INTERNATIONAL JOURNAL OF ONCOLOGY 38: 1319-1327, 2011
Abstract. Ganoderma lucidum is a herbal mushroom known
to have many health benefits, including the inhibition of tumor
cell growth. However, the effect of Ganoderma lucidum on
epithelial ovarian cancer (EOC), the most fatal gynecological
malignancy, has not yet been reported. In this study, we
determined whether Ganoderma lucidum regulates EOC cell
activity. Using several cell lines derived from EOC, we found
that Ganoderma lucidum strongly decreased cell numbers in
a dose-dependent manner. Ganoderma lucidum also inhibited
colony formation, cell migration and spheroid formation. In
particular, Ganoderma lucidum was effective in inhibiting
cell growth in both chemosensitive and chemoresistant cells
and the treatment with Ganoderma lucidum significantly
enhanced the effect of cisplatin on EOC cells. Furthermore,
Ganoderma lucidum induced cell cycle arrest at the G2/M
phase and also induced apoptosis by activating caspase 3.
Finally, Ganoderma lucidum increased p53 but inhibited Akt
expression. Taken together, these findings suggest that
Ganoderma lucidum exerts multiple anti-tumor effects on
ovarian cancer cells and can enhance the sensitivity of EOC
cells to cisplatin.
Ganoderma lucidum is a herbal mushroom that has been
widely used in preventive medicines in China and other Asian
countries for over 2,000 years. It has also become a popular
dietary supplement in Western countries. Ganoderma lucidum
contains many different bioactive compounds, which mainly
include triterpenoids, polysaccharides, nucleotides, sterols,
steroids, fatty acids, proteins/peptides and trace elements (1).
These substances are known to have many biological activities,
including anti-tumor (2), immunomodulatory (3), anti-viral
(4), anti-hepatitis (5), antioxidant (6), antihypertensive (7,8)
and anti-diabetic activities (9). It has been reported that
Ganoderma lucidum extracts can inhibit tumor formation and
the proliferation of breast and prostate cancer, hepatoma,
melanoma lymphoma and myeloid leukemia cell lines (10-12).
Thus, Ganoderma lucidum could be used as a potential thera-
peutic agent in the form of a dietary supplement for cancer
Epithelial ovarian cancer (EOC) is the most common form
of ovarian cancer and the leading cause of death from gyneco-
logical disorders (13). The high mortality rate of EOC is mainly
due to the late diagnosis and the lack of effective treatments
for the late stages of the disease (14). The most effective
treatment for EOC is surgery plus platinum-based chemotherapy,
with drugs such as cisplatin. However, the majority of patients
ultimately experience chemoresistance and recurrence of their
disease (15). Considering the high mortality rate of ovarian
cancer due to the absence of effective treatment in advanced
stages or during relapse, new therapeutic strategies are urgently
In this study, we examined the effects of Ganoderma
lucidum on cell proliferation and migration in several ovarian
cancer cell lines. Our results show that Ganoderma lucidum
inhibits cell growth, migration and spheroid formation in both
chemosensitive and chemoresistant ovarian cancer cells.
Ganoderma lucidum also induced cellular apoptosis by
down-regulating anti-apoptotic proteins. Ganoderma lucidum
greatly enhanced the sensitivity of chemoresistant cells to
cisplatin, possibly by up-regulating p53 and down-regulating
Materials and methods
Cell culture. The immortalized human ovarian surface
epithelial cell line, IOSE-398, and the EOC cell lines, OV2008,
C13*, A2780s and A2780-cp, were obtained and cultured as
described previously (16-18). Skov3 cells were obtained from
ATCC and cultured in McCoy 5A medium containing 10%
FBS and 1% penicillin/streptomycin. Cells were grown at
37˚C in an atmosphere with 5% CO2.
