Biomedical properties of saffron and its potential use in cancer therapy and chemoprevention trials

Abstract

Chemoprevention strategies are very attractive and have earned serious consideration as potential means of controlling the incidence of cancer. An important element of anticancer drug development using plants is the accumulation and analysis of pertinent experimental data and purported ethnomedical (folkloric) uses for plants. The aim of this review is to provide an updated overview of experimental in vitro and in vivo investigations focused on the anticancer activity of saffron (Crocus sativus L.) and its principal ingredients. Potential use of these natural agents in cancer therapy and chemopreventive trials are also discussed.
A computerized search of published articles was performed using the MEDLINE database from 1990 to 2004. Search terms utilized including saffron, carotenoids, chemoprevention, and cancer. All articles were obtained as reprints from their original authors. Additional sources were identified through cross-referencing.
Studies in animal models and with cultured human malignant cell lines have demonstrated antitumor and cancer preventive activities of saffron and its main ingredients, possible mechanisms for these activities are discussed. More direct evidence of anticancer effectiveness of saffron as chemopreventive agent may come from trials that use actual reduction of cancer incidence as the primary endpoint
This work suggests that future research be warranted that will define the possible use of saffron as effective anticancer and chemopreventive agent in clinical trials.

Full text

Review
Biomedical properties of saffron and its potential use in
cancer therapy and chemoprevention trials
F.I. Abdullaev PhD
a,
*, J.J. Espinosa-Aguirre PhD
b
a
Laboratorio Oncologı
´a Experimental, Instituto Nacional de Pediatrı
´a, Avenida Ima
´n#1TorredeInvestigacio
´n,
04530 Me
´xico D.F., Me
´xico
b
Instituto de Investigaciones Biome
´dicas, UNAM, Apartado Postal 70228, Ciudad Universitaria, Me
´xico D.F., Me
´xico
Accepted 2 September 2004
Abstract
Introduction: Chemoprevention strategies are very attractive and have earned serious consideration as potential means of controlling the
incidence of cancer. An important element of anticancer drug development using plants is the accumulation and analysis of pertinent
experimental data and purported ethnomedical (folkloric) uses for plants. The aim of this review is to provide an updated overview of
experimental in vitro and in vivo investigations focused on the anticancer activity of saffron (Crocus sativus L.) and its principal ingredients.
Potential use of these natural agents in cancer therapy and chemopreventive trials are also discussed.
Methods: A computerized search of published articles was performed using the MEDLINE database from 1990 to 2004. Search terms utilized
including saffron, carotenoids, chemoprevention, and cancer. All articles were obtained as reprints from their original authors. Additional
sources were identified through cross-referencing.
Results: Studies in animal models and with cultured human malignant cell lines have demonstrated antitumor and cancer preventive activities
of saffron and its main ingredients, possible mechanisms for these activities are discussed. More direct evidence of anticancer effectiveness of
saffron as chemopreventive agent may come from trials that use actual reduction of cancer incidence as the primary endpoint
Conclusions: This work suggests that future research be warranted that will define the possible use of saffron as effective anticancer and
chemopreventive agent in clinical trials.
#2004 International Society for Preventive Oncology. Published by Elsevier Ltd. All rights reserved.
Keywords: Saffron (Crocus sativus); Cancer chemoprevention; Cytotoxicity; Clinical trials
Contents
1. Introduction . . . ........................................................................... 427
2. Methods . . ............................................................................... 427
3. Results . . . ............................................................................... 427
3.1. Description . . . ....................................................................... 427
3.1.1. History and folk use .............................................................. 427
3.1.2. Chemical composition. . . .......................................................... 428
3.2. Medical–biological activities of saffron . ...................................................... 428
3.2.1. Toxicity....................................................................... 428
3.2.2. Precautions . ................................................................... 428
3.2.3. Effect on coronary artery disease . . . .................................................. 428
www.elsevier.com/locate/cdp
Cancer Detection and Prevention 28 (2004) 426–432
* Corresponding author. Tel.: +52 55 10 84 09 00x1474; fax: +52 55 10 84 38 83.
E-mail addresses: fikrat@sni.conacyt.mx, fikrat@servidor.unam.mx, fikrat@yahoo.com (F.I. Abdullaev).
