Pharmaceutical Biology

2003, Vol. 41, No. 4, pp. 271276

1388-0209/03/4104-271$16.00
Swets & Zeitlinger

Screening for Antitumor Activity of 11 Species of Indonesian

Zingiberaceae Using Human MCF-7 and HT-29 Cancer Cells
Chandra Kirana1,2,3, Ian R. Record2, Graeme H. McIntosh2 and Graham P. Jones4
Faculty of Mathematics and Natural Sciences, The University of Brawijaya, Malang, Indonesia; 2Health Sciences and
Nutrition, CSIRO, Kintore Ave Adelaide, South Australia; 3Departement of Medicine, Adelaide University, South Australia;
4
Department of Horticulture, Viticulture and Oenology, Adelaide University, South Australia

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Abstract
We have screened 11 important species of Zingiberaceae,
used as spices and for medicinal purposes in Indonesia, for
their antitumor activity using human HT-29 colon cancer and
MCF-7 breast cancer cells. They were Amommum cardamomum, Curcuma aeruginosa, C. longa, C. mangga, C. xanthorrhiza, Kaempferia galanga, K. pandurata, K. rotunda, Z.
aromaticum, Z. cassumunar, and Zingiber officinale. Ethanol
extracts of eight species showed strong inhibitory effect on
the growth of the cancer cells when evaluated using the colorimetric tetrazolium salt assay. Since curcumin, a yellow
pigment isolated from C. longa, has shown its potential anticancer activity in vitro and in vivo studies and is currently
undergone clinical trial in the US, we used an extract of C.
longa as a comparison. Extracts of K. pandurata and Z. aromaticum had very strong inhibitory activity against the two
cell lines similar to those of C. longa. However, curcumin
was not detectable in the extracts of those two plants. The
ethanol extracts of the active species had less effect on the
growth of a non-transformed human skin fibroblast cell line
(SF 3169). Microscopic examination of cancer cells exposed
to extracts of active species showed a characteristic morphology of apoptosis. Further study on Z. aromaticum
and K. pandurata, including identification of bioactive
compounds and elucidation of mechanism(s) likely to be
operating, has been carried out.
Keywords: Antitumor, apoptosis, gingers, Zingiberaceae.
Latin binomial:
Curcuma domestica VAL. (C. longa) (Auct.)
C. xanthorrhiza ROXB.

Zingiber aromaticum VAL.

Z. officinale ROSC.
K. rotunda LINN.
Amomum cardamomum WILLD.
C. mangga VAL.,
C. aeruginosa ROXB.
Z. cassumunar ROXB.
Kaempferia pandurata ROXB.
K. galanga LINN.

Introduction
The incidence of certain cancers, including colon and breast
cancers in Asia, is much lower than those found in developed
western countries (Hin-Peng, 1998; De Kok et al., 2000).
Diet plays a major role in cancer progression and prevention.
Members of the ginger family, Zingiberaceae, have been used
either as spices or traditional medicines in some countries
for centuries, especially in the Asian region. Some Zingiberaceae, for example turmeric, have been reported to possess
compounds with both anti-inflammatory and anti-oxidant
properties (Rao et al., 1995). Such anti-oxidant and antiinflammatory compounds may also be effective as anticancer
agents (Lee et al., 1998; Chun et al., 1999). In Indonesia,
various ginger species are widely used traditionally to treat
ailments such as stomach problems, sore throat, cough, liver
complaints, rheumatism, fever, bruises, swelling, muscular
pains and several other disorders. Rhizomes and leaves of
ginger species are also used as tonics and in cooking.
As many as 63 species of the family Zingiberaceae have
been identified in Indonesia (Hyene, 1987). However, only a

Accepted: August 8, 2002

Address correspondence to: Chandra Kirana, CSIRO Health Sciences and Nutrition, P.O. Box 10041 Adelaide. BC, South Australia 5000.
Tel.: +61 (8) 8303 8918; Fax: +61 (8) 8303 8899; E-mail: chandra.kirana@hsn.csiro.au

