Ovarian cancer cells with CD133+ phenotype is more resistant against Ngai Bun Boesenbergia pandurata extract than original ovarian cancer cells

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Progress in Stem Cell, 7(1):290-295

Original Research

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Ovarian cancer cells with CD133⁺phenotype is more resistant

against Ngai Bun Boesenbergia pandurata extract than original

ovarian cancer cells

Oanh Thi-Kieu Nguyen^1,2, Phuc Van Pham^1,2,3,4,*

ABSTRACT

Introduction: Ovarian cancer is one of the most common cancers in women. Due to the diﬃ-

culty in early detection and treatment of ovarian cancer, many research studies and clinical trials

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have been developed to discover more eﬃcient therapies. Besides Western medicine, traditional

medicine has gained increased interest as a research ﬁeld with potential to lead to the production of

marketable therapeutic products. With the diversity of tropical plants in Asia, traditional medicine

has been very popular and has served as a traditional therapy for generations. The Ngai bun (Boe-

senbergia pandurata) root is used not only as a food spice but also in ethnomedicine. This study

aimed to compare the anti-tumor activity of Boesenbergia pandurata root extract against ovarian

cancer cells and CD133⁺ovarian cancer cells that were enriched from the original ovarian cancer

cells. Methods: Crude extract of Boesenbergia pandurata roots were prepared in two kinds of sol-

vents (methanol and chloroform). The ovarian cancer cells OVP-10 were used in this study. The

population of CD133⁺ovarian cancer cells (CD133⁺OVP-10) were sorted from the OVP-10 cancer

cells. Both OVP-10 cells and CD133⁺OVP-10 cells were treated with these crude extracts. Adipose-

derived stem cells (ADSCs) were used as control normal cells for all assays. The anti-tumor activity

of extracts were evaluated based on the IC₅₀values. Results: Based on the IC₅₀index, the chlo-

roform extract had an anti-tumor activity higher than that of methanol extract, on both OVP-10

and CD133⁺OPV-10 cells (IC₅₀of methanol and chloroform extracts were 330.1 ꢀ 16.9 µg/mL and

246.5 ꢀ 21.2 µg/mL, respectively, for OVP-10 cells; IC₅₀of methanol and chloroform extracts were

411.8 ꢀ 83.7 µg/mL and 307 ꢀ 9.2 µg/mL respectively, for CD133⁺OVP-10 cells). The results also

showed that CD133⁺OVP-10 cells were more resistant to chloroform extract than were OVP-10 cells

(307 ꢀ 9.2 µg/mL vs. 246.5 ꢀ 21.2 µg/mL, respectively, for CD133⁺OVP-10 vs. OVP-10 cells, p <

0.05). Conclusion: The chloroform extract of Boesenbergia pandurata roots displayed strong anti-

tumor activity against ovarian cancer cells OVP-10 and CD133⁺OVP-10; the latter cells were found

to be more resistant than the original ovarian cancer cells.

¹Stem Cell Institute, University of Science

Ho Chi Minh City, Viet Nam

²Vietnam National University Ho Chi

Minh City, Viet Nam

³Cancer Research Laboratory, University

of Science Ho Chi Minh City, Viet Nam

⁴Laboratory of Stem Cell Research and

Application, University of Science Ho

Chi Minh City, Viet Nam

Correspondence

Phuc Van Pham, Stem Cell Institute,

University of Science Ho Chi Minh City,

Viet Nam

Key words: CD133+ cancer stem cells, ovarian cancer stem cells, ovarian cancer, Boesenbergia

pandurata

Vietnam National University Ho Chi Minh

City, Viet Nam

Cancer Research Laboratory, University

of Science Ho Chi Minh City, Viet Nam

irinotecan, and camptothecins) and microorganisms

INTRODUCTION

In 2019, the American Cancer Society estimated ovar-

Laboratory of Stem Cell Research and

Application, University of Science Ho Chi

Minh City, Viet Nam

(e.g. doxorubicin, mitomycin, and bleomycin)³.