0361-090X/$30.00 #2004 International Society for Preventive Oncology. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.cdp.2004.09.002

3.2.4. Effect on learning behavior and long-term potentiation . . . ................................... 428
3.2.5. Effects on ocular blood flow and retinal function . . . ....................................... 428
3.2.6. Effect on blood pressure . . . ........................................................ 428
3.2.7. Anticonvulsant effect . ............................................................ 428
3.2.8. Antinociceptive and anti-inflammatory effects ............................................ 428
3.2.9. Mutagenic or antimutagenic effects . . . ................................................ 428
3.2.10. Antigenotoxic effect . . ............................................................ 429
3.2.11. Tumoricidal effect . . . ............................................................ 429
3.2.12. Cytotoxic effect . ................................................................ 429
4. Conclusions. . ............................................................................. 430
Acknowledgements ............................................................................. 431
References . . ................................................................................. 431
1. Introduction
Since immemorial times, herbal plants have been used in
virtually every culture throughout the world as a source of
folk medicine [1,2]. Over two millennia ago, the father of
medicine Hippocrates mentioned about 400 medicinal
plants and advised, ‘‘let food be your medicine and let
medicine be your food’’ [1]. It is still true today and suggests
that prevention is more important than treatment. Currently,
chemoprevention strategies are very attractive and have
earned serious consideration as a potential means of
controlling the incidence of cancer [2]. Scientists and
medical professionals have shown increased interest in this
field, as they recognize the true health benefits of natural
remedies. An important element of chemopreventive drug
development using plants is the accumulation and analysis
of pertinent experimental data and purported ethnomedical
(folkloric) uses for plants. It is also very important to
note that suitable chemopreventive natural agents should
have little or no toxicity, a high efficacy, to be orally
administrable, to have a known mechanism of action and of
low cost [3]. The present study provides an updated
overview of experimental in vitro and in vivo investigations
on the biological activities of saffron (Crocus sativus L.)
and its principal ingredients, especially focusing on their
anticancer effect. Potential use of these natural agents in
cancer therapy and chemoprevention trials is also discussed.
2. Methods
A computerized search of published articles was
performed using the MEDLINE database from the period
of 1990–2004. This database, produced by the National
Library of Medicine (NLM), includes all medico-biological
literature dated from 1974 and so on. Depending on the
literature period of interest, it is offered either on-line or off-
line. Input data are obtained from approximately 3000
journal titles comprising of life sciences and/or medical
information. Approximately, 99% of the data included in
the database file are journal articles, of which, 65% are in
the English language. The remaining 1% of data represent
government documents. Retrieval provides bibliographic
data with an abstracted summary, obtained by using
keywords and/or subject headings. The search terms utilized
including saffron, carotenoids, chemoprevention, and
cancer. All articles were obtained as reprints from their
original authors. Additional sources were identified through
cross-referencing.
3. Results
3.1. Description
Saffron (Crocus sativus) is a bulbous perennial of the iris
family (Iridaceae) treasured for its golden-colored, pungent
stigmas, which are dried and used to flavor and color foods
as well as a dye. Saffron is a spice known only in cultivation
and principally grown in Spain and Iran, but also cultivated
on a lower scale in Greece, Turkey, India, Azerbaijan,
France, Italy, India, China, Morocco, Turkey, Israel, Egypt,
United Arab Emirates, Mexico, Switzerland, Algeria,
Australia, and New Zealand [4,5].
3.1.1. History and folk use
The name saffron comes from the Arabic za’faran, which
means yellow. The use of saffron also goes back to ancient
Egypt and Rome, where it was used as a dye, in perfumes,
and as a drug as well as for culinary purposes [6,7].Asa
medicinal plant, saffron has traditionally been considered an
anodyne, antidepressant, a respiratory decongestant, anti-
spasmodic, aphrodisiac, diaphoretic, emmenagogue, expec-
torant, and sedative. It was used in folk remedy against
scarlet fever, smallpox, colds, asthma, eye and heart disea-
ses, tumor, and cancer. Saffron can also be used topically to
help clear up canquer sores and to reduce the discomfort of
teething infants [4,5].