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272

C. Kirana et al.

few members have attracted scientific interest and have been

investigated for potential anticancer activity. The powdered
rhizomes of Curcuma longa Linn. (turmeric) have been used
as a spice and coloring agent worldwide, and is one of the
most extensively studied. Its major yellow pigment, curcumin (diferuloylmethane) has been shown to have significant potential inhibitory effect in cancer promotion and
progression. It has been shown to inhibit chemically induced
tumorigenesis in various tissues including colon and rectum
(Huang et al., 1994; Kawamori et al., 1999); skin (Huang
et al., 1997), forestomach (Singh et al., 1998), mammary
(Deshpande et al., 1998), lung (Menon et al., 1999) and liver
(Chuang et al., 2000). Another species of Zingiberaceae is
ginger, Zingiber officinale Rosc which has been used in beverages and cooking worldwide. Ethanol extracts of ginger
have been reported to inhibit skin tumorigenesis (Katiyar
et al., 1996). Alpinia oxyphilla Miquel, also a member of
Zingiberaceae, is used as a traditional oriental medicine,
and has also been shown to inhibit skin tumorigenesis
(Lee et al., 1998). The rhizomes of 11 species of ginger
have been reported by Vimala et al. (1999) to possess antitumor potential as determined by inhibition of 12-Otetradecanoylphorbol 13-acetate (TPA)-induced Epstein-Barr
virus activation in Raji cells. However, there have been no
reports on the activity of these gingers against established
cancer cell lines.
Breast cancer is a leading cause of death in women especially of developed countries, and the incidence of the
disease is also increasing in developing countries (Walker,
2000). Jamu, an Indonesian term for indigenous medicines
and tonics prepared from herbal and spice material, is often
consumed by women, but there are no epidemiological
studies of any relationship between drinking jamu and incidence of breast cancer. Colon cancer is the most common
cancer in many societies (Parkin, 1998) and it has been summarised by Fernandez et al. (2000) that dietary factors can
play a major role in its initiation and progression, as well as
protection from this disease. Therefore we have examined
the inhibitory activity of 11 species of Zingiberaceae, most
frequently used in local traditional medication and cooking
on the growth of HT-29 colon and MCF-7 breast cancer
cells. The effect of alcoholic extracts of Zingiberaceae on
the growth of non-transformed human skin fibroblasts and
morphological changes of treated cancer cells were also
examined.

Materials and methods

Ginger species
Roots and rhizomes of 11 species from the Zingiberaceae
family, Curcuma domestica VAL. (C. longa) (Auct.), C.
mangga VAL., C. xanthorrhiza ROXB., C. aeruginosa
ROXB., Zingiber aromaticum VAL., Z. cassumunar ROXB.,
Z. officinale ROSC., Kaempferia pandurata ROXB., K.

rotunda LINN., K. galanga LINN. and seeds of Amomum

cardamomum WILLD. were purchased from the market
place in Malang, East Java, Indonesia. They were sliced and
air-dried and brought to Adelaide, South Australia. All specimens are deposited in CSIRO Health Sciences and Nutrition
Adelaside South Australia.
Preparation of extracts
One hundred grams of dried sliced roots and rhizomes or
seeds were homogenised and extracted with absolute ethanol
(250 ml) overnight at room temperature. The alcohol extract
was then vacuum filtered, the extraction repeated three times
and the combined ethanol extract was evaporated to dryness
at 35 C under vacuum, and these extracts used for cell
culture investigations.
Cell Culture
HT-29 human colon cancer cells and MCF-7 human breast
cancer cells were purchased from the American Type Culture
Collection (ATCC) (Rockville, MD). SF 3169 skin fibroblasts were obtained from the Chemical Pathology Department of the Woman and Children Hospital, South Australia.
Tumor cell lines and skin fibroblasts were maintained in
monolayer culture in Dulbecco Minimum Essential Medium
(DMEM) supplemented with 10% heat-inactivated foetal
bovine serum (FBS), 20 mM HEPES (N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid) buffer, 0.1%
Amphostat B and 5 mg/ml gentamycin in a humidified atmosphere of 5% CO2/95% air at 37 C. The cells were dispersed
with a phosphate-buffered saline solution (PBS) containing
0.25% trypsin.
Dulbecco Minimum Essential medium (DMEM), heatinactivated FBS, HEPES, gentamycin, Amphostat B, PBS,
trypsin were all obtained from Trace, Australia. MTTtetrazolium salt (3-(4,5-dimethylthiasol-2yl)-2,5-diphenyl
tetrazolium bromide), N,N-dimethyl formamide, and lauryl
sulfate (SDS) were purchased from Sigma (St. Louis,
MO).
Assessment of cell viability
Exponentially growing cells were suspended at a density of
24 104 cells/ml in DMEM and treated with serial dilutions
at concentration range of 15 to 250 mg/ml of the extracts in
96-well flat bottom plates for 72 h. Controls were treated with
ethanol alone (concentration of ethanol 0.5%). The viability
of the cells was assessed by MTT tetrazolium salt assay. The
tetrazolium salt assay is based on the reduction of MTT by
the mitochondrial dehydrogenase of intact cells to a purple
formazan product (Hansen et al., 1989). The amount of formazan was determined by measuring the absorbance at
570 nm using Spectra Max 250 (Microplate Spectrophotometer, Molecular Devices, USA).

