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ORIGINAL ARTICLE
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Antiproliferative capacity of combined extracts from Paramignya trimera and Phyllanthus amarus against cancer cell lines


 Research, Development and Teaching Group on Functional Foods; Department of Food Technology, Faculty of Food Technology, Nha Trang University, Nha Trang, Vietna

Date of Submission07-Jan-2019
Date of Decision23-May-2019
Date of Acceptance22-Aug-2019
Date of Web Publication28-Jan-2020

Correspondence Address:
Van Tang Nguyen,
Department of Food Technology, No. 2 Nguyen Dinh Chieu, Nha Trang 57000
Vietna
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_14_19

Keywords: Antiproliferation, extracts, pancreatic cancer, Paramignya trimera, Phyllanthus amarus



How to cite this URL:
Nguyen VT. Antiproliferative capacity of combined extracts from Paramignya trimera and Phyllanthus amarus against cancer cell lines. J Can Res Ther [Epub ahead of print] [cited 2020 Oct 20]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=276990




 > Introduction Top


Pancreatic ductal adenocarcinoma or pancreatic cancer (PC) is an abnormal uncontrolled growth of cells in the pancreas, it is often referred to as a “silent disease” as it is frequently diagnosed in the later stages of growth, so PC has dire consequences due to it presents late and is rapidly progressive.[1],[2],[3] It was estimated that 45,220 Americans were diagnosed with PC in 2013 and 38,460 patients died from the disease.[1] While many other cancers are reducing in incidence, the incidence of PC continues to increase and outcomes are not improving, so it is predicted to be the second leading cause of cancer-related death by 2030.[3]

The major challenge of current anticancer drugs is that they are highly toxic with limited treatment results, as well as degradation in the quality of life. Therefore, the use of herbal medicines or natural products alone or in combination with conventional anticancer agents has become of great interest to researchers as they are typically less toxic with high activity and availability.[4]

Recently, some studies assessed the physicochemical, antioxidant, and cytotoxic properties of the individual extracts from Paramignya trimera root (PTR), P. trimera leaf (PTL), and Phyllanthus amarus (PA) and found that the PTR and PTL extracts possessed high levels of phenolics, flavonoids, proanthocyanidins, and saponins, which displayed potent antioxidant and cytotoxic activities.[5],[6],[7],[8] However, antiproliferative capacity against cancer cell lines of the combined extracts from P. trimera (PT) and PA has not yet been reported. With this in mind, the aim of this study was to assess antiproliferative capacity against different cancer cell lines, particularly three PC cell lines (MiaPaCa2, BxPc3, and CFPAC1) of the combined extracts from PTR, PTL, and PA for further development of novel anticancer drugs.


 > Subjects and Methods Top


Plant materials

PTR, PTL, and PA were collected and prepared as follows: PTR was obtained in January 2014 from Hon Heo, Ninh Hoa, Khanh Hoa, Vietnam, whereas PTL was collected in January 2016 from Hon Nghe, Vinh Ngoc, Nha Trang, Khanh Hoa, Vietnam. Both PTR and PTL were authenticated by the National Institute of Medicinal Materials, Ministry of Health, Vietnam. The fresh samples were rinsed in deionized water to remove sand and soil and completely drained. The fresh PTR was dried under the sun at 34.5°C to constant weight,[5] whereas the fresh PTL was dried in a microwave oven (Sharp R-G620VN, Bangkok, Thailand) at 450 W to constant weight.[6] The whole plant of PA was collected in January 2015 from Hon Nghe, Vinh Ngoc, Nha Trang city, Khanh Hoa province, Vietnam, and authenticated by the Quang Ngai Union of the Science and Technology Association, Vietnam. The fresh sample was placed in sealed plastic bags, covered with ice to minimize oxidation, and immediately taken to the laboratories at Nha Trang University. The fresh sample was then rinsed in deionized water to remove sand, soil, and foreign materials, completely drained, and dried by infrared at 30°C to constant weight in an infrared drying cabinet (SHN-L, Nha Trang University, Vietnam).[7] All dried samples were packaged in vacuum-sealed polyamide bags and stored at −20°C until required. The herbarium specimen numbers of 240,214 (PTR), 240,216 (PTL), and 240,115 (PA) were deposited at the School of Environmental and Life Sciences, University of Newcastle, Australia. The dried samples were then ground to a fine powder using an electric blender (Hamilton Beach Brands, Inc., China), screened through a stainless steel mesh with particle size ≤1.4 mm (Endecotts, London, England), and kept at −20°C until used for further investigations.

