In vitro antioxidant and anticancer effects of solvent fractions from prunella vulgaris var. lilacina
© Hwang et al.; licensee BioMed Central Ltd. 2013
Received: 12 July 2013
Accepted: 31 October 2013
Published: 9 November 2013
Recently, considerable attention has been focused on exploring the potential antioxidant properties of plant extracts or isolated products of plant origin. Prunella vulgaris var. lilacina is widely distributed in Korea, Japan, China, and Europe, and it continues to be used to treat inflammation, eye pain, headache, and dizziness. However, reports on the antioxidant activities of P. vulgaris var. lilacina are limited, particularly concerning the relationship between its phenolic content and antioxidant capacity. In this study, we investigated the antioxidant and anticancer activities of an ethanol extract from P. vulgaris var. lilacina and its fractions.
Dried powder of P. vulgaris var. lilacina was extracted with ethanol, and the extract was fractionated to produce the hexane fraction, butanol fraction, chloroform fraction and residual water fraction. The phenolic content was assayed using the Folin-Ciocalteu colorimetric method. Subsequently, the antioxidant activities of the ethanol extract and its fractions were analyzed employing various antioxidant assay methods including DPPH, FRAP, ABTS, SOD activity and production of reactive oxygen species. Additionally, the extract and fractions were assayed for their ability to exert cytotoxic activities on various cancer cells using the MTT assay. We also investigated the expression of genes associated with apoptotic cell death by RT-PCR.
The total phenolic contents of the ethanol extract and water fraction of P. vulgaris var. lilacina were 303.66 and 322.80 mg GAE/g dry weight (or fractions), respectively. The results showed that the ethanol extract and the water fraction of P. vulgaris var. lilacina had higher antioxidant content than other solvent fractions, similar to their total phenolic content. Anticancer activity was also tested using the HepG2, HT29, A549, MKN45 and HeLa cancer cell lines. The results clearly demonstrated that the P. vulgaris var. lilacina ethanol extract induced significant cytotoxic effects on the various cancer cell lines, and these effects were stronger than those induced by the P. vulgaris var. lilacina solvent fractions. We also investigated the expression of genes associated with apoptotic cell death. We confirmed that the P. vulgaris var. lilacina ethanol extract and water fraction significantly increased the expression of p53, Bax and Fas.
These results suggest that the ethanol extract from P. vulgaris var. lilacina and its fractions could be applied as natural sources of antioxidants and anticancer activities in food and in the pharmaceutical industry.
KeywordsPrunella vulgaris var. lilacina Antioxidative activity Anticancer activity
Oxidative stress is caused by reactive oxygen species (ROS), which are associated with many pathological disorders such as atherosclerosis, diabetes, ageing and cancer [1–3]. In order to protect human beings against oxidative damage, synthetic antioxidants such as BHA and BHT were created due to demand . However, there has been concern regarding the toxicity and carcinogenic effects of synthetic antioxidants [5, 6]. Thus, it is important to identify new sources of safe and inexpensive antioxidants of natural origin. Natural antioxidants, especially plant phenolics, flavonoids, tannins and anthocyanidins, are safe and are also bioactive . Therefore, in recent years, considerable attention has been focused on exploring the potential antioxidant properties of plant extracts or isolated products of plant origin .
Prunella vulgaris var. lilacina is widely distributed in Korea, Japan, China, and Europe, and it continues to be used to treat inflammation, eye pain, headache, and dizziness [9, 10]. It is rich in active compounds known to significantly affect human health, such as triterpenoid, rosmarinic acid, hyperoside, ursolic acid, and flavonoids [11–16]. Furthermore, P. vulgaris var. lilacina has been shown to have anti-allergic, anti-inflammatory, anti-oxidative, anti-microbial, and anti-viral effects [17–19]. However, reports on the antioxidant activities of P. vulgaris var. lilacina are limited, particularly concerning the relationship between its phenolic content and antioxidant capacity. Therefore, the aims of this study were to identify new sources of antioxidants from P. vulgaris var. lilacina extract. Additionally, the effects of the extraction solvent (70% ethanol, hexane, butanol, chloroform, or water) on the total phenolic content and antioxidant activities of P. vulgaris var. lilacina were investigated.
The reagents 1,1-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azinibis 3-ethyl benzothiazoline-6-sulfonic acid (ABTS), α-tocopherol, 2,4,6-tris(2-pyridyl)-s-triazine (TPTZ), iron(III) chloride hexahydrate, gallic acid, Folin and Ciocalteu’s phenol reagent, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lipopolysaccharides (LPS) were purchased from Sigma-Aldrich (St. Louis, MO, USA). Iron(II) sulfate heptahydrate and acetic acid were purchased from Junsei (Tokyo, Japan). A superoxide dismutase-WST kit was purchased from Dojindo (Kumamoto, Japan). Dulbecco’s Modified Eagle’s Medium (DMEM), RPMI 1640 medium, fetal bovine serum (FBS), and penicillin–streptomycin were obtained from Invitrogen (Carlsbad, CA, USA).