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Determination of IC50 values

For each ethanol extract, three sets of experiments measuring the cell growth inhibition of all the cancer cell lines and
fibroblasts were completed using the MTT assay. The percentage of viable cells was determined by taking the optical
density of each treated cell row and dividing it by the optical
density of the vehicle-treated cells in the same 96-well plate.
Each concentration of extract of species was then plotted
against the percentage cell survival. In this manner, a doseresponse curve was generated and the IC50, that is, the concentration of the extract required to inhibit cell growth by
50% was determined.

273

in vitro, therefore values of IC50 of C. longa was used as comparison for other species. The differences between C. longa
and other species were performed using Z score calculation
as follows:
Z score =

X-Y
2

SE(X) + SE(Y)

X = mean of IC50 of extract of C. longa

Y = mean of IC50 of extract of other species
SE(X) = standard error of IC50 of extract of C. longa
SE(Y) = standard error of IC50 of extract of other species
Two values are significantly different if -2 < Z < 2

Morphological examination of cancer cells

Results

Cancer cells were grown on cover slips at a density of

100,000 cells/ml in six well plates and allowed to attach for
24 h and then treated with ethanolic extracts of ginger
species. The cells were washed and then treated with the
extracts and incubated for 24, 48 and 72 h. Five hundred ml
of cell suspension were obtained from the wells and slides
were prepared using a cytocentrifuge (Shandon Southern
Products, Cheshire, UK) to examine the floating cells. Cover
slips and slides were air-dried, fixed in methanol and stained
using DiffQuick stain (Sigma, St. Louis, MO).

The anticancer activity of 11 species of Zingiberaceae was

assessed using two different cell lines, HT-29 and MCF-7
cancer cells, by using the MTT tetrazolium salt assay. The
ethanolic extracts of eight species of Zingiberaceae showed
strong inhibitory effects on the growth of both cell lines at
concentrations of 10100 mg/ml. They were A. cardamomum,
C. longa, C. xanthorriza, C. mangga, Z. officinale, Z.
cassumunar, Z. aromaticum, and K. pandurata. An extract
of C. aeruginosa was less active and extracts of two species
(K. galanga and K. rotunda) had no effect on the growth of
either cell lines at concentration up to 250 mg/ml. The IC50 of
the extracts are presented in Table 1. The IC50 of eight active
species were at concentrations between 10100 mg/ml while
the IC50 of the less active species fell between concentrations
of 100120 mg/ml. The IC50 of extracts of C. longa, K.