F.I. Abdullaev, J.J. Espinosa-Aguirre/ Cancer Detection and Prevention 28 (2004) 426–432 427

3.1.2. Chemical composition
The stigmas of the saffron flower contain many chemical
substances. Carbohydrates, minerals, musilage, Vitamins
(especially riboflavin and thiamine) and pigments including
crocin, anthocianin, carotene, lycopene, zigzantin, flavo-
noids, amino acids, proteins, starch, gums, and other
chemical compounds have also been described in saffron
[4–7].
The saffron stigma, which is what basically forms
commercial saffron, has a distinct and unique color, flavor
and aroma and some of the groups of chemical compounds
responsible for each of these properties have now been
identified. One of its principal coloring pigments is crocin,
which is easily soluble in water. In addition to crocin, saffron
contains crocetin as a free agent and small amounts of the
pigment anthocianin, a-carotene, b-carotene, and zegxantin
[5,8].
The principal element giving saffron its special ‘‘bitter’’
flavor is the glycoside picrocrocin. This bitter tasting
substance can be crystallized and produces glucose and the
aldehyde safranal by hydrolysis [5,8].
The main aroma factor in saffron is safranal, which
comprises of about 60% of the volatile components of
saffron. In fresh saffron, this substance exists as a stable
picrocrocin but as a result of heat and with the passage of
time, it decomposes releasing the volatile aldehyde, safranal
[5,8].
3.2. Medical–biological activities of saffron
3.2.1. Toxicity
The toxicity of saffron has been found to be quite low.
Animal studies indicate that the oral LD
50
of saffron was
20.7 g/kg administrated as a decoction [5].
3.2.2. Precautions
Saffron should always be obtained from a reputable
source that observes stringent quality control procedures and
industry-accepted good manufacturing practices. People
with chronic medical conditions should consult with their
physician before taking the herb. Pregnant women should
never take the herb for medicinal purposes, as saffron can
stimulate uterine contractions [9].
3.2.3. Effect on coronary artery disease
Fifty milligrams of saffron dissolved in 100 ml of milk
was administered twice a day to human subjects as reported
in an Indian study published in 1998. The significant
decrease in lipoprotein oxidation susceptibility in patients
with coronary artery disease (CAD) indicates the potential
of saffron as an antioxidant [10].
3.2.4. Effect on learning behavior and long-term
potentiation
Several Japanese studies have reported that the saffron
extract and two of its main ingredients crocin and crocetin,
improved memory and learning skills in ethanol-induced
learning behavior impairments in mice and rats [11–16].
These results suggest that oral administration of saffron may
be useful as treatment for neurodegenerative disorders and
related memory impairment. Recently, it was shown that
crocin isolated from saffron exhibits anti-apoptotic action in
PC-12 cells treated with daunorubicin [17]. These findings
suggest that crocin inhibits neuronal death induced by both
internal and an external apoptotic stimulus in highly
differentiated cells (neurons). This selective behavior
suggests important therapeutic implications, related to the
fact that programmed cell death is reduced in cancer and
increased in neurodegenerative disease [17].
3.2.5. Effects on ocular blood flow and retinal function
It was shown that crocin analogs isolated from saffron
significantly increased the blood flow in the retina and
choroid as well as facilitated retinal function recovery [18].
Authors suggest that crocin analogs could be used to treat
ischemic retinopathy and/or age-related macular degenera-
tion.
3.2.6. Effect on blood pressure
Recently, an Iranian study researches examined the
effects of saffron petal extract on blood pressure in
anesthetized rats and on responses of the isolated rat vas
deferens and guinea-pig ileum induced by electrical field
stimulation (EFS). It was shown that aqueous and ethanol
extracts of saffron reduced the blood pressure in a dose-
dependent manner. EFS of the isolated rat vas deferens also
were decreased by these saffron extracts [19].
3.2.7. Anticonvulsant effect
In Iranian traditional medicine, the saffron had been used
as an anticonvulsant remedy. Recently, in experiments with
mice using maximal electroshock seizure (MES) and
pentylenetetrazole (PTZ) tests, Iranian scientists have
demonstrated that the aqueous and ethanolic extracts of
saffron possess anticonvulsant activity. These authors
suggested that saffron extracts might be beneficial in both
absence and tonic clonic seizures [20].