Doxorubicin (DOX) is the most popular anti-cancer

ian cancer as the leading cause of death in gyneco-

Email: pvphuc@hcmuns.edu.vn;

phucpham@sci.edu.vn

drug, which is currently widely used for treatment of

many kinds of human cancers, both solid and hema-

tological⁴. DOX was shown to induce resistance in

3D spheroids, at a rate higher than that exhibited in

standard 2D cell culture⁵. Additionally, tirapazamine

(TPZ; 3-amino-1,2,4-benzotriazine 1,4 dioxide) is a

new class of cytotoxic drugs with a focus on treating

hypoxic mammalian cells⁶. When cultured in 2D,

the toxicity of DOX with target cells is more sensi-

tive than TPZ. Cell viability of cells with the testing

drug was identiﬁed by using the Alamar Blue assay.

By incorporating a ﬂuorometric/colorimetric growth

logical disease, ranking 5^thof the 10 leading cancer

types in women¹. Ovarian cancer is a rare disease, in

which early detection is diﬃcult and surgical strate-

gies are the ﬁrst step in treatment for this cancer².

However, the extent of surgery depends on how far

the ovarian cancer has spread; chemotherapy must be

used in the next steps to eradicate any residual cancer

cells still present in the body aꢀer surgery. e goal

of chemotherapy is to destroy the cancer by inhibit-

ing the proliferation of cancer cells. Chemotherapy

is a potential treatment for prolonging the cancer pa-

tient’s life. ere are many kinds of anti-cancer drugs

History

• Received: 22 January 2020

• Accepted: 05 March 2020

• Published: 19 March 2020

DOI : 10.15419/psc.v7i1.408

access article distributed under the

terms of the Creative Commons

Attribution 4.0 International license.

from natural sources, such as plants (e.g. vincristine, indicator based on detection of metabolic assay, the

Citethisarticle: NguyenOT, PhamPV. OvariancancercellswithCD133⁺phenotypeismoreresistant

against Ngai Bun Boesenbergia pandurata extract than original ovarian cancer cells. Progress Stem

Cell; 7(1):290-295.

290

Progress in Stem Cell, 7(1):290-295

CD133⁺cell sorting

Alamar blue assay can quantitatively measure the pro-

liferation of various human and animal cells. Many

new drugs and therapies have been under develop-

ment and are being tested in ongoing clinical trials,

with the aim of ﬁnding the most eﬀective therapy of

ovarian cancer.

OVP-10 cells were labelled with CD133 magnetic

beads and sorted by magnetic-activated cell sorting

(MACS), per the instructions of the Human CD133

MicroBead kit (kit and MACS sorting multi-stand

were obtained from Miltenyi Biotec Inc., Auburn,

Recently, besides modern medicine, ethnomedicine CA). e CD133⁺cancer cells were expanded to ob-

tain enough cells for the bioassays.

has also become a potential direction for the devel-

opment of new drugs. Ethnomedicine is a study of

the traditional medicine based on the use of plant

compounds. Ngai bun (Boesenbergia pandurata) is

Drugs

e standard drugs used in this study were doxoru-

a ginger species belonging to the Zingiberaceae fam- bicin (DOX) and tirapazamine (TPZ); both were pur-

chased from Sigma-Aldrich. Ngai bun extract was

isolated from fresh root, following a previously pub-

lished protocol, and dissolved in the diﬀerent sol-

vents⁷.

ily; it is cultivated in tropical countries such as South-

east Asia, India, Sri Lanka and South China. is

species has many local names, such as “ngai bun” in

Vietnam⁷, “temu kunci” in Indonesia⁸, krachai (or

krachai-dang) in ailand, and Chinese key (or ﬁn-

gerroot) in English⁹. is plant is mainly used as a

spice and contains several prenylated chalcones and

ﬂavonoids with many biological activities, including

antifungal, antibacterial, anti-inﬂammatory and anti-

Alamar Blue assay

e cell viability of ovarian cancer cells was tested by

Alamar Blue assay. Cells were plated in a 96-well plate

at a density of 2 x 10⁴cells/well. Aꢀer plating for

24 h, cells were treated with the drugs at six diﬀer-

ing concentrations (2000, 1000, 500, 250, 125, 62, and

0 µg/mL) for 48 h. e culture medium was then

removed and the wells were replaced with fresh me-

dia. As a negative control, fresh media was also added

to empty wells. All wells were added with 10 µl of

the Alamar Blue solution and then re-incubated at

37⁰C, 5% CO₂for 4 h. Data was collected by using

a DTX880 system (Beckman-Coulter, Brea, CA), and

ﬂuorescence was monitored at 530-560 nm excitation

wavelength and 590 nm emission wavelength.