Statistical analysis
Values were means SE. Extract of C. longa has been extensively studied and has showed anticancer activity in vivo and

Table 1. The IC50 (mg/ml) of extracts of the gingers on MCF-7 and HT-29 cancer cells and
non-transformed SF3169 skin fibroblasts.*
Species
(Use)
A. cardamomum (M,C)
C. aeruginosa (M)
C. longa (M,C)
C. mangga (M)
C. xanthorrhiza (M)
K. galanga (M,C)
K. panduratum (M,C)
K. rotunda (M)
Z. aromaticum (M)
Z. cassumunar (M)
Z. officinale (M,C)

MCF-7 cells
76.2 11.7a
119 5.8a
31.0 3.3
44.7 2.7a
47.2 7.9
>250a
21.3 0.3b
>250a
20.2 1.8b
54.5 11.5
40.6 1.4a

HT-29 cells

SF 3169 cells

79.2 23.2a
103.8 16.5a
28.1 2.7
91.0 5.9a
39.9 3.1a
>250a
32.5 1.5
>250a
11.8 1.0b
84.9 8.3a
53.5 5.0a

84.6 7.8a
>150a
30.9 3.8
77.6 5.3a
60.6 4.2a
ND
49.5 2.6a
ND
70.9 2.5a
>100a
72.7 8.2a

* Data represent the means of SE obtained from three separate determinations, ND not
done.

M = medicine, C = cooking.
Z score was calculated to compare the activity of extract of each species with extract of
C. longa. The analysis is applied within each columns, a significantly greater than C. longa;
b
significantly less than C. longa.

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C. Kirana et al.

pandurata and Z. aromaticum showed that they were the most

active species. The IC50 of extract of K. pandurata was not
significantly different from that of C. longa while the IC50 of
Z. aromaticum was significantly less than that of C. longa on
HT-29 cells. Using MCF-7 cells the IC50 of K. pandurata and
Z. aromaticum were significantly less than that of C. longa.
These species had a very similar inhibitory effect on both
cell lines. Individual dose-response curves are presented in
Figures 1 and 2.
We also assessed the toxicity of extracts of ginger species
on non-transformed skin fibroblast cells SF 3169. It appeared
that cancer cell lines were more susceptible to ethanol
extracts of species of Zingiberaceae than non-transformed
skin fibroblasts. The IC50 shows the 50% growth of cells at a
given concentration. In this case, the higher the IC50 value

means the less toxic the extract. The IC50 of the extracts on
SF 3169 skin fibroblasts is shown in Table 1. The IC50 of
extracts of other species was significantly greater than that
of C. longa indicated that those extracts were less toxic than
extract of C. longa. With the exception of the extract of
turmeric (C. longa) (IC50 = 30.9 mg/ml), extracts of other
species had an IC50 on non-transformed fibroblasts higher
than those on cancer cell lines.
The morphological characteristic of apoptosis including
membrane blebbing, nuclear condensation and emergence of
apoptotic bodies were observed in both cancer cells treated
with the extracts of all active species (Fig. 3).
Discussion
Screening for antitumor activity of some members of
Zingiberaceae has been conducted using activated Epstein
Bar Virus (EBV) on Raji cells (Murakami et al., 1998;
Vimala et al., 1999). In this study we screened ethanol
extracts of eleven species of Indonesian Zingiberaceae most
frequently used for traditional medicine and in food, using
two established cancer cell lines. The extracts of eight species
of Zingiberaceae were found to strongly inhibit the growth
of MCF-7 and HT-29 cells. They were A. cardamomum,
C. longa, C. xanthorrhiza, C. mangga, Z. aromaticum, Z.
cassumunar, Z. officinale, and K. pandurata. C. mangga, C.
xanthorrhiza, C. aeruginosa, Z. aromaticum, Z. cassumunar,
which have been used for medicinal purposes, while Z. officinale and K. pandurata and A. cardamomum have been used
as traditional medicine as well as in cooking. Interestingly,
often due to shortages in supply, K. pandurata has been used
to replace K. rotunda as a main component of popular tradi-

Figure 1. The growth of MCF-7 breast cancer cells exposed

to ethanol extracts of C. longa (CL), Z. aromaticum (ZA) and K.
pandurata (KP) after 72 h. Values are means SE of three independent experiments.

Figure 2. The growth of HT-29 colon cancer cells exposed

to ethanol extracts of C. longa (CL), Z. aromaticum (ZA) and K.
pandurata (KP) after 72 h. Values are means SE of three independent experiments.

