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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 LD5 0 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 ow and retinal
function
It was shown that crocin analogs isolated from
saffron significantly increased the blood ow 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 degeneration.
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 med icine, 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-in ammatory
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-in ammatory
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), 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 Tcell mitogen
phytohemagglutinin, saffron stimulated non- specific
proliferation of lymphocytes in vitro [36],
suggesting 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
adenocarcinoma 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 depend ent 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 hypo thesis that the action of
carotenoids was dependent upon its conversion to
retinal (Vitamin A), because most of the evidence
supporting the anticancer effects of caroten oids
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 rotein 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 fib roblasts) 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 crocinwith 50% inhibition (ID50 )
reached at concentrations of 0.8 and 2 mM,
respectively, [38,42]. Cytotoxicity of dimeth yl-
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.
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 (ID50 =
2.3 mg/ml) was mainly due to crocin (ID5 0 of 3 mM),
where picrocrocin and safranal, with an ID50 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].AnID5 0 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 f the ef ux 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 ID5 0
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. ID5 0 values ranged from
7 to 22 mg/ml for tumor cells, and 100 mg/ml for
normal fibroblasts. Comparison of ID50 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].
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