DSpace at VNU: The Function of Saffron and its Constituent in Gastroenterological Tissues

Global Journal of Gastroenterology & Hepatology, 2015, 3, 31-38

31

The Function of Saffron and its Constituent in Gastroenterological
Tissues
T. Tanaka1,2, T. Mori3, C.S. Yuan4, S. Soed5, N.H. Tung6 and Y. Shoyama7,*
1

Department of Tumor Pathology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan

2

Department of Diagnostic Pathology (DDP) & Research Center of Diagnostic Pathology (RC-DiP), Gifu
Municipal Hospital, Gifu City, Gifu 500-8513, Japan
3

Department of Pharmacy, Ogaki Municipal Hospital, 4-86 Minaminokawa-cho, Ogaki 503-8502, Japan

4

Tang Center for Herbal Medicine Research, The Pritzker School of Medicine, University of Chicago,
Chicago, KL 60637, USA
5

Faculty of Pharmaceutical Science, Fukuoka University, Fukuoka 871-6631, Japan

6

School of Medicine and Pharmacy, Vietnam National University, Hanoi, 144Xuan Thuy St. Cau Giay, Hanoi,
Vietnam

7

Faculty of Pharmaceutical Science, Nagasaki International University, Nagasaki 859-3298, Japan
Abstract: Japan has been moving towards a super aging society, resulting in a rapidly increasing prevalence of lifestyle
diseases, including colon cancer. Japanese patients survey by the Ministry of Health, Labour and Welfare reported
235,000 colon cancer patients in 2015, and this number is quickly increasing due to the change of dietary life style from
the typical Japanese food to the westernized style food. Although the cancer chemotherapy has been widely developing
recently, some natural product support, having wide spectra of bioactivity, however mild, are required. Saffron finds use
as folk medicines as well as a flavoring and a coloring agent. Saffron consists of three main chemical components; red
color, crocetin glycosides; a bitter taste, picrocrocin; and spicy aroma, safranal. In this chapter, we evaluate the activities
of saffron extracts and a major crocetin glycoside, crocin. against colorectal cancer in in vitro and in vivo trials. Saffron
crude extracts, which contain approximately 40% of crocin, significantly inhibited the growth of colorectal cancer cell
lines HCT-116, HT-29 and SW-480, although crocin did not affect for non-cancer cells. Crocin significantly inhibited the
development of colonic adenocarcinomas induced by azoxymethane and dextran sodium sulfate in mice during 18
weeks feeding. The crocin feeding experiment for 4 weeks evidently inhibits the dextran sodium sulfate induced colitis
and, then, the clear suppression for the mRNA expression of tumor necrosis factor
, interleukin- (IL-) 1,IL-6, interferon
, NF-B, cyclooxygenase-2, and inducible nitric oxide synthase, and the increase of Nrf2 mRNA expression in the
colorectal mucosa occurred. From these results we suggest that crocin can suppress chemically induced colitis and
colitis-related colon carcinogenesis in mice mainly through the inhibition of inflammation related cytokines, indicating that
saffron and crocin are suitable candidates for the prevention of colitis and inflammation-associated colon carcinogenesis.
We further review the supporting phenomena like strong anti-oxidant and anti-inflammation activities of crocin using our
previous publications.

Keywords: Crocus sativus, saffron, crocin, colorectal cancer cell line, colon carcinogenesis, anti-inflammation
activity.
1. INTRODUCTION
Japan has been moving towards a super aging
society, resulting in a rapidly increasing prevalence in
lifestyle diseases, including colon cancer. Japaneses
patient survey by the Ministry of Health, Labour and

Welfare reported 235,000 colon cancer patients in
2015, and this number is quickly increasing due to the
change of dietary life style from the typical Japanese
food to the westernized style food. Although the cancer
chemotherapy has been widely developing recently,
some natural product support, having wide spectra of
bioactivity, however mild, are required. This is the
reason why natural products having preventive
activities for cancers are particularly desirable in Japan.
*Address correspondence to this author at the Faculty of Pharmaceutical
Science, Nagasaki International University, Nagasaki 859-3298, Japan;
Tel/Fax: +81-956-20-5653; E-mail:
E-ISSN: 2308-6483/15