cancer functions^7,8

e cancer stem cell (CSC) theory proposes that in

the cancer cell population, there exists a small popu-

lation of stem cells which have the capability of self-

renewal and tumor-initiation. Recent research studies

had revealed that CSCs in ovarian cancer are not only

responsible for primary tumor growth and metastasis

but also for chemotherapy resistance¹⁰. In studies on

ovarian cancer stem cells, CD133 is one of most pop-

ular cell surface markers which has been used for the

isolation of CSCs from various type of cancers, such

as breast, colon, ovarian and prostate cancer^10,11

Statistical analysis

In this research study, we aimed to test the toxicity

of Ngai bun (Boesenbergia pandurata) extract in dif-

ferent solvents on ovarian cancer OVP-10 cells and

CD133⁺sorted OVP-10 cells (CD133⁺OVP-10 cells)

to assess the therapeutic potential of this plant for

ovarian cancer treatment.

Each experiment was repeated three times. e IC₅₀

and signiﬁcant diﬀerences between mean values were

calculated by using GraphPad Prism 7.0 (GraphPad

Inc., La Jolla, CA), with p-value < 0.05 set as statistical

signiﬁcance.

RESULTS

MATERIALS AND METHODS

Isolation of human ovarian cancer

CD133⁺OVP-10 cells

Cell culture

Human ovarian cancer OVP-10 cells were grown in

DMEM/F12 with 10% fetal bovine serum (Sigma-

Aldrich, St. Louis, MO). e cells were maintained

in cell culture ﬂasks (25-cm²and 75-cm²) in an in-

cubator set at 37⁰C and 5% CO₂. Cells were cultured

and passaged two to three times before processing in

the bioassays.

Human ovarian cancer OVP-10 cells were cultured

and expanded in 75-cm²ﬂasks. When cells reached

approximately 70% conﬂuency (Figure 1 B), cells

will be trypsinized and subcultured in DMEM/F12

medium supplemented with 10% FBS. Aꢀer pass-

ing two to three times, OVP-10 cells were subjected

to bioassays, and/or sorted for CD133⁺cells using

291

Progress in Stem Cell, 7(1):290-295

MACS (Figure 1A). CD133⁺OVP-10 cells were la- with CD133⁺OVP-10 cells, no signiﬁcant diﬀerences

belled with CD133 magnetic beads, isolated and cul- were observed between the two cell lines; the IC₅₀

of the corresponding cells (ADSCs vs. CD133⁺OVP-

10 cells) with MeOH solvent, respectively, were 497.2

ꢀ 32.4 µg/mL and 411.8 ꢀ 83.7 µg/mL (Figure 3B)

(p > 0.05). In Figure 3C, with the same cells in a

diﬀerent solvent (CHCl₃), the IC₅₀index of OVP-10

cells was 246.5 ꢀ 21.2 µg/mL, which was signiﬁcantly

diﬀerent from the IC₅₀of 474.6 ꢀ 18.8 µg/mL for

ADSCs (p < 0.05). e results inFigure 3D showed

that CD133⁺OVP-10 cells treated with CHCl₃extract

corresponded to an IC₅₀index that was signiﬁcantly

lower than that for ADSC cells (307 ꢀ 9.2 µg/mL vs.

474.6 ꢀ 18.8 µg/mL, respectively) (p < 0.05).

tured to conﬂuency before treatment with the com-

pounds (Figure 1C). e morphology of OVP-10 cells

and CD133⁺OVP-10 cells showed no signiﬁcant dif-

ferences; however, in culture, the proliferation time of

CD133⁺OVP-10 cells was slightly longer than that of

OVP-10 cells.