Ganoderma lucidum exerts anti-tumor effects on ovarian
cancer cells and enhances their sensitivity to cisplatin
SUFEn ZHAO1,2, GANG YE1, GUOdONG FU1, JIAn-XIn CHEnG3, BUrTOn B. YAnG4 and CHUn PEnG1
1Department of Biology, York University, Toronto, Canada;
2Department of Obstetrics and Gynecology, The Second Hospital of Hebei Medical University;
3Department of Obstetrics and Gynecology, The Fourth Hospital of Hebei Medical University, Shijiazhuang,
P.r. China; 4Sunnybrook research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada
received December 7, 2010; Accepted January 10, 2011
Correspondence to: Dr Chun Peng, Department of Biology, York
University, 4700 Keel Street, Toronto, On M3J 1P3, Canada
Key words: Ganoderma, ovarian cancer, chemoresistant cells
ZHAO et al: AnTI-TUMOr EFFECTS OF Ganoderma On OVArIAn CAnCEr CEllS
Preparation of Ganoderma lucidum. The Ganoderma lucidum
used in this study is a mixture containing sporoderm-broken
spores by enzymatic methods and polysaccharides extracted
from fruiting bodies, as previously described (19). A stock
solution of 50 mg/ml was prepared by adding water and then
boiling for 5 min. After a brief centrifugation, the supernatant
was collected and passed through a 0.2 µm filter. The stock
solution was stored at 4˚C.
Cell proliferation and viability assays. Cell proliferation and
viability were determined using manual counting and WST-1
assays. For manual counting, cells were seeded in 24-well
plates. After treatment with Ganoderma lucidum, cells were
fixed with methanol containing 1 µg/ml DAPI. The DAPI-
stained cells were viewed at x100 magnification under a
fluorescent microscope (nikon Eclipse TE 2000-U). Five
randomly selected fields in each sample were photographed,
scored and averaged for cell numbers. For WST-1 assay, cells
were seeded on 96-well culture plates at a density of 10,000
cells per well and cultured for 24 h prior to treatment. After
treatment with different concentrations of Ganoderma for
48 h, WST-1 reagent was added to the cells and absorbance
was measured at 450 nm using an ElISA plate reader.
Treatment with cisplatin. The cells were cultured in 24-well
plates at a density of 6x104 cells per well and treated with
0.5 mg/ml Ganoderma lucidum and different concentrations
of cisplatin for 48 h. At the end of the experiment, live cell
numbers were counted as described above.
Cell cycle analysis. To determine the cell cycle profile following
Ganoderma treatment, flow cytometry was performed. Briefly,
2x106 cells were collected, washed twice with PBS, and fixed
with 3 ml ice-cold 70% ethanol. The cells were then washed
twice with cold PBS, resuspended with 1 ml staining buffer
containing 50 µg/ml rnase A and stained with 50 µg/ml
propidium iodide for 1 h at room temperature in the dark.
Finally, samples were analyzed by flow cytometry using
FACScalibur (BD Biosciences, San Jose, CA, USA).
Hanging drop culture for spheroid formation. Skov3 cells
were cultured in McCoy 5A medium containing 10% FBS and
1% penicillin/streptomycin. Cells were then trypsinized,
resuspended in the same culture medium, and treated with
different doses of Ganoderma lucidum (0.5, 1, 2 mg/ml).
Hanging drop culture was performed using a method previously
described for ovarian cancer cells (20) with slight modifi-
cations. Briefly, 15 µl droplets, each containing 10,000 cells,
were seeded on the inner surface of a Petri dish cover. The
covers were then inverted and placed on a dish containing
15 ml of PBS. The formation of spheroids was examined and
photographed on the fourth day after the plating of the
Assessment of apoptosis by Hoechst 33258. Apoptotic cells
were identified morphologically by Hoechst 33258 DnA
staining (Sigma, Oakville, On, Canada). Briefly, cells were
cultured on 6-cm dishes at 5x104 cells/dish and treated with
1 mg/ml Ganoderma lucidum for 48 h. At the end of the
experiment, the cells were fixed in 4% paraformaldehyde at
room temperature for 20 min, and then incubated with 1 µg/ml
Hoechst 33258 for 15 min. After washing with PBS, cells
were assessed for typical apoptotic nuclear morphology (nuclear
shrinkage, condensation and fragmentation) using a fluorescent
microscope (nikon Eclipse TE 2000-U).
