9770 g/cm
3
. 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).
Medicinal Properties
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)
3138
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)
3139
compounds exhibited cytotoxicity against HL-60 cells with
IC
50
values of 1.5 and 4.3 μM, and against A549 cells with
IC
50
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
of lignans.
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
3
H-thymidine in
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
action (44).
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
cm
2
) 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
Against Cancer
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
of G
1
, S, G
2
and M phases in which G
1
and G
2
are gap
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)
3140
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
2
/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
2
/M
phase arrest in these cells. Knockdown of p21 in A431 cells
or knockdown of both p21 and p53 in UACC-62 cells did not
change G
2
/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
G
2
/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
2
/M regulatory
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
G
2
/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)
3141
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
2
, thromboxane B
2
,
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)
3142
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,
respectively (60).
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
50
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)
3145
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... Its wood is highly aromatic, and it is the secondmost expensive wood after African Blackwood (Dalbergia melanoxylon Guill. & Perr.) [127]. The aromatic oil of sandalwood accumulates in the tree's heartwood and roots for 15-20 years. ...
... Sandalwood is a hemiparasitic root tree. Its wood is highly aromatic, and second-most expensive wood after African Blackwood (Dalbergia melanoxylon Perr.) [127]. The aromatic oil of sandalwood accumulates in the tree's heartwood a for 15-20 years. ...
... At present, research on the anti-cancer potential of sandalwood has increased considerably [128,160,161,163,181]. It also been proven effective for treating skin papilloma and carcinoma [127,163]. ...
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Non-Timber Forest Products (NTFPs) management can lead to various benefits for community livelihood and forest sustainability. However, such management has not been carried out optimally and sustainably in Indonesia, due to various limiting factors including ineffective policies, undeveloped cultivation technologies, and inadequate innovation in processing technologies. Further, the diversity of NTFPs species requires that policy-makers determine the priority species to be developed. Agarwood (Aquilaria spp. and Gyrinops spp.), benzoin (Styrax spp.), sandalwood (Santalum album L.), and cajuput (Melaleuca cajuputi Powell) are aromatic NTFPs species in Indonesia that forest-dwellers have utilized across generations. This paper reviews the current governance, cultivation systems, processing and valuation, and benefits and uses of these species. We also highlights the future challenges and prospects of these NTFPs species, which are expected to be useful in designing NTFPs governance, in order to maximize the associated benefits for the farmers and all related stakeholders.
... Its anticancer activity is based on inducing apoptosis in cells but also on suppression of viability of the cells (Figure 4). Different scientists from the world found that compounds from sandalwood have anticancer activities in many types of skin cancer and leukaemia cells [82][83][84][85][86]. Matsuo and Mimaki [83] found new neolignan and known lignans in sandalwood and this study, they showed that new neolignan was cytotoxic towards HL-60 cells, which are human promyelocytic leukaemia cells. ...
... In different work, Matsuo et al. [84] showed that cis-β-santalol and -β-santaldiol were cytotoxic against HL-60 human promyelocytic leukaemia cells by inducing apoptosis in them. According to Santha and Dwivedi [85]; α-santalol from sandalwood oil from Santalum album have anticancer properties, because it can induce apoptosis, have an anti-angiogenic effect and also antioxidant activity on various types of cancer cells. ...
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Santalum genus belongs to the family of Santalaceae, widespread in India, Australia, Hawaii, Sri Lanka, and Indonesia, and valued as traditional medicine, rituals and modern bioactivities. Sandalwood is reported to possess a plethora of bioactive compounds such as essential oil and its components (α-santalol and β-santalol), phenolic compounds and fatty acids. These bioactives play important role in contributing towards biological activities and health-promoting effects in humans. Pre-clinical and clinical studies have shown the role of sandalwood extract as antioxidant, anti-inflammatory, antibacterial, antifungal, antiviral, neuroleptic, antihyperglycemic, antihyperlipidemic, and anticancer activities. Safety studies on sandalwood essential oil (EO) and its extracts have proven them as a safe ingredient to be utilized in health promotion. Phytoconstituents, bioactivities and traditional uses established sandalwood as one of the innovative materials for application in the pharma, food, and biomedical industry.
... α-Santalol, an active component of sandalwood oil, has shown chemopreventive effects on skin cancer in different murine models 46 . Many studies support anti-cancer activities of sandalwood, sandal safed (Santalum album) 47 . The histopathological examination of heart tissue of Group-I and III rats showed normal myocardial fibers and muscle bundles with normal architecture. ...