Analytical chemicals

The chemicals used in this study include Folin–Ciocalteu reagent, 2,2'-Azino-bis (3-ethylbenzothiazoline-6-sulfonic acid), 2,2-diphenyl-1-picrylhydrazyl, gallic acid, rutin, catechin, ostruthin, gemcitabine, trolox, neocuproine, 2, 4, 6-tripyridyl-s-triazine, saponin-enriched Quillaja bark extract, and iron (III) chloride, which were the analytical products of Sigma-Aldrich Pty. Ltd. (Castle Hill, Sydney, Australia). Sulfuric acid and hydrochloric acid were purchased from Ajax Finechemicals (New South Wales, Australia). Acetic acid was obtained from BDH Laboratory Supplies (Poole, England). Vanillin, potassium persulfate, methanol, and acetonitrile were the products of Merck (Darmstadt, Germany). Sodium acetate trihydrate was obtained from the Government Stores Department (Australia). Ammonium acetate was purchased from BDH Chemicals (Victoria, Australia). Copper (II) chloride was obtained from Standard Laboratories (Victoria, Australia). Aluminum chloride was purchased from Arcos (New Jersey, USA). Sodium carbonate anhydrous was obtained from Chem-Supply (Gillman, South Australia). Sodium hydroxide was purchased from Ajax Chemicals (New South Wales, Australia). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Dulbecco's Modified Eagle's Medium (DMEM), and keratinocyte serum-free medium (KSFM) were purchased from Gibco by Life Technologies (Grand Island, NY, USA). Dojindo Cell Counting Kit-8 (CCK-8) was obtained from Dojindo Molecular Technologies, Inc., Maryland, USA.

Preparation of Paramignya trimera and Phyllanthus amarus extracts

To prepare the methanol extracts from PTR, PTL, and PA, microwave-assisted extraction (MAE) was applied based on the previously reported procedures.[5],[6],[7] Briefly, 10 g of dried samples was soaked in 1000 mL of 100% methanol at room temperature (21°C ± 1°C) for 20 min, followed by MAE using a microwave oven (Sharp Carousel, Sharp Corporation, Thailand) at a power of 360 W, an irradiation time of 7 s/2 min, and an extraction time of 40 min. Next, the extracts were rapidly cooled to room temperature using an ice water bath and filtered through qualitative No. 1 filter papers (Bacto Laboratories Pty. Ltd., NSW, Australia). The extracts were then evaporated under reduced pressure (−10 mbar) at 40°C using Rotavapor (Buchi, Flawil, Switzerland) and dried to constant weight using a freeze drier (Rietschle Thomas Australia Pty. Ltd., NSW, Australia) at −45°C, 0.1 atm for 48 h to obtain the powdered PTR, PTL, and PA extracts. Finally, the powdered extracts were stored at −20°C until used for further analysis.

Cell growth inhibition of combined extract from Paramignya trimera and Phyllanthus amarus

Antiproliferative capacity of a combined extract from PTR and PA (1:1 w/w) against different cancer cell lines including MiaPaCa-2 (pancreas); HT29 (colon); A2780 (ovarian); H460 (lung); A431 (skin); Du145 (prostate); BE2-C (neuroblastoma); MCF-7 (breast); and U87, SJ-G2, and SMA (glioblastoma) and one noncancer-derived cell line MCF-10A (normal breast) was assessed using MTT assay based on the previously described methods.[5],[9] Briefly, all cancer cell lines were cultured in DMEM supplemented with 10% fetal bovine serum (FBS), 50 IU/mL penicillin, 50 μg/mL streptomycin, and 2 mM L-glutamine. The MCF-10A cells were cultured in DMEM:F12 (1:1) cell culture media, 5% heat-inactivated horse serum, supplemented with 50 IU/mL penicillin, 50 μg/mL streptomycin, 20 mM 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid (HEPES), 2 mM L-glutamine, 20 ng/mL epidermal growth factor (EGF), 500 ng/mL hydrocortisone, 100 ng/mL cholera toxin, and 10 μg/mL insulin. Cells were plated in triplicate in 100 μL DMEM on a 96-well plate, at a density of 2500–4000 cells per well. When cells were at logarithmic growth after 24 h, medium without (control) and with combined extract of PTR and PA (100 μL, 1:1 w/w) was added to each well to give a final at concentrations of 100 μg/mL (day 0). MTT assay was employed where absorbance was read at 540 nm to determine growth inhibition after 72 h of incubation based on the difference between the optical density values on day 0 and those at the end of drug exposure. Cell growth inhibition was determined as a percentage where a value of 100% is indicative of total growth inhibition, whereas a value >100% is indicative of growth inhibition and cell death.