Considering such recent health circumstances in
Japan, we select saffron for preventing and increasing
quality of life against cancers, and its function will be
reviewed in this chapter because we have been
clarified the multifunctional activity of saffron and its
constituent, crocin [1], although saffron was not listed in
the NCI report indicating the 40 foods having anticancer activity [2].
Crocus sativus L. (Iridaceae) is a perennialherb that
is widely cultivated mainly in Iran, which produces 90%
of saffron, and in other countries like Greece, Spain
and Morocco for its red stigmatic lobes that constitute
saffron from 3500 years ago. This plant blooms only
once a year and the manual harvest of stigmas should
be performed within a very short time [3].

© 2015 Synergy Publishers

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Global Journal of Gastroenterology & Hepatology, 2015, Vol. 3, No. 2

Tanaka et al.

Figure 1: Blooming of Crocus sativus L. (left) and saffron (right).

The manual cultivation methods practiced with
saffron crocus contribute greatly to its high price. About
100,000 flowers give about 1,000 g of the dried saffron.
The stigmas can be collected from full blooming C.
sativus (Figure 1 Left). We confirmed that the
concentration of crocin increases until full blooming and
then decreases. Therefore, stigmas can be collected in
full blooming season in order to keep the higher
concentration of crocin [4].

models of brain disorders, such as cerebral ischemia
[17], Alzheimer disease [18], depression [19], memory
impairment [20-22] and neuroprotective activity
[7,17,23,24].

Saffron finds use as folk medicines and traditional
Chinese medicine (TCM) as well as a flavoring and a
coloring agent. Saffron has three main chemical
components: the bright yellow coloring carotenoids, a
bitter tastingpicrocrocin, and spicy aroma, safranal. The

carotenoid pigments consist of crocetin-diglucoside,
crocin-2, crocin-3, crocin-4 and crocetin-di-(
-Ddigentiobiosyl)-ester (crocin) (Figure 2). More recently
we succeeded to isolate a novel crocetin glycoside,
trans-crocetin-1-al 1-O-
-gentiobiosyl ester (Figure 2)
[5]. We confirmed that drying is important because an
endogenous
-glucosidase is still active when moisture
remains [4]. Therefore, drying is completed in about 3045min, after which the drug is cooled and stored under
dry condition [4].
Saffron can be used as an antispasmodic,
anticatarrhal, and nerve sedative ingredient, and is
reported to be useful in treating various human
disorders such as heart and blood disorders [6]. Crocin
has a wide range of activities including antioxidant
[7,8], hypolipidemic [9,10,11] like lowering of
cholesterol and triglyceride levels in serum by crocin
and crocetin [12], an inhibitory effect on the increase of
bilirubin in blood [13] and anti-inflammatory effects [1416]. The neuroprotective activities of crocin have also
been demonstrated in various experimental animal

Figure 2: Structures of saffron constituents.

Since it becomes clear that saffron and its
constituent, crocin have the wide pharmacological
activities as described above, we focus to confirm the
incorporation of crocin into cells first and the anticolorectal cancer activities of saffron and crocin in vitro
and in vivo in this chapter.


The Function of Saffron and its Constituent in Gastroenterological Tissues

Global Journal of Gastroenterology & Hepatology, 2015, Vol. 3, No. 2

2. PREPARATION OF ANTI-CROCIN MONOCLONAL
ANTIBODY (MAB) AND CONFIRMATION FOR
INCORPORATION OF CROCIN INTO CELLS BY
IMMUNOSTAINING

had
light chains. The reactivity of IgG type MAb 12a
was tested by varying antibody concentration and by
performing a dilution curve, and then the antibody
concentration was selected for competitive ELISA. The
measuring range of this ELISA system extends from 10
to 200 ng/ml of crocin [25].