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Background: In the Unani System of Medicine, Sandal safed (Sandalwood) is used in many cardiac problems as it possesses Mufarreh (exhilarant) and Muqawwi Qalb (cardiotonic) activities. The present study was designed to evaluate the cardioprotective effect of Sandal safed in Isoproterenol-induced Myocardial Infarction. Methods: Male Wistar rats, weighing 150-200gm, divided into five groups of ten in each. Group I and III rats were given 5% gum acacia (vehicle) and Sandalwood powder in the dose of 800 mg/kg body weight, orally once daily for seven days, followed by subcutaneous administration of normal saline on the 8th and 9th day. Group II, IV & V were administered 5% gum acacia, test drug in the dose of 600 & 800mg/kg body weight, orally once daily for seven days, respectively, followed by isoproterenol hydrochloride (50 mg/ kg body weight) subcutaneously, twice at an interval of 24 h on 8th and 9th day. On 10th day, animals were sacrificed, heart and adrenal glands were weighed, and serum cardiac enzymes and lipid profile were analysed. Histopathological study of apex of the heart was carried out. Results: In group-II rats, serum cardiac enzymes, serum cholesterol, TG, LDL, VLDL, and weight of the heart and adrenal gland were found to be increased significantly (P< 0.001), and HDL, cardiac glycogen and adrenal ascorbic acid were decreased significantly along with gross pathological changes in heart tissues, but in group IV & V rats, the above parameters were normal. Conclusion: Sandal safed revealed cardioprotective effect in dose dependent manner without any side effects.
... Santalum album L. is a semi-parasitic tree that belongs to the Santalaceae family. It has a high economic value, which is mainly reflected in its heartwood, which is often used as a raw material for carving crafts, and it is often made into incense commonly used in perfume, while sandal essential oil extracted from its heartwood has displayed anti-cancer [22,23], antioxidant [24], anti-inflammatory and analgesic [25,26] properties, and has been used in the treatment of skin diseases [27,28]. The main components of sandal essential oil are αand β-santalol [29]. ...
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Santalum album L., a semi-parasitic evergreen tree, contains economically important essential oil, rich in sesquiterpenoids, such as (Z) α- and (Z) β-santalol. However, their transcriptional regulations are not clear. Several studies of other plants have shown that basic-helix-loop-helix (bHLH) transcription factors (TFs) were involved in participating in the biosynthesis of sesquiterpene synthase genes. Herein, bHLH TF genes with similar expression patterns and high expression levels were screened by co-expression analysis, and their full-length ORFs were obtained. These bHLH TFs were named SaMYC1, SaMYC3, SaMYC4, SaMYC5, SabHLH1, SabHLH2, SabHLH3, and SabHLH4. All eight TFs had highly conserved bHLH domains and SaMYC1, SaMYC3, SaMYC4, and SaMYC5, also had highly conserved MYC domains. It was indicated that the eight genes belonged to six subfamilies of the bHLH TF family. Among them, SaMYC1 was found in both the nucleus and the cytoplasm, while SaMYC4 was only localized in the cytoplasm and the remaining six TFs were localized in nucleus. In a yeast one-hybrid experiment, we constructed decoy vectors pAbAi-SSy1G-box, pAbAi-CYP2G-box, pAbAi-CYP3G-box, and pAbAi-CYP4G-box, which had been transformed into yeast. We also constructed pGADT7-SaMYC1 and pGADT7-SabHLH1 capture vectors and transformed them into bait strains. Our results showed that SaMYC1 could bind to the G-box of SaSSy, and the SaCYP736A167 promoter, which SaSSy proved has acted as a key enzyme in the synthesis of santalol sesquiterpenes and SaCYP450 catalyzed the ligation of santalol sesquiterpenes into terpene. We have also constructed pGreenII 62-SK-SaMYC1, pGreenII 0800-LUC-SaSSy and pGreenII 0800-LUC-SaCYP736A167 via dual-luciferase fusion expression vectors and transformed them into Nicotiana benthamiana using an Agrobacterium-mediated method. The results showed that SaMYC1 was successfully combined with SaSSy or SaCYP736A167 promoter and the LUC/REN value was 1.85- or 1.55-fold higher, respectively, than that of the control group. Therefore, we inferred that SaMYC1 could activate both SaSSy and SaCYP736A167 promoters.
... Sesquiterpenes A sesquiterpene isolated from Santalum spp. (sandalwood), α-santalol, has demonstrated anticancer effects, inducing cell-cycle arrest and apoptosis in both in vitro and in vivo models of prostate cancer [248]. Likewise, sesquiterpenes viz. ...