Figure 3. (A) Untreated HT-29 colon cancer cells, (B) features of

apoptosis of HT-29 cancer cells after treatment with an extract of
K. pandurata, top, nucleus shrinkage and chromatin condensation;
middle, chromatin condensation and pyknotic nuclei; bottom,
nucleus fragmentation into smaller nuclear bodies (apoptotic
bodies). Original magnification 100.

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Antitumor activity of indonesian zingiberaceae

tional tonics and medicines, especially for women. The IC50
of extracts of these species were between concentrations of
10100 mg/ml. A comparison of the IC50 values represents a
means of determining the potency of a given extract in
inhibiting cell growth by 50%. The lower the IC50 value, the
more potent is the extract as an inhibitor of tumor cell
growth. Extract of C. aeruginosa was found to be less active
with the IC50s at 100120 mg/ml, while extracts of K. rotunda
and K. galanga were not active at concentrations up to
250 mg/ml. We found that the values of IC50 of some extracts
were quite different on different cell lines. For example,
extracts of C. mangga (44.7 mg/ml for MCF-7 and 91.0 mg/ml
for HT-29 cells) and Z. cassumunar (54.5 mg/ml for MCF-7
and 84.9 mg/ml for HT-29 cells). This effect could be due to
the sensitivity of cell lines to the nature of active compounds
present in the extracts and could represent a tissue-specific
response. In the previous study using Raji cells, it was
reported that extract of K. galanga was less active compared
to the other species (Murakami et al., 1998) and its ethanol
extract showed inhibitory activity at a concentration of
320 mg/ml (Vimala et al., 1999).
Compared to the number of members of Zingiberaceae,
only a few members have previously been investigated, and
our study has shown that some members of Zingiberaceae
have potential anticancer activity. Each species of ginger contains unique compounds with structures similar to curcumin
such as yakuchinones in A. oxyphylla (Chun et al., 1999),
and cassumunin A and B from Z. cassumunar (Oyama et al.,
1998) or different from curcumin such as paradol and gingerol from Z. officinale (Lee & Surh, 1998). The yellow
pigment curcumin is the bioactive compound isolated from
C. longa and has been extensively studied, therefore we used
an ethanol extract of C. longa to compare the activity of
extracts from other species. Curcumin was not detected in
the extracts of K. pandurata and Z. aromaticum (data not
shown). These two species had similar or greater inhibitory
effect to extract of C. longa in inhibiting the growth of cancer
cell lines indicating that extracts of these two species may
have more effective anticancer agents than curcumin.
The inhibitory activity of curcumin has been reported to
result from an inhibition of protein kinase C (PKC) (Liu et
al., 1993) and phosphorylase kinase (Reddy & Agarwal,
1994) which are involved in the regulation of cell proliferation and growth and induction of apoptosis in various cancer
cell lines (Jiang et al., 1996; Kuo et al., 1996). Lee et al.
(1998) found that a methanol extract of A. oxyphylla inhibited the growth of HL 60 cells and was also found to induce
apoptosis. Gingerol, vanilloids and paradol isolated from Z.
officinale have also been shown to induce apoptosis in vitro
(Lee & Surh, 1998). In the present study morphological characteristics of apoptosis (membrane blebbing and chromatin
condensation, apoptotic bodies) were also observed following incubation of either tumor cell lines with extracts of
active species.
In this study, except for C. longa, extracts of active ginger
species have been found to be more active against cancer cell

275

lines than non-transformed fibroblast cells. Jiang et al. (1996)

and Ramachandran and You (1999) found that curcumin
inhibited the growth of cancer cells more effectively than
normal cells. Gautam et al. (1998) also found similar results,
however, at concentrations higher than 25 mM, curcumin had
similar effect to inhibit the growth of both cancer cells and
normal fibroblast cells. Currently we are attempting to fractionate the active ingredients from Z. aromaticum and K.
pandurata to determine the active ingredient(s), to evaluate
their mode(s) of action, and to evaluate their anticancer activity using animal models.

Acknowledgements
The authors thank to Estelle Sotelo of Auffargis in France for
her help in this project and Phil Leppard, statistician of
CSIRO Health Sciences and Nutrition Adelaide. This project
was funded by AusAID as part of postgraduate scholarship
and The Adelaide University and CSIRO Collaborative
Grants Program 2000.

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