In the first stage of anti-colorectal cancer
investigations, we prepared monoclonal antibody
(MAb) against crocin [25]. In the first step for
preparation of MAb against crocin, the conjugate of
crocin with carrier protein for immunization is
necessary. Therefore, crocin was treated with NaIO4 to
cut sugar moiety releasing aldehyde in a molecule
following addition of carrier protein. As the other way,
the crocin-hemisuccinate was prepared first, and then
conjugated with BSA to give crocin-hemisuccinate BSA
conjugate as indicated in Figure 3. The molecular
weight of prepared schiff base was analyzed by
MALDI-tof-mass spectrometry to determine the hapten
number in the conjugate for suitability of immunization.
Since the hapten number in crocin-hemisuccinate BSA
conjugate was determined to be 8.6, which was

suitably enough for immunization rather than that of
crocin-BSA conjugate prepared by NaIO4 treatment,
the former was used as an antigen. Hybridoma
producing MAb reactive to crocin was obtained by
general procedure, and classified into IgG2a, which

33

In order to confirm the incorporation of crocin and
the localization of crocin into PC-12 cells, we
immunostained cells using the anti-crocin MAb
prepared. Clear incorporation of crocin into PC-12 cells
was confirmed after 30 min comparing with the control
cells as indicated in Figure 4 [24]. The incorporation
after the addition of crocin in the medium was not
enough after 15 min (Figure 4B). After 30 min, the clear
staining occurred (Figure 4C and D). From this
evidence we confirmed that crocin can be incorporated
into the cell and be functioned.
3. ANTI-PROLIFERATION ACTIVITIES OF SAFFRON
EXTRACT AND CROCIN AGAINST HUMAN
COLORECTAL CELL LINES
Anti-tumour activity of saffron on mice transplanted
with sarcoma-180, Ehrlich as cites carcinoma and
Dalton’s lymphoma as cites tumours [26], inhibitory
effects of saffron on chemical carcinogenesis in mice
using two-stage assay system [27,28,29] and the effect
of crocetin on skin papillomas and rous sarcoma [30].
Escribano et al. (1996) reported crocin inhibits the
growth of Hela cells and suggested apoptosis induction

[31]. Effects of saffron extracts and crocin on the
proliferation of colorectal cancer cell lines, we
investigated HCT-116, SW-480 and HT-29 [32].
Figure 5A shows the relationship between saffron
extract concentration and the inhibition of proliferation
for the three cell lines. At 0.25 and 0.5 mg/ml levels of
saffron extract no inhibition occurred in three cell lines.
When 1.0 mg/ml of saffron extract was added, the
decrease of proliferation ratio was observed resulting in
45.5, 91.0 and 79.2 %, in HCT-116, SW-480 and HT29 cells, respectively. In the case of 3.5 mg/ml of
saffron extract, strong inhibition appeared in all cells as
6.8, 17.6 and 12.9 %, respectively (Figure 5A). From
these results HCT-116 cells were the most sensitive to
saffron extract, suggesting the major constituent of
saffron, crocin, might be strongly affective for three cell
lines.

Figure 3: Synthetic pathway of hapten for preparation of
monoclonal antibody against crocin.

The same tendency was observed with the addition
of crocin (Figure 5B). At a 1.0 mM concentration of
crocin, HCT-116, SW-480 and HT-29 cells proliferation
was significantly reduced to 2.8, 52 and 16.8%


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Global Journal of Gastroenterology & Hepatology, 2015, Vol. 3, No. 2

Tanaka et al.

Figure 4: Immunostaining of crocin in PC-12 cells using anti-crocin monoclonal antibody.
A Control cells.
B Culturing for 15 min C Culturing for 30 min D Culturing for 1h.

Figure 5: Effects of saffron extract (A) and crocin (B) on proliferation of human colorectal cancer cells, HCT-116, SW-480 and
HT-29.

proliferation, respectively (P < 0.01), although at 0.03,
0.1 and 0.3 mM the affect was not strong. Consistent
with the saffron data, crocin has the most significant
anti-proliferative effect on HCT-116 cells. Since the
concentration of crocin in the saffron crude extract is
approximately 40 % [4], 3 mg of saffron extract and 1

mM of crocin are nearly equivalent. Therefore, the
above two results (Figure 5A and B) are satisfactory
although the other minor crocetin-glycosides are
contained in saffron extract as previously documented
[4].