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Prostate cancer is a heterogeneous disease, the second deadliest malignancy in men and the most commonly diagnosed cancer among men. Traditional plants have been applied to handle various diseases and to develop new drugs. Medicinal plants are potential sources of natural bioactive compounds that include alkaloids, phenolic compounds, terpenes, and steroids. Many of these naturally-occurring bioactive constituents possess promising chemopreventive properties. In this sense, the aim of the present review is to provide a detailed overview of the role of plant-derived phytochemicals in prostate cancers, including the contribution of plant extracts and its corresponding isolated compounds.
Chapter
TCM researches are tightly associated with multi-omics including genomics, proteomics, metagenomics, metabolomics, transcriptomics etc. (Fig. 3.1). The integration and mining of multi-omics data are becoming the mainstream in TCM researches, largely due to the fact that multi-omics studies could reveal the underline pattern and regulation principles on molecular biology level for medicinal plants and TCM preparations (Bonta 1995).
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Indian sandalwood (Santalum album), esteemed for its heartwood and oil is subjected to various important diseases which cause a lack of growth and consequently loss of the valuable heartwood and oil or may kill the trees. This can lead to a devastating economic loss to farmers. There is a pressing need to conserve health of sandalwood trees by determining disease prevention measures and to investigate pragmatic solutions to reduce losses caused by destructive diseases. The purpose of this review is mainly to inform the scientific community about so far reported deleterious pathogenic diseases in India, China, Australia, Bangladesh and their impact, thereby helping to facilitate development of a suitable suite of practices for combating the scourge of diseases affecting sandalwood, ultimately helping the sandalwood farming communities. A comprehensive review on the same is presented.
Chapter
The essential oil produced by steam distillation from the heartwood of East Indian sandalwood trees (Santalum album) has been used as a traditional medicine for centuries due to its broad spectrum of biological properties. Recent biochemical studies have begun to elucidate the specific mechanisms of action of the oil and its major components. The creation of guidelines for the development of botanical drugs as a special category by regulatory agencies such as the United States Food and Drug Administration (FDA) has allowed the development of complex mixtures such as sandalwood oil as potential pharmaceutical agents. Sandalwood oil has been shown in several early Phase 2 clinical trials in the USA to give promising results. Extensive pivotal clinical studies are required to confirm the beneficial activity and favourable safety profile seen in these early human studies.
Chapter
Natural products have been widely used by different cultures from around the world for many centuries for their associated health benefits and ability to prevent and reverse the development of various ailments. Medicinal value of a variety of phytochemicals is well known, and emerging literature provides evidence about their health promoting and disease fighting potential. One such natural product, sandalwood oil, is known to be part of traditional medicine by various cultures for treating numerous ailments, including cancer. It constitutes a wide variety of components including alpha-santalol. This sesquiterpene is widely investigated for its health benefits and ability to modulate different signalling pathways involved in the development of the malignant disease. For example, the antitumour and cancer-preventive properties of alpha-santalol are shown to involve cell death induction through apoptosis and cell cycle arrest in various cancer models. The current chapter summarizes our knowledge of sandalwood oil and alpha-santalol and their biological aspects attributed to the cancer-preventive and antitumour effects against various cancers with relevant clinical evidence.
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Anti-ulcer Activity of Sandalwood (Santalum album L.) Stem Hydro-alcoholic Extract in Three Gastric-Ulceration Models of Wistar Rats Boletín Latinoamericano y del Caribe de Plantas Medicinales y Aromáticas, vol. 12, núm. 1, enero, 2013, pp. 81-91 Universidad de Santiago de Chile Santiago, Chile How to cite Complete issue More information about this article Journal's homepage Boletín Latinoamericano y del Caribe de Plantas Medicinales y Aromáticas, ISSN (Printed Version): www.redalyc.org Non-Profit Academic Project, developed under the Open Acces Initiative
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Santalum album commonly known as Sandalwood is used traditionally for health and wellness. It is an evergreen and hemi-parasitic tree and has a long history in Indian religious rituals and traditional Chinese medicine. Due to its wide application in cosmetics and therapeutics, we have done this study to explore the possibility of using aqueous extract of S. album as antibacterial and antioxidant agent. The S. album extract was prepared in distilled water. The activity of aqueous extract was evaluated against eight bacterial pathogens including two strains of Escherichia coli, one each of Klebsiella pneumoniae, Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, Aeromonas species and Klebsiella oxytoca. The anti-oxidant activity was analyzed by two most common radical scavenging assays of FRAP (ferric reducing antioxidant power) and DPPH (1,1- diphenyl- 2-picrylhydrazyl). Results showed that S. album had strongest inhibitory activity against S. aureus (MTCC 902) i.e. 87% whereas; it showed no inhibition against E.coli (ATCC 25922) and B. subtilis (MTCC736). The S. album extract showed DPPH radical scavenging activity in a concentration–dependent manner with maximum scavenging of 64% in presence of 500μl of aqueous extract. The FRAP assay also proved antioxidant potential of S. album with the highest value of 0.628mM at 200μl of aqueous extract.