Antiproliferative capacity of combined extracts from Paramignya trimera and Phyllanthus amarus against pancreatic cancer cell lines

Cell culture

Human PC cell lines (primary: MiaPaCa2 and BxPc3 and secondary: CFPAC1) and normal human pancreatic ductal epithelial (HPDE) cell line were cultured based on the previously described methods with some modifications.[4],[5] Briefly, the cells were grown in DMEM supplemented with 10% FBS, 2.5% horse serum, and 1% L-glutamine for MiaPaCa2; RPMI or IMDM supplemented with 10% FBS and 1% L-glutamine for BxBc3 or CFPAC1; or KSFM supplemented with 2.5 μg EGF human recombinant and 25 mg bovine pituitary extract for HPDE at 37°C with 5% CO2, respectively.

Cell viability

Cell viability was determined using CCK-8 assay based on the formerly reported studies with some modifications.[4],[5] Briefly, cells were seeded into a 96-well plate at 3 × 103 cells per well for MiaPaCa2, BxPc3, and CFPAC1, or 7 × 103 cells per well for HPDE and allowed to adhere for 24 h at 37°C with 5% CO2. Media was removed and the cells were then treated with various concentrations of combined extracts in the media (200–12.5 μg/mL), and gemcitabine (50 nM) as a positive control, Quillaja bark extract (200 mg/mL) as a comparative sample, and 0.5% dimethyl sulfoxide as a control. After 72 h incubation at 37°C with 5% CO2, the media was removed and 100 μL of 10% CCK-8 solution in the media was added and incubated at 37°C with 5% CO2 for 2 h. Absorbance was measured at 450 nm, and cell viability was expressed as a percentage of control.

Statistical analysis

The data were analyzed by the SPSS software (version 22, Chicago, IL, USA), and the results were expressed as means ± standard deviations. Statistical comparisons were made using one-way analysis of variance and Duncan's multiple range tests. Differences were considered to be significant when P < 0.05.


 > Results and Discussion Top


Cell growth inhibition of combined extract from Paramignya trimera and Phyllanthus amarus

[Table 1] shows that among 12 different cell lines, the combined extract from PTR and PA (PTR:PA) at 100 μg/mL (1:1 w/w) exhibited the strongest growth inhibition on A2780 cancer cells (76%), followed by Du145, A431, and MCF-7 (63%, 62%, and 61%, respectively) and the weakest effect on SJ-G2 cancer cells (18%). This result revealed that the PTR:PA extract at the same concentration displayed weaker cell growth inhibition than the individual PTR extract[5] (≥ 100% on all cell lines) and being comparable to the individual PA extract[7] (31%–74%). The reason for this may be due to the significant difference in saponin content within the PTR and PA extracts (7331 and 1658 mg escin equivalents/g dried extract, respectively), which is mainly responsible for cell growth inhibition. The cell growth inhibition of the PTR:PA extract at 100 μg/mL against HT29 and MCF-7 cancer cells in this study is comparable to that of three monoterpenoids in terms of carvone, perillyl alcohol, and alpha-terpineol and the Malus floribunda leaf extract (<100%),[10],[11] but it is weaker than that of the pitomba (Talisia esculenta) extract and the M. floribunda leaf extract against MCF-7 cancer cells (≥100%).[11],[12] The antiproliferative effect on A2780 cancer cells of the PTR:PA extract at 100 μg/mL in this study is also much greater than that of anthocyanin-rich fractions from blueberry and blackcurrant juices (approximately 15%–20%).[13] The finding from this study shows that the PTR:PA extract moderately inhibited the growth on a panel of cancer cell lines; therefore, this extract is a promising source for the development of novel anticancer drugs.
Table 1: Antiproliferative capacity of a combined extract from Paramignya trimera root and Phyllanthus amarus (1:1 w/w) against different cancer cell lines

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Antiproliferative capacity of combined extracts fromParamignya trimera and Phyllanthus amarus against pancreatic cancer cell lines