The Function of Saffron and its Constituent in Gastroenterological Tissues

Global Journal of Gastroenterology & Hepatology, 2015, Vol. 3, No. 2

In the above evaluation of saffron extract and
crocin, we confirmed the specificity of saffron and
crocin against cancer cell lines. We also evaluated the

effects of saffron extract and crocin on non-small cell
lung cancer (NSCLC) cells in addition to colorectal
cancer cells. Our data showed that at 1.0 mg/ml and
3.0 mg/ml, saffron extract reduced the NSCLC
proliferation to 83.9% (P < 0.05) and 34.1% (P < 0.01),
respectively. At 1.0 mM crocin concentration, the cell
proliferation was reduced to 43.3% (P < 0.01). Saffron
extract did not affect the proliferation of non-cancer
(young adult mouse colon) YAMC cells. In this part of
the study, the effect of saffron extract on YAMC cells
was compared to that of the HCT-116 cells. At the
tested concentration range, saffron extract did not
show any significant inhibition of the YAMC cells, while
cell growth was significantly inhibited in HCT-116 cells
at 1.0 mg/ml (P < 0.01).

incidence of high-grade dysplastic crypts significantly
decreased by feeding the mice with all three
concentrations of crocin compared tothe AOM + DSS
group. The multiplicity of high-grade dysplastic crypts
also decreased by the crocin treatment at the higher
concentrations (100 and 200 ppm).

4. ANTI-COLORECTAL
CROCIN IN VIVO

CANCER

ACTIVITY

35

OF

Previous in vitro investigation clearly showed that
the real constituent having anti-cancer activity in
saffron was crocin. First of all, we confirmed that no
observable clinical toxicity was found in the mice by
histopathological survey of liver and kidneys, by
weights of the whole body and liver, and by the colon
length after feeding of crocin for 8 weeks. This is in
good agreement with the previous data that the oral
LD50 of saffron was approximately 20 g/kg [33],
meaning it is a very safe food.
Following the in vitro data of crocin using three
colorectal cell lines we started the in vivo experiments
using mice with the feeding of azoxymethan (AOM) and
dexran sodium sulfate (DSS),which were applied as the
promotional agent for the induction of colorectal lesions
[34]. The feeding of AOM and/or DSS in mice was
investigated. The AOM and/or DSS treatment indicated
the occurrence of several colorectal lesions, such as
colitis with mucosal ulcers, dysplastic crypts, tubular
adenoma and tubular adenocarcinoma resulting in the
clear incidences and multiplicity of colorectal
inflammation with mucosal ulcers and the presence of
dysplasia after 18 weeks.
The incidence of inflammation with mucosal ulcers
significantly decreased after feeding of all three
concentrations of crocin (50, 100 and 200 ppm)

compared to AOM + DSS group. Similarly, the
inflammation score decreased after crocin treatment at
the higher concentrations (100 and 200 ppm). The

Figure 6: Histopathological survey of colonic proliferative
lesions (tubular adenocarcinoma) induced by azoxymethane
(AOM) and dextran sodium sulfate (DSS).

The incidence and multiplicity of colonic tumors
after 18 weeks of feeding were observed. The AOM +
DSS group clearly indicated colonic adenocarcinoma
with an incidence of 90% and a multiplicity of 3.15 ±
1.87. On the other hand the treatment with three
concentrations of crocin significantly reduced the
incidence and multiplicity of adenocarcinoma. Crocin
also significantly decreased the incidence of adenomas
and the multiplicities of colonic adenoma.
The expression of minichromosome maintenance
protein 2 (MCM2) related to the DNA replication in
colonic adenocarcinoma areas was surveyed by the
immunohistochemical analysis using anti- MCM2 rabbit
MAb in order to determine the effects of crocin on the
proliferation of cancer cells. From this analysis, a clear
decrease of staining in adenocarcinoma was observed
in the treatment with crocin compared to that of AOM +
DSS group, indicating that crocin evidently decreased
the cancer cell proliferation (Figure 7).
To make sure the expression of NF-kB and Nrf2 by
the
treatment with or without crocin,

the
immunohistochemical analysis in the adenocarcinomas
that will be developed into the colons was investigated.
When compared with the AOM + DSS group, the
treatment of crocin at 100 ppm and200 ppm
significantly suppressed the immunohistochemical
score for NF-
B, while significantly enhancing the


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Global Journal of Gastroenterology & Hepatology, 2015, Vol. 3, No. 2

Tanaka et al.

