Research ArticleExperimental Studies

Lapathoside A Isolated from Fagopyrum esculentum Induces Apoptosis in Human Pancreatic Cancer Cells

MI SOOK KANG, YOUNG-MIN HAM, DAE-JU OH, YONG-HWAN JUNG, SONG-I HAN and JAE HOON KIM
Anticancer Research February 2021, 41 (2) 747-756; DOI: https://doi.org/10.21873/anticanres.14826

Abstract

Background/Aim: Lapathoside A, a phenylpropanoid ester, was isolated from the roots of buckwheat by searching for bioactive compounds against human pancreatic cancer cells. Materials and Methods: Buckwheat root extracts, prepared by 70% ethanol, were separated into n-hexane, methylene chloride, ethyl acetate, n-butanol, and water fraction by solvent partitioning. Seven fractions were obtained from the ethyl acetate fraction by liquid chromatography, and fraction No. 6 contained lapathoside A. The effects of lapathoside A on Panc-1 and SNU-213 human pancreatic cancer cell lines were examined. Results: The structure of lapathoside A was determined by liquid chromatography–mass spectrometry, liquid chromatography–tandem mass spectrometry, and nuclear magnetic resonance analysis. Next, we investigated whether lapathoside A has anticancer activity in human pancreatic cancer cell lines (PANC-1 and SNU-213). After treatment with 25 μM lapathoside A, viability of PANC-1 and SNU-213 cells decreased to about 40 and 27%, respectively. In addition, lapathoside A treatment also increased apoptosis while affecting the expression levels of apoptotic proteins. Conclusion: The effect of lapathoside A on apoptosis was confirmed in pancreatic cancer cell lines, supporting the application of lapathoside A in the treatment of pancreatic cancer.

Key Words:

Pancreatic cancer is one of the deadliest cancers and its 5-year relative survival rate is about 9% (1, 2). According to the report of American cancer society in 2018, deaths from pancreatic cancer have been steadily rising worldwide over the last decade (3). In addition, pancreatic cancer is the fourth leading cause of cancer death in the USA, accounting for 7% of all deaths caused by cancer (3). Despite advances in surgery, chemotherapy, and radiotherapy over the past several years, pancreatic cancer still has a very poor prognosis. When pancreatic cancer is diagnosed, the cancer has already spread to other organs, making it difficult for most patients to undergo surgery. This is because pancreatic cancer does not show symptoms until disease progresses (4, 5). In addition, pancreatic cancer is resistant to chemotherapy or radiation therapy, so this treatment has limited effectiveness (6-8). Therefore, it is very important to find new drug candidates in natural products for pancreatic cancer treatment (9).

Buckwheat is a common pseudo-cereal plant of the genus Fagopyrum in the family Polygonaceae. Common buckwheat (Fagopyrum esculentum) and Tartary buckwheat (Fagopyrum tataricum) are mainly cultivated species. F. esculentum has a strong adaptability to the environment and is grown worldwide in areas such as Asia, Middle East, Europe, and North America (10).

According to previous studies, buckwheat seeds contain not only complex carbohydrates, but also many health-important ingredients such as natural antioxidants, minerals, dietary fiber, flavones, flavonoids, phytosterols, and pagopyrins (11-13). Although the composition in these compounds varies depending on the species, growth environment, and part of the plant (14-16), they are known to have antioxidant, anti-inflammatory and anticancer effects.

However, little is known about the natural compounds present in buckwheat roots.

In the present study, lapathoside A was isolated from buckwheat roots by searching for bioactive compounds. Cell viability assay, flow cytometric analysis, and western blot analysis were performed to investigate the anticancer effects of lapathoside A on human pancreatic cancer cell lines.