Western blot analysis. The protein lysates were separated in
12% SDS polyacrylamide gels, transferred to Immobilon PVDF
Membranes (Millipore, Toronto, On, Canada), and probed with
anti-Bcl-2, Bcl-xL, cleaved caspase 3, Akt, phosphor-Akt
(1:1000 dilution, Cell Signaling, Danvers, MA, USA) and
anti-p53 antibodies (1:1000, Santa Cruz Biotechnology, Santa
Cruz, CA, USA). The ECl kit (GE Healthcare, Baie d'Urfe,
Quebec, Canada) was used for the chemiluminescent detection
of immobilized proteins. Protein loading was evaluated using
mouse anti-β-actin (Sigma).
Wound healing assay. OV2008 and C13* cells were cultured
in 6-well plates until cells reached near confluence and a
wound was made using a 200 µl pipette tip. After scratching,
the culture medium was refreshed and different doses of
Ganoderma lucidum (0, 0.5, 1, 2 mg/ml) were added. Ten
points were marked randomly down the wound and photo-
graphs were taken at the same points before and 24 h after
incubation with Ganoderma lucidum. The area migrated by
the cells was measured by computer Simple PCI software
(Compix Inc., Cranberry Township, PA, USA).
Cell clonogenic assay. Clonogenic assay was performed
according to a previously described protocol (21) with a slight
modification. Briefly, Skov3 cells were seeded onto 60-mm
culture dishes at a density of 5x103 cells/well in McCoy 5A
complete culture medium in a humidified 37˚C, 5%CO2
incubator. Following cellular attachment, different concen-
trations of Ganoderma lucidum were added to the culture
medium. Cultures were maintained for 7 days until the visible
clones appeared. The colonies were fixed with 4% paraformal-
dehyde and stained with 0.5% crystal violet. The plates were
Statistical analysis. The data were expressed as the means ±
SEM. Statistical significance was determined using one-way
analysis of variance and the Student-newman-Keuls test for
multiple group comparison. The Student's t-test was used for
comparison between two groups. Statistical significance was
defined as a value of p<0.05.
Ganoderma lucidum inhibits cell growth and viability in
ovarian cancer cells. To determine the effect of Ganoderma
on ovarian cancer cells, we first treated cells with 0.1, 0.5 and
1 mg/ml of Ganoderma. The immortalized ovarian epithelial
cell line, IOSE-398, and two pairs of ovarian cancer cell lines,
A2780-s (chemosensitive)/A2780-cp (chemoresistant) and
OV2008 (chemosensitive)/C13* (chemoresistant), were used.
As shown in Fig. 1A, with the exception of IOSE-398 cells, all
other cell lines showed a decrease in the number of cells after
treatment with higher doses of Ganoderma. A significant
effect on cell growth was observed at 1 mg/ml Ganoderma
INTERNATIONAL JOURNAL OF ONCOLOGY 38: 1319-1327, 2011
(Fig. 1B). In order to confirm these results, WST-1 assays were
performed and we observed that IOSE-398 cells were not
affected by Ganoderma until cells were treated with a very
high dose (5 mg/ml) for 48 h. In contrast, OV2008 cells
treated with 2.5 and 5 mg/ml of Ganoderma exhibited a very
significant decrease in cell viability at 24 and 48 h after
treatment (Fig. 2A). In 2780-s and 2780-cp cells, treatment
with Ganoderma reduced cell viability, with the maximal
effect observed at 1 mg/ml (Fig. 2B).