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Background Frankincense (Boswellia carterii, known as Ru Xiang in Chinese) and sandalwood (Santalum album, known as Tan Xiang in Chinese) are cancer preventive and therapeutic agents in Chinese medicine. Their biologically active ingredients are usually extracted from frankincense by hydrodistillation and sandalwood by distillation. This study aims to investigate the anti-proliferative and pro-apoptotic activities of frankincense and sandalwood essential oils in cultured human bladder cancer cells. Methods The effects of frankincense (1,400–600 dilutions) (v/v) and sandalwood (16,000–7,000 dilutions) (v/v) essential oils on cell viability were studied in established human bladder cancer J82 cells and immortalized normal human bladder urothelial UROtsa cells using a colorimetric XTT cell viability assay. Genes that responded to essential oil treatments in human bladder cancer J82 cells were identified using the Illumina Expression BeadChip platform and analyzed for enriched functions and pathways. The chemical compositions of the essential oils were determined by gas chromatography–mass spectrometry. Results Human bladder cancer J82 cells were more sensitive to the pro-apoptotic effects of frankincense essential oil than the immortalized normal bladder UROtsa cells. In contrast, sandalwood essential oil exhibited a similar potency in suppressing the viability of both J82 and UROtsa cells. Although frankincense and sandalwood essential oils activated common pathways such as inflammatory interleukins (IL-6 signaling), each essential oil had a unique molecular action on the bladder cancer cells. Heat shock proteins and histone core proteins were activated by frankincense essential oil, whereas negative regulation of protein kinase activity and G protein-coupled receptors were activated by sandalwood essential oil treatment. Conclusion The effects of frankincense and sandalwood essential oils on J82 cells and UROtsa cells involved different mechanisms leading to cancer cell death. While frankincense essential oil elicited selective cancer cell death via NRF-2-mediated oxidative stress, sandalwood essential oil induced non-selective cell death via DNA damage and cell cycle arrest.
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Objective: The study objective was to assess the effectiveness of a turmeric- and sandal wood oil-containing cream [Vicco(®) turmeric cream (VTC); Vicco Laboratories, Parel, India] on radiodermatitis in patients with head and neck cancer undergoing radiotherapy. Methods: A total of 50 patients with head and neck cancer requiring >60 Gy of curative radiotherapy/chemoradiotherapy were enrolled in the study. The volunteers were randomly divided into two groups of 25 patients. Group 1 was assigned to a topical application of Johnson's(®) baby oil (Johnson & Johnson Ltd, Baddi, India) and Group 2 for VTC. Prophylactic application of the cream was initiated on Day 1 and continued every day until 2 weeks after the end of treatment. Both agents were symmetrically applied within the irradiated field five times a day, and the acute skin reactions were assessed twice weekly in accordance with the Radiation Therapy Oncology Group scores by an investigator who was unaware of the details. Results: The incidence of radiodermatitis increased with the exposure to radiation and was the highest in both groups at Week 7. However, a significant reduction in grades of dermatitis were seen in cohorts applying VTC at all time points, including 2 weeks post radiotherapy (p < 0.015 to p < 0.001). The occurrence of Grade 3 dermatitis was lower in the cohorts using VTC and was statistically significant (p < 0.01). Additionally, follow-up observations 2 weeks after the completion of radiotherapy also showed a reduced degree of radiodermatitis in cohorts applying VTC, which was significant (p = 0.015). Conclusion: VTC is shown to be effective in preventing radiodermatitis and needs to be validated in larger double-blind trials. Advances in knowledge: For the first time, this study shows that the turmeric- and sandal oil-based cream was effective in preventing radiation-induced dermatitis.