Materials and Methods

Extraction and isolation of lapathoside A from buckwheat roots. Buckwheat was cultivated in the Aewol, Jeju Island, South Korea and its roots were collected in June. The collected buckwheat roots were washed, dried in a cold wind, and ground. The dried powder of buckwheat roots was extracted by stirring in 70% ethanol for 24 h at room temperature. Then the crude extract of buckwheat roots was filtered, concentrated under reduced pressure, and lyophilized. Sequential solvent fractionation was carried out with 10 g of the buckwheat root extract using n-Hexane (n-Hex), methylene chloride (MC), ethyl acetate (EtOAc), and butanol (BuOH). The solvent fractions of buckwheat root extract were subjected to vacuum liquid chromatography (VLC) using n-Hex (100%), MC (100-50%), and EtOAc (0-50%) as mobile phases.

Identification of lapathoside A. High-performance liquid chromatography (HPLC) analysis was performed on buckwheat root extract, solvent fraction, and VLC fraction. The High-performance liquid chromatography system e2695 equipped with a Photodiode array detector 2998 (Waters Corp., Milford, MA, USA) was used for HPLC analysis. Cadenza CD-C18 column (3 μm, 150 mm × 4.5 mm) was used and the column temperature was 40°C. Extracts and fractions were dissolved in 70% ethanol. Lapathoside A was dissolved in methanol and then filtered with a 0.5 μm syringe filter. H2O (with 0.5% Acetic acid, A) and acetonitrile (B) were used as mobile phases. The composition was changed from A 75% to A 60% during a period of 40 min and the flow rate was 1 ml/min.

LCQ-Fleet Ion Trap Mass Spectrometer (Thermo Fisher Scientific, Waltman, MA, USA) was used for liquid chromatography–tandem mass spectrometry (LC-MS/MS) analysis to identify the structure of the single isolated compound. The ionization method of LC-MS/MS was ESI negative using the Hypersil GOLD (50×2.1 mm, 1.9 μm) column at 275°C of capillary temperature. H2O (with 0.1% formic acid, A) and acetonitrile (B) were used as mobile phases. The flow started with composition 95% A and maintained for 1 min. Then the composition was changed to 0% A for 13 min and the flow rate was 200 μl/min. Finally, the structure of the isolated compound was characterized using 1H and 13C NMR (CD3OD, 500 MHz) with Avance III NMR spectrometer (Bruker BioSpin, Rheinstetten, Germany).

Cell culture. Human pancreatic cancer cell lines, PANC-1 and SNU-213, were purchased from Korean Cell Line Bank (KCLB, Seoul, Republic of Korea). 293T kidney epithelial cells were provided by KCLB as a noncancerous cell line. PANC-1 and 293T cells were maintained in DMEM (Gibco-BRL, Gaithersburg, MD, USA) containing 10% fetal bovine serum (FBS, Gibco-BRL) and 1% Penicillin-Streptomycin (Pen-Strep, Gibco-BRL). SNU-213 cells were cultured in RPMI 1640 medium (Gibco-BRL) supplemented with 10% FBS and 1% Pen-Strep. Cells were incubated with 5% CO2 at 37°C.

Cell viability assay. Cell viability was measured by WST-1 analysis using the EZ-Cytox cell viability assay kit (Daeil Lab Service, Seoul, Republic of Korea). Cells were seeded at 1.25×104 cells/well in 24-well plates and treated with lapathoside A for 72 h. After 72 h, cells were incubated with 10% WST-1 reagent for 30 min at 37°C in a 5% CO2 incubator for cell viability analysis. After the reaction was completed, the absorbance was measured at 450 nm using a Multiskan GO spectrophotometer (Thermo Fisher Scientific).

Flow cytometric analysis. Apoptotic cell death was detected using the FITC Annexin V Apoptosis Detection Kit from BD Pharmingen (San Diego, CA, USA). Cells were seeded at a density of 1.25×104 cells/well in a 35mm dish and treated with lapathoside A. After 72 h of treatment, cells were trypsinized, harvested, and washed with cold PBS. The cells were then resuspended in 500 μl of binding buffer containing Annexin V-FITC (5 μl) and propidium iodide (5 μl). Cells were incubated for 15 min at 37°C in the dark. Apoptotic cells were detected by the flow cytometer LSRFortessa (BD Biosciences, CA, USA). Cells that were Annexin V (−) and PI (−) were considered as viable cells. Cells that were Annexin V (+) and PI (−) were considered as early-stage apoptotic cells. Cells that were Annexin V (+) and PI (+) were considered as late-stage apoptotic cells or necrotic cells. The percentage of total apoptotic cells was calculated by combining the percentages of early-stage apoptotic cells and late-stage apoptotic cells.