Ganoderma enhances the effect of cisplatin on ovarian cancer
cells. As we observed that Ganoderma was effective in
inhibiting growth/viability in both chemosensitive and chemo-
resistant cells, we examined whether it could enhance the
Figure 1. Ganoderma lucidum inhibited ovarian cancer cell growth. (A) Morphology of cells treated with different doses of Ganoderma. Photographs were
taken at 48 h after treatment. (B) Cell numbers in the control and Ganoderma-treated groups. The OV2008 cell line and its chemoresistant countpart, the C13*
cell line, were treated with Ganoderma for 48 h. Cells were then fixed, stained with DAPI and counted. Data represent the means ± SEM (n=4). *P<0.05 vs. other
ZHAO et al: AnTI-TUMOr EFFECTS OF Ganoderma On OVArIAn CAnCEr CEllS
sensitivity of ovarian cancer cells to the chemotherapeutic
agent, cisplatin. A2780-s and A2780-cp cells were treated
with different concentrations of cisplatin in the presence or
absence of a low dose of Ganoderma. The Ganoderma
treatment alone slightly decreased the cell numbers. However,
in the co-treatment with cisplatin, it significantly enhanced
the effect of cisplatin on cellular growth inhibition (Fig. 3).
We repeated these experiments using OV2008 and C13* cells
and obtained similar results (data not shown).
Ganoderma inhibits cell migration and spheroid and colony
formation. As Ganoderma inhibited cellular growth and
viability in ovarian cancer cells, we hypothesized that it could
have anti-tumor effects. To test this hypothesis, several
experiments were performed. Firstly, OV2008 and C13* cells
were treated without or with different doses of Ganoderma
and a wound healing assay was carried out to determine
whether Ganoderma affects cell migration. As shown in
Fig. 4A, Ganoderma strongly inhibited wound closure in both
cell lines. Secondly, the effect of Ganoderma on spheroid
formation was assessed using a hanging drop culture. Skov3 is
an invasive ovarian cancer cell line. When droplets of these
cells were plated on the inner cover of a culture dish, the cells
proliferated, aggregated and formed tight spheroids. However,
in the cells treated with 1 and 2 mg/ml Ganoderma, only
loose and irregular spheroids were observed (Fig. 4B). Finally,
clonogenic assays were used to test the effect of Ganoderma
on cell colony growth. Skov3 cells were treated with or
without Ganoderma and plated. At 7 days after plating,
colonies were stained and photographed. Ganoderma strongly
inhibited colony formation in a dose-dependent manner
Ganoderma induces apoptosis and blocks cell cycle progression
at the G2/M phase. To examine how Ganoderma inhibited
cell growth and viability, we used flow cytometry to determine
the effect of Ganoderma on cell cycle progression. Analysis
of the cell cycle profile in control and Ganoderma-treated
cells revealed that Ganoderma increased the population of
cells at the G2/M phase. It did not change the percentage of
cells at the S phase but decreased the number of cells at the
G1 phase (Fig. 5). We then determined whether Ganoderma
regulates apoptosis. Hoechst staining showed that there were
more cells showing features of apoptotic nuclei in the
Ganoderma-treated cells. Using Western blot analysis, we
found that Ganoderma inhibited the expression of the anti-
apoptotic proteins, Bcl-2 and Bcl-xL, and increased the level
of activated caspase 3 (Fig. 6).
Ganoderma induces p53 activation and inhibits Akt. Two
molecules, p53 and Akt, have been reported to be involved in
chemoresistance in ovarian cancer cells (22). To understand
the mechanisms underlying the chemoenhancing effect of
Ganoderma, we tested whether it could regulate p53 and Akt
Figure 2. Ganoderma reduces the cell viability as measured by WST-1 assays. (A) IOSE-398 and OV2008 cells were treated with 0, 2.5 and 5 mg/ml of
Ganoderma for 24 and 48 h. *P<0.05 vs. the untreated control. (B) A2780-s and A2780-cp cells were treated with or without Ganoderma for 24 h. Data
represent the means ± SEM (n=6). *P<0.05 vs. the untreated control. #P<0.05 vs. 0.5 mg/ml treatment.
INTERNATIONAL JOURNAL OF ONCOLOGY 38: 1319-1327, 2011
expression and activation. In OV2008 and A2780-s cells,
Ganoderma increased p53 and decreased total Akt levels
(Fig. 7A). A slight inhibition of Akt activity was also observed
with the high dose of Ganoderma (Fig. 7A). When OV2008
and C13* cells were treated with a combination of Ganoderma
and cisplatin, a strong induction of p53 and an inhibition of
Akt expression were observed (Fig. 7B).