Testing an ovarian cell model for drug

screening with standard drugs

e cell concentration also aﬀected the in vitro bioas-

say for anti-cancer drug screening¹². e growth of

OVP-10 cells was tested and the model for screening

the diﬀerent extracts was optimized. As seen in Fig-

ure 2A, OVP-10 cells continued to proliferate aꢀer 7

days. e bioassay was performed in 3 days: on the

ﬁrst day, cells were plated in wells and incubated for

24 h; next, cells were treated with compounds for 48

h; on the third day, cells were processed for Alamar

blue assay and the IC₅₀indexes were calculated. Dur-

ing these days, OVP-10 cells were still stable and there

was little increase in cell number (Figure 2A). e

OVP-10 cells were treated with standard drugs (dox-

orubicin or tirapazamine) to conﬁrm that the OVP-

10 cell model could be used for screening. Doxoru-

bicin is popular standard drug which used as a control

in many studies of drug screening. Speciﬁcally, dox-

orubicin only aﬀected the monolayer cell model but

not the three-dimensional (3D) cell culture model.

In contrast, tirapazamine was only eﬀective in the

3D cell culture model. As shown in Figure 2B and

Figure 2C, the IC₅₀of doxorubicin in OVP-10 cells

(168.9 ꢀ 2.3 nM) and that of CD133⁺OVP-10 cells

(567.7 ꢀ 95.7 nM) were highly diﬀerent (p < 0.01).

DISCUSSION

Ovarian cancer is the most serious gynecologic can-

cer, typically diagnosed at an advanced stage^13,14

e current standard treatment for ovarian cancer is

surgery and chemotherapy. e chemotherapy strat-

egy is faced with many obstacles including cancer

metastasis and resistance of tumor with drugs. is

has motivated the development of drug discovery to

help ﬁnd novel potentially therapeutic compounds for

anti-cancer treatment. In drug screening, cells must

be in the proliferation stage and should be stable in

the testing with drugs. In this study, the OVP-10 cells

continued to proliferate for 7 days and were suitable

for our assay. Aꢀer 24 h of plating, OVP-10 cells

showed a low increase in cell number and aꢀer 3 days

(i.e. the day of the Alamar blue assay), cells were still

in log phase of proliferation.

Despite the disadvantage of the 2D model and the

development of the 3D model, the 2D model is still

very popular for drug screening. Evaluation of the 2D

model using in vitro bioassays, such as MTT or Ala-

mar Blue assay, is necessary to assess the eﬃciency of

the 2D model in anti-cancer drug screening¹². e

cell concentration and drug concentration parame-

ters have a great eﬀect on the success of the in vitro

bioassays. As shown in this study, the cell concen-

tration for plating in 96-well plates was 1000-2500

cells/well, and 6 parameters of drugs or extract con-

centrations were at the very least required for calcula-

Ngai bun extract dissolved in chloroform

solvent had a greater eﬀect on both OVP-

10 and CD133⁺OVP-10 cancer cells than

methanol solvent

e IC₅₀index of Ngai bun extract in chloroform sol-

vent (CHCl₃) had a greater eﬀect on killing ovarian

cancer OVP-10 cells when compared with the eﬀect

of this extract on adipose-derived stem cells (ADSCs),

which were used as the control. e IC₅₀of methanol

(MeOH) and chloroform (CHCl₃) solvent were 330.1

ꢀ 16.9 µg/mL and 246.5 ꢀ 21.2 µg/mL, respec-

tively. As indicated inFigure 3A, the MeOH extract

had a diﬀerent eﬀect on ADSCs and OVP-10 cells,

tion of the IC₅₀index¹⁵

Use of the traditional extract from plants could kill

cancer cells with fewer eﬀects on normal cells. In

this study, Ngai bun (Boesenbergia pandurata) extract

was demonstrated to be toxic for OVP-10 cells, when

compared with adipose derived stem cells as control.