Western blot analysis. The M-PER Mammalian Protein Extraction Reagent for cell lysis was purchased from Thermo Fisher Scientific (USA). Primary antibodies (AKT, FAK, GAPDH, etc.) were purchased from Cell Signaling Technology (Beverly, MA, USA) and secondary antibodies from Merck (Darmstadt, Germany). Cells were treated with different concentrations of lapathoside A after 24 h of seeding on 6-well plates. After treatment, cells were lysed with cell lysis buffer (M-PER Mammalian Protein Extraction Reagent containing 2 mM sodium vanadate, 30 mM sodium pyrophosphate, 100 mM sodium fluoride, 0.1 M PMSF, and protein inhibitors) and the lysates were centrifuged. The concentration of proteins in the cell lysates was quantified using the Bradford assay. Cell lysates were mixed with the SDS-PAGE sample loading buffer and then heated at 99°C for 10 min. Proteins were separated through SDS-PAGE on 12% SDS polyacrylamide gel and transferred to nitrocellulose membrane. The membranes were blocked with 5% skim milk in TBST for 8 h and incubated with primary antibodies (FAK, phospho-FAK, AKT, phospho-AKT, GAPDH) at 4°C overnight. Then the membranes were washed with TBST and incubated with Donkey anti-Rabbit or anti-Mouse IgG antibody for 1 h at room temperature. The blots were developed with the BS ECL Plus Kit (Biosesang, Gyeonggi-do, Republic of Korea) and the bands conjugated with the antibodies were detected by HIGH X-DOL (Poohung, Gyeonggi-do, Republic of Korea) and HIGH X-FIX (Poohung, Republic of Korea) using X-ray film.

Results

Isolation and identification of lapathoside A. Extraction of buckwheat root and isolation of lapathoside A were performed according to the scheme described in Figure 1A. The dried powder of buckwheat root was extracted in 70% ethanol for 24 h at room temperature to obtain a crude extract. Analysis of the buckwheat root extract by HPLC showed the highest peak at retention time of 29.664 min (Figure 1B). Ten g of the buckwheat root extract were subjected to sequential solvent fractionation and the EtOAc fraction was obtained as 500 mg of powder. Seven fractions were obtained by applying the EtOAc fraction to vacuum liquid chromatography. Seventy-six mg of the compound was obtained from fraction 6, which had the same retention time as the single peak identified in the crude extract. The isolated compound was a light brown solid powder. The liquid chromatography–mass spectrometry (LC-MS) analysis confirmed the m/z 985.09 (M-H)- molecular weight peak (Figure 1C). An m/z 838.96 (M-coumaroyl)-daughter-ion was identified in LC-MS/MS Fragmentation ions (Figure 1D). In the 1H NMR, multiplet signal was detected near δ 3 to 4 and the anomeric proton was detected at 5.57 (d, J=3.5) (Figure 2A). This shows that there is at least one sugar. The 13C NMR spectrum (Figure 2B) was compared with the DEPT135 data and confirmed the presence of four carbonyl groups. Typical O-Me signals were detected at δ 3.87 and 3.82 peaks and confirmed that two p-coumaric acids and two ferrous acids were acylated in sucrose (Table I). Compared with the previous reports, the isolated compound was identified as lapathoside A (Figure 3) (20).

Figure 1.
Figure 1.
Figure 1.

Extraction and isolation of compound 1. (A) The scheme for extraction of buckwheat roots and isolation of compound 1. (B) High-performance liquid chromatography- Photodiode array chromatogram of buckwheat roots extract. (C) Liquid chromatography–mass spectrometry spectrum of compound 1. (D) Liquid chromatography–tandem mass spectrometry fragmentation spectrum of compound 1.

View this table:
Table I.

1H and 13C nuclear magnetic resonance spectroscopic data of compound 1 in CD3OD at 500 MHz.

Figure 2.
Figure 2.