The viability of three PC cell lines (MiaPaCa2, BxPc3, and CFPAC1) treated with different concentrations (12.5–200 μg/mL) of combined extracts from PTR and PA(PTR:PA) and PTL and PA(PTL:PA) in comparison with gemcitabine (50 nM) and Quillaja bark extract (200 μg/mL) is shown in [Figure 1], [Figure 2], [Figure 3],[Figure 4], [Figure 5], [Figure 6]. Overall, the growth inhibition on PC cells of the PTR:PA extract was higher than that of the PTL: PA extract at the same concentrations. This discrepancy may be due to the dissimilarity in the phytochemical composition within the PTR and PTL extracts. In particular, the antiproliferative capacity against PC cells of these combined extracts was comparable to gemcitabine (a positive control) and Quillaja bark extract (a comparative sample).
Figure 1: Viability of MiaPaCa2 cells treated with different concentrations of a combined extract from Paramignya trimera root and Phyllanthus amarus (1:1 w/w). Dimethyl sulfoxide, gemcitabine, and Quillaja bark extracts were used as a control, a positive control, and a comparative sample, respectively. Different letters in the columns were significant differences (P < 0.05) between treatments

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Figure 2: Viability of MiaPaCa2 cells treated with different concentrations of a combined extract from Paramignya trimera leaf and Phyllanthus amarus (1:1 w/w). Dimethyl sulfoxide, gemcitabine, and Quillaja bark extracts were used as a control, a positive control, and a comparative sample, respectively. Different letters in the columns were significant differences (P < 0.05) between treatments

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Figure 3: Viability of BxPc3 cells treated with different concentrations of a combined extract from Paramignya trimera root and Phyllanthus amarus (1:1 w/w). Dimethyl sulfoxide, gemcitabine, and Quillaja bark extracts were used as a control, a positive control, and a comparative sample, respectively. Different letters in the columns were significant differences (P < 0.05) between treatments

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Figure 4: Viability of BxPc3 cells treated with different concentrations of a combined extract from Paramignya trimera leaf and Phyllanthus amarus (1:1 w/w). Dimethyl sulfoxide, gemcitabine, and Quillaja bark extracts were used as a control, a positive control, and a comparative sample, respectively. Different letters in the columns were significant differences (P < 0.05) between treatments

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Figure 5: Viability of CFPAC1 cells treated with different concentrations of a combined extract from Paramignya trimera root and Phyllanthus amarus (1:1 w/w). Dimethyl sulfoxide, gemcitabine, and Quillaja bark extracts were used as a control, a positive control, and a comparative sample, respectively. Different letters in the columns were significant differences (P < 0.05) between treatments

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Figure 6: Viability of CFPAC1 cells treated with different concentrations of a combined extract from Paramignya trimera leaf and Phyllanthus amarus (1:1 w/w). Dimethyl sulfoxide, gemcitabine, and Quillaja bark extracts were used as a control, a positive control, and a comparative sample, respectively. Different letters in the columns were significant differences (P < 0.05) between treatments

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Regarding the PTR:PA extract, the viability of MiaPaCa2 cancer cells treated with 200 μg/mL (4.6%) was significantly lower (P<0.05) than that treated at lower concentrations of 100–12.5 μg/mL (55.3%–97.2%) and 50 nM of gemcitabine (27.2%), and it was not significantly different from that of Quillaja bark extract (4.2%) and individual PTR extract (4.2%)[5] [Figure 1]. In particular, the antiproliferative capacity of the PTR:PA extract against BxPc3 and CFPAC1 cancer cells was greater than that of the PTR:PA extract against the MiaPaCa2 cancer cells at the same concentrations. The viability of BxPc3 and CFPAC1 cancer cells treated with 200 μg/mL of the PTR:PA extract (2.2% and 8.0%, respectively) was not significantly different (P< 0.05) from those treated with 100 μg/mL of the PTR:PA extract (10.3% and 8.5%, respectively), 50 nM of gemcitabine (15.2% and 16.0%, respectively), and 200 μg/mL of Quillaja bark extract (2.2% and 7.9%, respectively) [Figure 3] and [Figure 5].