Ganoderma has been extensively used as a herbal medicine
for the treatment of diseases, including cancer, for centuries in
China, Japan and Korea (23). During the past decade, the
anti-cancer effect of Ganoderma has also been widely tested
in different cancer models in vivo and in vitro (24-26). In this
study, we demonstrate that Ganoderma has potent anti-tumor
effects on chemosensitive and chemoresistant ovarian cancer
cells and we uncover potential mechanisms by which
Ganoderma regulates cell proliferation, apoptosis and chemo-
sensitivity. To the best of our knowledge, this is the first report
of Ganoderma on ovarian cancer cells.
To test the effect of Ganoderma lucidum on ovarian
cancer cells, we treated several EOC cell lines and a non-
tumorigenic IOSE cell line with Ganoderma and performed a
varity of assays. Firstly, in cell viability/proliferation assays,
we found that Ganoderma has potent cytotoxic effects on
Figure 3. Ganoderma enhances the effect of cisplatin on inhibiting cell growth. A2780-s and A2780-cp cells were treated with the indicated concentrations
of cisplatin in the absence or presence of 0.5 mg/ml Ganoderma. Cell morphology and cell numbers were determined at 48 h after treatment. Data represent
the means ± SEM (n=4). *P<0.05 vs. the corresponding control (without Ganoderma treatment).
ZHAO et al: AnTI-TUMOr EFFECTS OF Ganoderma On OVArIAn CAnCEr CEllS
EOC cells. However, such an effect was not prominent in
normal ovarian epithelial cells, especially at a low dose,
suggesting that malignant tumor cells are more sensitive to
Ganoderma. This result is consistent with a recent study
conducted on lung cancer cells showing that Ganoderma
extracts are more cytotoxic in tumor cells than in normal cells
(26). Secondly, using wound healing assays, we observed that
Ganoderma treatment led to the attenuation of cell migration
in a dose-dependent manner. The anti-migratory effect of
Ganoderma has been shown in many cancer cell lines (27,28),
suggesting its potency in reducing tumor invasiveness. Thirdly,
Ganoderma markedly suppressed the spheroid aggregation.
The control or low-dose Ganoderma lucidum-treated Skov3
cells formed very tight and compact globular spheroids,
whereas the spheroids from the cells treated with higher
concentrations of Ganoderma exhibited loose and irregular
structures, indicating the strong efficacy of Ganoderma on
ovarian cancer cell adhesion. Finally, Ganoderma remarkably
Figure 4. Ganoderma inhibits cell migration, spheroid formation and colony formation. (A) Wound healing assays. OV2008 and C13* cells were plated and a
wound was created. Cells were then treated with different concentrations of Ganoderma for 24 h. The distance between two sides of the wound was measured
before and after treatment. A strong inhibition on migration was observed in the Ganoderma-treated cells (means ± SEM, n=3). *P<0.05 vs. no treatment,
#p<0.05 vs. 0.5 mg/ml treatment, +p<0.05 vs. 1 mg/ml treatment. (B) Hanging drop culture showing the effect of Ganoderma on spheroid formation. (C) A
representative colony formation assay performed in Skov3 cells. A strong dose-dependent inhibitory effect of Ganoderma on cells growth was observed.
INTERNATIONAL JOURNAL OF ONCOLOGY 38: 1319-1327, 2011
prevented the colony formation of Skov3 cells dose-dependently.