3.2.8. Antinociceptive and anti-inflammatory effects
An Iranian experimental study with mice indicated that
saffron stigma and petal extracts exhibited antinociceptive
effects in chemical pain test as well as acute and/or chronic
anti-inflammatory activity [21]. It was suggested that these
effects of saffron extracts might be due to their content of
flavonoids, tannins, anthocyanins, alkaloids, and saponins
[22].
3.2.9. Mutagenic or antimutagenic effects
It was reported that crocin and dimethyl-crocetin isolated
from saffron were non-mutagenic [23]. Recently, data from
our laboratory, using the Ames/Salmonella test system
(strains TA97; TA98; TA100; TA102, and TA1538),
F.I. Abdullaev, J.J. Espinosa-Aguirre/ Cancer Detection and Prevention 28 (2004) 426–432428

demonstrated that the saffron extract itself in concentration
up to 1500 mg/plate was non-toxic, non-mutagenic, and non-
antimutagenic [24,25].
3.2.10. Antigenotoxic effect
It was reported that the topical administration of saffron
extracts (100 mg/kg body weight) inhibited the initiation/
promotion of 7,12-dimethylbenz [a] anthracene (DMBA)-
induced skin tumors in mice, delaying the onset of papilloma
formation and reducing the mean number of papillomas per
mouse [26]. The oral administration of the same dose of
saffron extracts restricted tumor incidence of 20-methyl-
cholanthrene (MCA)-induced soft tissue sarcomas in mice
[23,26]. Extracts from saffron stigmas prolonged the life
span of cisplatin-treated mice and partially prevented the
decrease in body weight, leukocyte count and hemoglobin
levels [27–29].
Pretreatment with the aqueous extract of saffron
(composed mainly by carotenoids) in experiments with
Swiss albino mice significantly inhibited the genotoxicity of
cisplatin, cyclophosphamide, mitomycin, and urethane [30].
It was suggested that saffron rich in carotenoids might exert
its chemopreventive effects by the modulation of lipid
peroxidation, antioxidants, and detoxification systems [31].
Crocetin from saffron also ameliorates bladder toxicity of
the anticancer agent cyclophosphamide without altering its
antitumor activity [28].
The treatment of animals with cysteine (20 mg/kg body
weight) together with saffron extract (50 mg/kg body
weight) significantly reduced the toxic effects caused by
cisplatin, such as nephrotoxicity and changes in enzyme
activity [32].
3.2.11. Tumoricidal effect
It has been previously shown that saffron was more active
parenterally than by oral route, and oral administration
might be improved by the liposome encapsulation of the
drug. It was reported that the liposome encapsulation of
saffron produced a significant inhibitory effect on the growth
of transplanted tumor cells in mice [33]. Recently, in an
animal model (frog embryos), it was demonstrated that
crocetin, isolated from saffron was effective in treating
certain types of cancer treatable with all-trans retinoic acids
(ATRA). It was suggested that crocetin might also be a safer
alternative to treat ATRA-sensitive cancers in women of
childbearing age [34].
The oral administration of the saffron ethanolic extract
increased the life span of Swiss albino mice intraperitoneally
transplanted with sarcoma-180 (S-180) cells, Ehrlich ascites
carcinoma (EAC) or Dalton’s lymphoma ascites (DLA)
tumors. The authors did not identify the exact nature of the
active compound from saffron stigmas, but suggested that
this compound showed the presence of glycosidic linkage.
Liposome encapsulation of saffron effectively enhanced its
antitumor activity against S-180 and EAC solid tumors in
mice, promoting significant inhibition in the growth of these
tumors [35,36]. On the other hand, in the presence of the T
cell mitogen phytohemagglutinin, saffron stimulated non-
specific proliferation of lymphocytes in vitro [36], suggest-
ing that the antitumor activity might be immunologically
mediated. Another study [37] examined the effects of long-
term treatment with crocin on tumor growth and life span of
rats bearing colorectal tumors, induced by rat adenocarci-
noma DHD/K12-PROb cells injected subcutaneously.
Crocin treatment significantly increased their survival time
and decreased tumor growth rate, more intensely in females.