Nuclear magnetic resonance (NMR) spectrum of compound 1 in CD3OD at 500 MHz. (A) 1H NMR spectrum. (B) 13C NMR spectrum.

Figure 3.
Figure 3.

Molecular structure of lapathoside A.

Inhibitory effects of lapathoside A on proliferation of pancreatic cancer cells. To investigate the cytotoxic effects of the buckwheat root extract on pancreatic cancer cells, PANC-1 and SNU-213 cells were treated with 0-500 μg/ml buckwheat root extracts for 72 h. Then cell viability was measured using the WST-1 assay. The viabilities of PANC-1 and SNU-213 cells were about 48.41 and 48.47% at 200 μg/ml of buckwheat root extract, respectively, compared with the control (Figure 4A). Buckwheat root extracts decreased cell viability in a dose dependent manner in both PANC-1 and SNU-213 cells, showing that the buckwheat root extract may be the source of a novel natural antitumor agent.

Figure 4.
Figure 4.

Cytotoxic effects of buckwheat root extracts and lapathoside A in PANC-1 and SNU-213 cells. (A) Cell viability of PANC-1 and SNU-213 cells after treatment with buckwheat root extracts for 72 h. (B) Cell viability of PANC-1 and SNU-213 cells after lapathoside A treatment for 72 h. All data are presented as the mean±S.D. Stars indicate a significant difference compared to control, *p<0.05, **p<0.01, ***p<0.001.

Next, cell viability assay was performed using lapathoside A isolated from buckwheat root extract. As shown in Figure 4B, lapathoside A decreased the proliferation of both PANC-1 and SNU-213 cells in a dose-dependent manner. The viability of PANC-1 cells was about 39.73% at 25 μM of lapathoside A. In SNU-213 cells, viability decreased from 36.90% at 15 μM to 20.07% at 25 μM of lapathoside A, respectively (Figure 4B). In control 293T cells, lapathoside A showed less effect on cell viability than in pancreatic cancer cell lines.

Effects of lapathoside A on apoptotic cell death. To determine the apoptotic effects of lapathoside A, flow cytometric analysis was performed using the Annexin V/PI staining of PANC-1 and SNU-213 cells treated with lapathoside A. The percentage of early and late apoptotic cells was increased after lapathoside A treatment (Figure 5A). As shown in Figure 5A and B, lapathoside A treatment had no significant effect on control 293T cells, but the percentage of apoptotic cells increased from 5.47% to 21.83% in PANC-1 cells and from 11.33% to 38.77% in SNU-213 cells. The results suggested that lapathoside A can induce apoptosis of both PANC-1 and SNU-213 cells.

Figure 5.
Figure 5.
Figure 5.

Effects of lapathoside A on apoptosis induction in PANC-1 and SNU-213 cells. (A) Flow cytometry analysis using Annexin V-FITC binding in PANC-1 and SNU-213 cells after 25 μM lapathoside A treatment for 72 h. (B) Quantitative analysis of the percentage of total apoptotic cells. (C) The effects of lapathoside A on the expression levels of PARP and Cleaved-PARP in PANC-1 and SNU-213 cells. (D) The effects of lapathoside A on the expression levels of phosphorylated FAK and Akt in PANC-1 and SNU-213 cells. Data are presented as the mean±S.D. Stars indicate a significant difference compared to control, *p<0.05.

It has been reported that there is over-expression of Akt in most human cancers, including pancreatic cancer, and that focal adhesion kinase (FAK) is upstream of Akt. To investigate the cellular signaling pathway regulated by lapathoside A, we examined the expression and phosphorylation of FAK and Akt.

As shown in Figure 5C, Fak and Akt proteins were detected in PANC-1 cells, and the levels of phosphorylation of FAK (Tyr397) and Akt (Ser473) decreased after the treatment with lapathoside A. In contrast, lapathoside A did not show a significant effect on 293T control cells under the same conditions, demonstrating that lapathoside A specifically acts on pancreatic cancer cells.