Figure 7: Immunohistochemical staining for minichromosome maintenance protein 2 (MCM2) by anti-MCM2 monoclonal
antibody.
Left colorectal tissues treated with azoxymethane (AOM) and dextran sodium sulfate (DSS).
Right Treatment with AOM/DSS and crocin 200 ppm.

expression of Nrf2 at 200 ppm crocin. In the crocin
alone group (200 ppm) and the untreated group, the
immunohistochemical expressions of NF-B and Nrf2
in the colonic mucosa were very weak.
The colonic mucosa of mice treated with 200 ppm of
crocin alone showed almost normal histology. On the
other hand the DSS treatment induced severe colitis
with mucosal ulcers. The induction of colitis in the mice
treated with DSS and crocin at 100 ppm or 200 ppm
decreased, and regenerative crypt cells covered and

healed the mucosal ulcers as shown in Figure 8.

surveyed comparing with the DSS alone group by an
RT-PCR analysis. The expression levels of all genes
except iNOS and Nrf2 in the mice treated with DSS
were dose-dependently decreased by the combination
with crocin. On the other hand the expression levels of
Nrf2 and iNOS were increased by the treatment with
crocin.

Figure 9: Inflammation score in colorectum with DSS and/or
crocin.

5. CONCLUSION

Figure 8: Histopathological survey of colorectal mucosa.
Treated with DSS and 200 ppm of crocin.

The inflammation scores of the DSS + 50 ppm
crocin (P <0.05), DSS + 100 ppm crocin (P <0.01), and
DSS + 200 ppm crocin (P <0.001) groups were
significantly decreased dose-dependently than those of
the DSS alone group as indicated in Figure 9.
The relative mRNA expression levels of COX-2,
iNOS, IFN-, TNF-
, IL-1, IL-6, NF-B and Nrf2 were

In cancer chemotherapy, the induction of cancer cell
apoptosis has been emphasized, and the cell apoptosis
is mediated by many factors. Among them, p53 gene is
a transcription factor placed at the nexus of a number

of pathways that mediate apoptosis in response to a
wide range of cellular stresses [35]. HCT-116 cells are
p53 gene wild-type, while SW-480 and HT-29 cells are
mutant in the p53 tumor suppressor gene. Since the
effects of saffron extract and crocin on HCT-116 are
stronger than that of HT-29 and SW480, it suggests
that some activity of p53 gene may be linked to the
saffron extract and crocin to express the anti-cancer
effects [36]. Furthermore, crocin has anti-tumor effects


The Function of Saffron and its Constituent in Gastroenterological Tissues

on cellular DNA and RNA synthesis [26,37]. Another
mechanism for the anti-tumor action of saffron extract
and crocin is the inhibitory effect on free radical chain
reactions [38], because most carotenoids are lipidsoluble and might act as membrane-associated highefficiency free radical scavengers, connects with their
anti-oxidant properties [7,39,40].
The feeding of crocin significantly suppressed
several inflammatory events and NF-B expression in
the colorectal mucosa of the mice fed with DSS.
Inflammatory genes, such as COX2, iNOS, TNF-
, and
IL-1, are the most common target genes participating
in the activation of NF-B and are associated with a
number of chronic inflammatory diseases, including
inflammatory bowel disease (IBD) and IBD-related
colorectal carcinogenesis [41-45]. We observed
decreases in the mRNA expression levels of NF-B,
COX-2, TNF-
, IL-1, and IL-6 in the mice treated with
DSS and crocin compared to the mice with DSS alone.

These evidences suggest that crocin suppressed the
mouse colonic inflammation induced by DSS by
modulating the NF-B signaling pathway. The NF-B
signaling pathway also has a major role in
inflammation-associated
carcinogenesis
[46].
Therefore,
NF-B
is
a
target
for
cancer
chemoprevention [47,48], and natural compounds that
suppress NF-B expression may be useful for cancer
chemoprevention [49]. As previously documented
crocin has the anti-inflammatory effects [14-16], these
evidences might be related to a range of inflammation
gene expression. Since rocin did not produce any
chromosome damage in mammalian cells in culture
[50], the clinical trials of crocin may be possible.
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