The selective action of crocin in female rats as compared
with male rats suggests that the effects of crocin in animals
might be partially dependent on hormonal factors. An
increase in the levels of b-carotene and Vitamin A in the
serum of laboratory animals under oral administration of
saffron extracts was detected [32]. It was suggested that
saffron carotenoids possessed provitamin A activity
according to the hypothesis that the action of carotenoids
was dependent upon its conversion to retinal (Vitamin A),
because most of the evidence supporting the anticancer
effects of carotenoids were referred to b-carotene [38].
3.2.12. Cytotoxic effect
Incubation of HeLa cells (derived from a cervical
epitheloid carcinoma) with ethanolic saffron extract resulted
in significant inhibition of colony formation and cellular
DNA and RNA synthesis, with 50% inhibition obtained at
concentrations from 100 to 150 mg/ml, whereas inhibition of
protein synthesis was not detected even at high extract
concentrations [39]. In other study on the effect of the
ethanolic saffron extract on macromolecular synthesis in
three human cell lines: A549 cells (derived from a lung
tumor), WI-38 cells (normal lung fibroblasts) and VA-13
cells (WI-38 cells transformed by SV40 virus), it was found
that the malignant cells were more sensitive than the normal
cells to the inhibitory effects of saffron on both DNA and
RNA synthesis [40]. It has been suggested that the inhibitory
effect on cellular DNA and RNA synthesis, but not on
protein synthesis, is one of the main mechanisms of action
for saffron’s antitumor and anticarcinogenic activities
[5,36,39–41]. The inhibitory effect of crocetin, isolated
from saffron, on intracellular nucleic acid and protein
synthesis in three malignant human cell lines, HeLa, A549
(lung adenocarcinoma), and VA13 (SV-40 transformed
foetal lung fibroblasts) was reported [41]. Crocetin caused a
dose-dependent inhibition of nucleic acid and protein
synthesis, but had no effect on colony formation. Other
studies described the inhibition of growth of human chronic
myelogenous leukaemia K562 and promyelocytic leukae-
mia HL-60 cells by dimethyl-crocetin, crocetin, and crocin
with 50% inhibition (ID
50
) reached at concentrations of 0.8
and 2 mM, respectively, [38,42]. Cytotoxicity of dimethyl-
crocetin and crocin to various tumors cell lines (DLA, EAC,
S-180, L1210 leukemia, and P388 leukemia) and to human
primary cells from surgical specimens (osteosarcoma,
fibrosarcoma, and ovarian carcinoma) has been reported.
F.I. Abdullaev, J.J. Espinosa-Aguirre/ Cancer Detection and Prevention 28 (2004) 426–432 429

These authors also detected significant inhibition in the
synthesis of nucleic acids, and suggested that dimethyl-
crocetin could disrupt DNA-protein interactions (e.g.
toposiomerases II) important for cellular DNA synthesis
[26,36].
The inhibitory effect of the ethanolic saffron extract on
the in vitro growth of HeLa cells (ID
50
= 2.3 mg/ml) was
mainly due to crocin (ID
50
of 3 mM), where picrocrocin and
safranal, with an ID
50
of 3 and 0.8 mM, respectively, played
a minor role in the cytotoxicity of saffron extracts [43].It
was suggested that sugars might play a key role in cytotoxic
effect of crocin, since its deglucosylated derivative crocetin
did not cause cell growth inhibition even at high doses.
These findings are in accordance with the results [42], which
found no effect of crocetin on colony formation in HeLa
cells and two other solid tumor cell lines. However, they are
in disagreement with results from other authors who
reported cytotoxicity for crocetin against a cell line derived
from a non-solid tumor [38] and various tumor cell lines and
human primary cells from surgical specimen [34].AnID
50
of 0.4 and 1.0 mM was reported for crocin on the rat
adenocarcinoma DHD/K12-PROb cells and human colon
adenocarcinoma HT-29 cells, respectively [37].
In other study using saffron, ginsenoside, and cannabi-
noid derivatives to determine potential membrane-asso-
ciated antitumor effects of these substances, it was
demonstrated that saffron derivatives were ineffective on
the reversal of multidrug resistance of lymphoma cells (the
reversal of multidrug resistance is the result of the inhibition
of the efflux pump function in the tumor cells) [44].