Discussion

Buckwheat is a common pseudo-cereal plant in the genus Fagopyrum in the family Polygonaceae. Common buckwheat and Tartary buckwheat are mainly cultivated species. In general, F. esculentum is grown worldwide (10). Buckwheat seeds contain complex carbohydrates, proteins, minerals, dietary fiber, and many health beneficial compounds (14, 15). In addition, agricultural waste of buckwheat contains more organic compounds than other plants (17, 18). The roots of F. tataricum have been traditionally used by folk medicine in China and its chemical properties have been investigated. However, after F. esculentum seeds are harvested, parts of the plant like stems and roots are disposed of as agricultural waste. To the best of our knowledge, the secondary metabolites in F. esculentum root and their beneficial effect are not known. Therefore, in the present study, the roots of buckwheat were extracted and examined for bioactive compounds.

In previous studies, phenylpropanoid sucrose esters (PSEs) have been found in various plants (18, 19) and have been reported to have antioxidant, antibacterial, and anti-inflammatory effects, as well as anti-cancer effects on different human cancer cell lines (20). Lapathoside A is one of the tetrasubstituted phenylpropanoid sucrose esters, isolated from several Polygonaceous plants. Lapathoside A isolated from Polygonum lapathifolium has been shown to inhibit Epstein-Barr virus-early antigen (EBV-EA) induced by tetradecanoylphorbol-13-acetate (TPA) (17). TPA, an agonist of protein kinase C (PKC), is known to induce EBV reactivation through NF-ĸB and AP-1 and regulate gene expression associated with EBV reactivation via PKC (21). Besides, TPA promotes skin tumorigenesis by increasing production of reactive oxygen species (ROS) (22). It has been reported that lapathoside A exhibits anti-tumor-promoting effects on mouse two-stage skin carcinogenesis induced by 7,12-dimethylbenz(a)anthracene (DMBA) and TPA (23). However, the anticancer effect of lapathoside A on pancreatic cancer cell lines has not been reported.

Programmed cell death plays a crucial role in a variety of biological processes in developing fetus and adult tissue. Physiologically, cell death occurs by apoptosis, not necrosis. Because the deregulation of apoptosis is a feature of all cancers, induction of apoptosis in cancer cells is described as an effective strategy of cancer treatment. Deficiency of the apoptotic pathway and dysregulation of apoptotic proteins play a significant role in the development of pancreatic cancer. Lack of reaction to apoptotic stimuli induces resistance to curative therapy of pancreatic cancer such as chemotherapy and radiotherapy (24). Therefore, there is need for new treatments for pancreatic cancer, and many studies have recently been conducted to develop anti-cancer drugs from natural products that are more effective and have lower toxicity (25-27).

Thus, in the present study, we demonstrated that lapathoside A isolated from buckwheat roots can inhibit the proliferation of PANC-1 and SNU-213 cells in vitro. Considering the anti-proliferation activity and low toxicity, lapathoside A has the potential to be developed as an anticancer agent for the treatment of pancreatic cancer. Furthermore, we confirmed that lapathoside A induces apoptosis on PANC-1 and SNU-213 cells. In addition, lapathoside A decreased the phosphorylation of FAK and AKT in PANC-1 cells not in 293T cells. This is consistent with previous studies that inhibition PI3K/AKT signaling pathway induces apoptosis in pancreatic cancer (28, 29).

Acknowledgements

This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2016R1A6A1A03012862) and Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, Forestry and Fisheries (IPET) through Agri-Bio Industry Technology Development Program, funded by Ministry of Agriculture, Food and Rural Affairs (MAFRA) (315027-4).

Footnotes

  • Authors’ Contributions

    MS Kang and YM Ham performed the experiments and MS Kang drafted the main manuscript. DJ Oh and JH Kim participated in research design. YH Jung analyzed data and supported this work. JH Kim and SI Han supervised the project. All authors read and approved the final manuscript.

  • Conflicts of Interest

    The Authors declare that they have no competing interests in relation to this study.

  • Received December 15, 2020.
  • Revision received January 3, 2021.
  • Accepted January 5, 2021.

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Lapathoside A Isolated from Fagopyrum esculentum Induces Apoptosis in Human Pancreatic Cancer Cells
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