When comparing diﬀerent Boesenbergia species (B.

as shown by the IC₅₀index of 497.2 ꢀ 32.4 µg/mL armeniaca, B. rotunda, or B. pulchella var attenuate),

and 330.1 ꢀ 16.9 µg/mL, respectively. However, Jing et al. showed that Boesenbergia rotunda extract in

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Progress in Stem Cell, 7(1):290-295

Figure 1: Isolation and expansion of CD133⁺OVP-10 cells from OVP-10 ovarian cancer cells. (A) Procedure

of CD133⁺OVP-10 cells isolation by magnetic activated cell sorting. (B) Human ovarian cancer OVP-10 cells. (C)

Human ovarian carcinoma CD133⁺OVP-10 cells. Pictures were taken at 20 X magniﬁcation.

methanol had the strongest inhibitory eﬀects against the IC₅₀of Ngai bun extract which could kill 50% of

CD133⁺OVP-10 cells, that concentration could kill

more than 50% of OVP-10 cells but less than 50% of

ADSC cells. is shows that the dose of drug used for

treatment must be chosen carefully.

In this study, two kind of solvents were chosen to eval-

uate which was the best solvent for dissolving Ngai

bun (Boesenbergia pandurata) extract, and still main-

tain the functions of the extract. As observed, the

chloroform-dissolved extract induced better toxicity

than the methanol-dissolved extract. Besides the ap-

propriate concentrations, the suitable solvent is also a

key factor for determining the success of drug discov-

ery.

CaOV₃ovarian cancer and diﬀerent types of can-

cers, such as breast cancer MDA-MB231 (IC₅₀66.5 ꢀ

2.12 µg/mL), MCF7 (IC₅₀51 µg/mL), cervical can-

cer HeLa (IC₅₀66.5 ꢀ 2.12 µg/mL), and colon cancer

HT-29 (IC₅₀52 ꢀ 2.12 µg/mL). Boesenbergia genera

is potentially potent extract for treatment of ovarian

cancer. OVP-10 cells is one of the targets for investi-

gation of drug cytotoxicity against ovarian cancer¹⁶

Moreover, the synergistic anti-tumor eﬀect would be

combined to develop new therapies for ovarian can-

cer treatment¹⁷. From diﬀerent studies, the extract of

Boesenbergia genera exhibit robust potency that can

be utilized as an potential candidates for the devel-

opment of new anti-cancer drugs. Advances in drug

discovery will require identifying and developing new

and innovative marketable pharmaceutical products.

Future studies from this research should focus further

on the discovery of such compounds.

Besides the toxicity towards ovarian cancer OVP-10

cells in a dose-dependent manner, Ngai bun (Boesen-

bergia pandurata) extract in chloroform was demon-

strated to inhibit the cell viability of CD133⁺OVP-

10 cells, representing ovarian cancer stem cells. At

CONCLUSION

Overall, the data obtained from this study shows

that Ngai bun (Boesenbergia pandurata) chloroform-

dissolved extract is more toxic on OVP-10 cells

than on CD133⁺OVP-10 cells. e cytotoxicity of

the chloroform extract was also higher that of the

methanol extract.

293

Progress in Stem Cell, 7(1):290-295

Figure 2: Model for screening the eﬃciency of Ngai bun extract. (A) Proliferation of human ovarian cancer

OVP-10 cells in 96-well plates over10 days. (B, C) Eﬀect of standard drugs (doxorubicin or tirapazamine) on human

ovarian cancer OVP-10 cells (B) and CD133+ sorted human ovarian cancer (CD133⁺OVP-10) cells. ^∗∗∗: p < 0.001.

Abbreviations: DOX: dororubicin, TPZ: tirapazamine

Figure 3: The IC₅₀of human ovarian cancer OVP-10 cells and CD133⁺OVP-10 cells in diﬀerent solutions.

(A) methanol (MeOH), (B) chloroform (CCl₃). Each experiment was processed three times, and statistical analysis

was performed by GraphPad Prism 7.0 with *p<0.05 (** p<0.0021, ***p<0.0002). Abbreviations: ADSCs: Adipose

derived stem cells.

294

Progress in Stem Cell, 7(1):290-295

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ABBREVIATIONS

CSC: Cancer stem cell

DOX: Doxorubicin

IC₅₀: the half-maximal inhibitor concentrations

TPZ: Tirapazamine

CONFLICT OF INTEREST

e authors report no conﬂicts of interest in this work.

AUTHORS’ CONTRIBUTION

All authors equally contributed in this work and ap-

proved the ﬁnal version of manuscript for submission.

ACKNOWLEDGEMENT

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