Microscopy studies revealed that HeLa cells treated with
crocin exhibited vacuolated areas, size reduction, cell
shrinkage, and piknotic nuclei [37,43], suggesting that
programmed cell death is induced by crocin, as was
previouly proposed by Morjani [42]. A remarkable bioactive
agent has been isolated from the corms of the saffron plant
[45,46]. This agent showed an ID
50
of 9 mg/ml against HeLa
cells. The cytotoxic activity of this agent on human
malignant cell lines (HeLa, breast carcinoma MDA-MB-
231, and fibrosarcoma HT-1080), a non-malignant cell line
(fibroblasts ASJ-4), and blood cells and hair follicles in
culture, was also analyzed. ID
50
values ranged from 7 to
22 mg/ml for tumor cells, and 100 mg/ml for normal
fibroblasts. Comparison of ID
50
values for fibrosarcoma
cells and normal fibroblasts, both of mesenchymal origin,
showed that this agent is near eight times more toxic on
tumor cells than on non-tumor cells [47].
4. Conclusions
Saffron Crocus sativus L. and their associated carotenoid
ingredients are extensively studied for their biomedical
properties, especially for their chemopreventive potential
against cancer, during the last decade [5–7,25,36,48–50].
Since ancient times, saffron was used in folk medicine as an
anticancer agent against different kinds of tumors and
cancers [49,50]. In the early 1990s, Indian studies and our
own have demonstrated that crude saffron extracts present
antitumor and anticarcinogenic activities as well as
cytotoxic and antimutagenic effects [35,39,40]. A number
of in vivo and in vitro experiments discussed above and in
our recent review [5] clearly indicate that saffron and its
main ingredients have the potential to reduce the risk of
developing several types of cancer. Different hypotheses for
the mode of anticancer action of saffron and its ingredients
have been proposed (Table 1) and in detail discussed in our
previous review [5]. Recently, it was reported that three new
monoterpenoids and a new naturally occurring acid were
isolated from methanol extracts of the petals of saffron.
Among them, crocusatin H, crocin-1, and crocin-3 showed
significant tirosine inhibitory activity [51,52]. Iranian
scientists have demonstrated that three L-lactate dehydro-
genase termostable isoenzymes were detected in saffron
corms [53–54]. To date, the exact mechanism of anticancer
effect of saffron is not clear. However, all of the available
information from animal and in vitro studies indicated that
saffron and their main constituents possess anticancer and
antitumor activities. These findings have not yet been
verified by clinical trials in humans. Comprehensive, in-
depth studies still need to be conducted to define the
mechanisms involving in the therapeutic properties of
saffron and in addition to performing clinical trials in
humans. Indoor cultivation and modern biotechnological
F.I. Abdullaev, J.J. Espinosa-Aguirre/ Cancer Detection and Prevention 28 (2004) 426–432430
Table 1
Proposed mechanism of chemopreventive agent actions
Chemopreventive agents Mechanism of action Reference
Saffron extract Inhibition of itracellular nucleic acid synthesis [4,5,34]
Saffron extract and its carotenoids ingredients Inhibition of free radical chain reaction [5,30,33,35]
Saffron extract Stability to irradiation [49]
Carotenoids Metabolic conversion of carotenoids to retinoids [5,38]
Carotenoids Reaction with topoisomerase II [33,35]
Carotenoids Blocked the cytochrome C activation of caspase-3 [21]
Saffron extract and its carotenoids ingredients Increase of intracellular SH compounds [33,38,39]
Saffron extract Inhibition of genotoxicity [29,31–33]
Saffron extract and its carotenoids ingredients Induction of apoptosis [5,41,42]
Saffron extract and its carotenaoids ingredients Inhibition of different cellular enzymes activity [30,34,43]
Saffron extract and its carotenoids ingredients Inhibition of cell proliferation [5,35,37,42]

methods will prove advantageous in achieving the largest
amount and highest quality of saffron as well as in reducing
its cost of production. In the continued search for new anti-
tumor agents, investigators dedicate their efforts to the study
of natural compounds and their effects in modifying cancer
risks, delaying carcinogenesis, or inhibiting tumor forma-
tion. This work suggests that future research be guaranteed
to evaluate the possible use of saffron as an effective
anticancer agent in clinical trials.
Acknowledgement
This work was partially supported by funds from
CONACyT (Grant 40011).
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