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Sandalwood (Santalum album L.) is a valuable tree associated with Indian culture. It is the second most expensive wood in the world. The heartwood of the tree is treasured for its aroma and is one of the finest natural materials for carving. Sandalwood oil is used in perfumes, cosmetics, aromatherapy and pharmaceuticals. The monopoly of sandalwood trade by the Governments of Karnataka, Tamil Nadu and Kerala and its consequences have resulted in severe exploitation, pushing S. album into the vulnerable category of the IUCN Red List. Extensive research has shown that sandalwood exhibits considerable genetic diversity for different traits. However, information pertaining to heartwood and oil content is meagre mainly because of non-availability of sandalwood plantations. Carrying out further research on these two important traits is difficult as natural populations have dwindled rapidly. We strongly urge that it is essential to encourage the establishment of community/corporate sandalwood plantations in different parts of India with appropriate incentives and adequate protective measures. These plantations can form the base population sources to regain the leadership of India in the sandalwood industry for perfumery and the precious art of carving.
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Medicinally, sandalwood oil (SO) has been attributed with antiinflammatory properties; however, mechanism(s) for this activity have not been elucidated. To examine how SOs affect inflammation, cytokine antibody arrays and enzyme-linked immunosorbent assays were used to assess changes in production of cytokines and chemokines by co-cultured human dermal fibroblasts and neo-epidermal keratinocytes exposed to lipopolysaccharides and SOs from Western Australian and East Indian sandalwood trees or to the primary SO components, α-santalol and β-santalol. Lipopolysaccharides stimulated the release of 26 cytokines and chemokines, 20 of which were substantially suppressed by simultaneous exposure to either of the two sandalwood essential oils and to ibuprofen. The increased activity of East Indian SO correlated with increased santalol concentrations. Purified α-santalol and β-santalol equivalently suppressed production of five indicator cytokines/chemokines at concentrations proportional to the santalol concentrations of the oils. Purified α-santalol and β-santalol also suppressed lipopolysaccharide-induced production of the arachidonic acid metabolites, prostaglandin E2, and thromboxane B2, by the skin cell co-cultures. The ability of SOs to mimic ibuprofen non-steroidal antiinflammatory drugs that act by inhibiting cyclooxygenases suggests a possible mechanism for the observed antiinflammatory properties of topically applied SOs and provides a rationale for use in products requiring antiinflammatory effects. Copyright © 2013 John Wiley & Sons, Ltd.
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Cancer is frequently considered to be a disease of the cell cycle. As such, it is not surprising that the deregulation of the cell cycle is one of the most frequent alterations during tumor development. Cell cycle progression is a highly-ordered and tightly-regulated process that involves multiple checkpoints that assess extracellular growth signals, cell size, and DNA integrity. Cyclin-dependent kinases (CDKs) and their cyclin partners are positive regulators or accelerators that induce cell cycle progression; whereas, cyclin-dependent kinase inhibitors (CKIs) that act as brakes to stop cell cycle progression in response to regulatory signals are important negative regulators. Cancer originates from the abnormal expression or activation of positive regulators and functional suppression of negative regulators. Therefore, understanding the molecular mechanisms of the deregulation of cell cycle progression in cancer can provide important insights into how normal cells become tumorigenic, as well as how new cancer treatment strategies can be designed.
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Sandalwood oil, the essential oil of Santalum album L., was tested for in vitro antiviral activity against Herpes simplex viruses-1 and -2. It was found that the replication of these viruses was inhibited in the presence of the oil. This effect was dose-dependent and more pronounced against HSV-1. A slight diminution of the effect was observed at higher multiplicity of infections. The oil was not virucidal and showed no cytotoxicity at the concentrations tested.
Article
One of the primary components of the East Indian sandalwood oil (EISO) is α-santalol, a molecule that has been investigated for its potential use as a chemopreventive agent in skin cancer. Although there is some evidence that α-santalol could be an effective chemopreventive agent, to date, purified EISO has not been extensively investigated even though it is widely used in cultures around the world for its health benefits as well as for its fragrance and as a cosmetic. In the current study, we show for the first time that EISO-treatment of HaCaT keratinocytes results in a blockade of cell cycle progression as well as a concentration-dependent inhibition of UV-induced AP-1 activity, two major cellular effects known to drive skin carcinogenesis. Unlike many chemopreventive agents, these effects were not mediated through an inhibition of signaling upstream of AP-1, as EISO treatment did not inhibit UV-induced Akt, or MAPK activity. Low concentrations of EISO were found to induce HaCaT cell death, although not through apoptosis as annexin V and PARP cleavage were not found to increase with EISO treatment. However, plasma membrane integrity was severely compromised in EISO-treated cells, which may have led to cleavage of LC3 and the induction of autophagy. These effects were more pronounced in cells stimulated to proliferate with bovine pituitary extract and EGF prior to receiving EISO. Together, these effects suggest that EISO may exert beneficial effects upon skin, reducing the likelihood of promotion of pre-cancerous cells to actinic keratosis (AK) and skin cancer.