A similar potency has been shown in breast cancer and
myelogenous leukemia cells (29-31). Thus, our findings strongly
suggest that Ganoderma has anti-tumor effects on ovarian
The inhibition of apoptosis, rather than enhanced cell
proliferation, is considered to be a more important factor
contributing to the development of cancer (32). Therefore,
targeting apoptotic pathways and inducing apoptosis in tumor
cells have been implied as critical mechanisms of anti-cancer
agents. The anti-apoptotic Bcl-2 family members, Bcl-2 and
Bcl-xL, act as repressors of apoptosis by blocking the release
of cytochrome-c, and the inhibition of caspase 3 activation
(33). In this study, we observed that Ganoderma induced
morphological changes in the cell nuclei which are characteristics
of apoptosis, decreased Bcl-2 and Bcl-xL levels and activated
caspase 3. These results indicate that Ganoderma induces
apoptosis in EOC cells. The pro-apoptotic effect of Ganoderma
has been well established in several other cancer cell lines,
such as breast, prostate and lung cancer cells (30,34,35).
It has been widely reported that Ganoderma lucidum
extracts interfere with the cell cycle to act as anti-cancer
agents. Ganoderma has been found to arrest the cell cycle at
the G2/M phase in several tumor cells, such as hepatoma,
prostate cancer, myeloid leukemia and bladder cancer cells
(27,28,34,36). Consistent with these reports, we also observed
an increase in G2/M cell population following Ganoderma
treatment in ovarian cancer cells. p53 has been shown to
regulate the G2/M transition either through the induction of
the downstream signaling cascade in the cytoplasm (37,38) or
Figure 5. Ganoderma blocked cell cycle progression at the G2/M phase. OV2008 cells were treated with or without Ganoderma and cell cycle profiles were
analyzed by flow cytometry at 48 h after treatment.
Figure 6. Ganoderma induced apoptosis. (A) OV2008 cells were treated
with 1 mg/ml of Ganoderma for 48 h, followed by Hoechst staining. nuclei
apoptotic features (DnA condensation and fragmentation, indicated by
arrows) were observed in the Ganoderma-treated cells. (B) Western blot
analysis of Bcl-2, Bcl-XL and cleaved caspase 3 in the control and
Ganoderma-treated OV2008 cells. Equal protein loading was evaluated
using anti-β-actin antibody.
ZHAO et al: AnTI-TUMOr EFFECTS OF Ganoderma On OVArIAn CAnCEr CEllS1326
through the induction of apoptosis (39,40). Our data also
demonstrate that p53 protein expression is up-regulated after
Ganoderma treatment. Thus, the G2/M cell cycle arrest is
likely to be an outcome of p53 elevation.
The most interesting finding from this study is that
Ganoderma sensitized the ovarian cancer cell response to
cisplatin. Since we found that Ganoderma was effective in
inhibiting cell growth, survival, migration and/or spheroid
formation in several chemoresistant EOC cell lines, such as
A2780-cp, C13* and Skov3, we tested whether Ganoderma
could enhance the sensitivity of EOC cells to cisplatin. The
Ganoderma treatment greatly potentiated the cisplatin effects
in A2780s, a chemosensitive ovarian cancer cell line, as well
as in its chemoresistant counterpart, the A2780cp cell line.
Similar results were also observed in another pair of EOC
cells, OV2008 and C13*. The Akt signaling pathway plays an
important role in the control of cell survival. Many chemo-
therapeutic agents have been found to inhibit cancer cell
growth and induce apoptosis through the inhibition of the Akt
pathway (41). In EOC cells, it has been reported that Akt
confers chemoresistance partly by inhibiting p53 activity
(42,43). We found that when a low dose of Ganoderma was
combined with cisplatin, the Akt level was decreased while
the p53 level was up-regulated. These findings suggest that
Ganoderma modulates the sensitivity of EOC cells to cisplatin
by regulating, at least in part, Akt and p53 expression.
Taken together, our results demonstrate that Ganoderma
lucidum exerts multiple anti-tumor effects on ovarian cancer
cells. We also provide evidence that Ganoderma enhances the
chemosensitivity of EOC cells to cisplatin. Our findings
suggest that Ganoderma lucidum could be useful in the
treatment of chemosensitive and chemoresistant EOC.
This study was supported by a CIHr grant (MOP-89931) to
C.P. S.Z. was supported by a visiting professorship from
Hebei Province Government. C.P. is a recipient of a Mid-
Career Award from OWHC/CIHr.
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