Considering the PTL: PA extract, the growth inhibition capacity on the BxPc3 and CFPAC1 cancer cells of the PTL: PA extract at various concentrations was greater than that of the PTL:PA extract on the MiaPaCa2 cancer cells. At 200 μg/mL, the viability of BxPc3 and CFPAC1 cancer cells was 9.9% and 16.4%, respectively, when compared to that of MiaPaCa2 cancer cells (52.7%). Particularly, the viability of BxPc3 and CFPAC1 cancer cells treated with 200 μg/mL of the PTL:PA extract was not significantly different (P< 0.05) from those of gemcitabine at 50 nM (15.2% and 16.0%, respectively) and Quillaja bark extract at 200 μg/mL (2.2% and 7.9%, respectively) [Figure 4] and [Figure 6].

The viability of MiaPaCa2 cancer cells treated with 200 μg/mL of the PTR:PA extract in this study (4.6%) was much lower than that treated with 200 μg/mL of lilly pilly (Solanum paniculatum) extract[14] (~23%), Euphorbia tirucalli extracts[15] (~7.0%–30.0%), and 100 μg/mL of papaya and Eucalyptus robusta leaf extracts (96.0% and 15%, respectively).[9],[16] While, the growth inhibition of MiaPaCa2, BxPc3, and CFPAC1 cancer cells by the PTR:PA and PTL: PA extracts at 200 μg/mL in this study was comparable to that of the ginger extract (45%, 8%, and 7%, respectively).[17]

[Figure 7] and [Figure 8] describe the antiproliferative activity of the PTR:PA and PTL: PA extracts against normal HPDE cells. Of these, the viability of the HPDE cells treated by these extracts at all concentrations was not significantly different (P< 0.05) from that of gemcitabine and Quillaja bark extract. The viability of HPDE cells treated by the PTR:PA and PTL: PA extracts at 200 μg/mL (2.5% and 2.2%, respectively) in this study was similar to that of the individual PTR, PTL, and PA extracts (2.4%, 2.2%, and 2.2%, respectively),[5] but it was much lower than that of S. paniculatum extract (58%).[14] This shows that the PTR:PA and PTL: PA extracts are able to destroy the normal cells, and these extracts are, therefore, very potential for any therapeutic application.
Figure 7: Viability of human pancreatic ductal epithelial cells treated with different concentrations of a combined extract from Paramignya trimera root and Phyllanthus amarus (1:1 w/w). Dimethyl sulfoxide, gemcitabine, and Quillaja bark extracts were used as a control, a positive control, and a comparative sample, respectively. Different letters in the columns were significant differences (P < 0.05) between treatments

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Figure 8: Viability of human pancreatic ductal epithelial cells treated with different concentrations of a combined extract from Paramignya trimera leaf and Phyllanthus amarus (1:1 w/w). Dimethyl sulfoxide, gemcitabine, and Quillaja bark extracts were used as a control, a positive control, and a comparative sample, respectively. Different letters in the columns were significant differences (P < 0.05) between treatments

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Based on DNA sequencing revealing that PC has ≥1000 somatic mutations comprising 12 critical pathways, i.e., DNA damage control, apoptosis, regulation of the G1/S transition, homophilic cell adhesion, regulation of invasion, Hedgehog signaling, integrin signaling, c-Jun N-terminal kinase signaling, KRAS signaling, other small GTPase-dependent signaling, Wnt/Notch signaling, and transforming growth factor-β signaling.[5],[18] A recent study indicated that the most potent fraction-1 from the aqueous crude Eucalyptus microcorys extract induced apoptosis by regulating key apoptotic proteins – Bcl-2, Bak, Bax, cleaved PARP, procaspase-3, and cleaved caspase-3 in MIA PaCa-2 cancer cells, suggesting the involvement of intrinsic mitochondrial apoptotic pathway and arrested cells at G2/M phase.[19] However, this study is a preliminary assessment on the antiproliferative capacity of the combined extracts from PT and PA. Hence, further studies must focus on the molecular mechanism of the PTR:PA and PTL: PA extracts against PC cell lines.


 > Conclusions Top


The results obtained from this study show that the combined extracts from PTR, PTL, and PA are a potential source for the development of novel anticancer drugs. However, further research is needed to understand the molecular mechanism of these combined extracts on the different cancer cell lines for their application.

Acknowledgment

The author would like to thank the support from the University of Newcastle, Australia, and the Vietnamese Government. The National Foundation for Science and Technology Development is also gratefully acknowledged.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
 
 
    Tables

  [Table 1]



 

 
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