Sample preparation and extraction
Whole plants of P. vulgaris var. lilacina were purchased from the Plant Extract Bank (#007-017, Dae-Jeon, Korea). Dried P. vulgaris var. lilacina was milled into powder of 80-mesh particle size and stored at -70°C. The dried P. vulgaris var. lilacina was extracted three times with 70% ethanol. The 70% ethanol extract powder (10 g) was suspended in 500 mL of distilled water and extracted with 500 mL of the following solvents in a stepwise manner: hexane, chloroform, and butanol. Each fraction was filtered through Whatman filter paper No. 2 (Advantec, Tokyo, Japan). Subsequently, the filtrates were combined and evaporated under a vacuum and then lyophilized with a freeze dryer (Ilshine Lab, Suwon, Korea) at -70°C under reduced pressure (< 20 Pa). The dry residue was stored at -20°C. For further analysis, we reconstituted the dry extract and fractions with DMSO.
Total phenolic content
The total phenolic contents of P. vulgaris var. lilacina extract and its fractions were determined using the Folin-Ciocalteu method . The extract and each fraction were oxidized with Folin–Ciocalteu’s reagents, and then, the reaction was neutralized with 10% sodium carbonate. After incubation at room temperature for 1 h, the absorbance of the reaction mixture was measured at 725 nm using a microplate reader (Molecular Devices, Sunnyvale, CA, USA). Quantification was performed based on a standard curve with gallic acid. Results were expressed as milligrams gallic acid equivalent (GAE) per gram of dry weight of extract (or fractions).
DPPH radical scavenging activity
Analysis of DPPH radical-scavenging activity was carried out according to the Blois method . 0.3 mM DPPH was added to each sample. After incubation for 30 min in the dark at room temperature, the absorbance was measured at 518 nm using a microplate reader. α-Tocopherol was used as a positive control. Percent reduction of the DPPH radical was calculated in the following way: inhibition concentration (%) = 100 - (Asample/Acontrol) × 100,
where Acontrol is the absorbance of the control reaction (containing all reagents except the test sample), and Asample is the absorbance of the test sample. Tests were carried out in triplicate. For the final results, RC50 values (the concentrations required for 50% reduction of DPPH by 30 min after starting the reaction) were calculated from the absorbance diminished by 50%. The experiment was performed in triplicate.
Ferric-reducing antioxidant power (FRAP) activity
FRAP activity was determined using manual assay methods . The working fluid was freshly prepared by mixing acetate buffer (300 mM, pH 3.6) with TPTZ in HCl and iron (III) chloride hexahydrate. Each sample solution or α-tocopherol was added to 3 mL of working fluid, and the mixture was left for 4 min at room temperature. The absorbance was measured at 593 nm. The results were expressed as iron (II) sulfate heptahydrate (FeSO4) equivalents.
ABTS radical cation scavenging activity
The ABTS assay was based on the ability of different fractions to scavenge the ABTS radical cation in comparison to a standard (α-tocopherol) . The radical cation was prepared by mixing 7 mM ABTS with 2.45 mM potassium persulfate (1:1 v/v) and leaving the mixture for 24 h until the reaction was completed and the absorbance was stable. The ABTS radical solution was diluted with PBS to an absorbance of 0.7 ± 0.02 at 732 nm. The photometric assay was conducted with 180 μL of ABTS radical solution and 20 μL of samples; measurements were taken at 732 nm after 1 min. The antioxidative activity of the tested samples was calculated by determining the decrease in absorbance. The free radical scavenging capacity was expressed by RC50.
Superoxide dismutase (SOD) activity
Superoxide dismutase activity was determined using the highly water-soluble tetrazolium salt WST-1, which produces a water-soluble formazan dye upon reduction with a superoxide anion. SOD activity was determined using an SOD assay kit (Dojindo, Kumamoto, Japan) in accordance with the manufacturer’s instructions. Briefly, WST working solution was made by diluting 1 mL of WST solution into 19 ml of buffer solution. Enzyme working solution was made after the enzyme solution tube was centrifuged for 5 sec. Fifteen microliters of enzyme solution were diluted with 2.5 mL of dilution buffer. SOD activity was expressed as the percentage of inhibition rate.
Cells and culture
The mouse macrophage cell line RAW264.7, human liver cancer cell line HepG2, human colon cancer cell line HT29, human lung cancer cell line A549, human stomach cancer cell line MKN-45 and human cervical cancer cell line HeLa were purchased from the Korean Cell Line Bank (Seoul, Korea). The cell lines were grown in RPMI 1640 medium or DMEM with 10% FBS and 1% penicillin-streptomycin and incubated at 37°C in 5% CO2.
Cell cytotoxicity assay
Exponentially growing cells were collected and plated at 5 × 103 - 1 × 104 cells/well. P. vulgaris var. lilacina ethanol extract and its solvent fractions in DMSO were diluted in PBS to obtain final concentrations of 10, 50 and 100 μg/mL. Cells were treated with samples for 24 h, and MTT solution was added. After 4 h, the media was removed, and DMSO was added to each well. The resulting absorbance was measured at 540 nm .
Intracellular reactive oxygen species (ROS) scavenging activity
For microscopic detection of ROS formation, RAW264.7 cells were grown to 80% confluence in six-well plates and treated with samples for 24 h. After incubation, cells were incubated with dichlorofluorescein diacetate (DCF-DA) (25 μM) for 30 min at 37°C in the dark. After several washings with PBS, cells were observed with a fluorescence microscope (Carl ZEISS, Oberkochen, Germany).
Real-time reverse transcription polymerase chain reaction analysis (RT-PCR)
To determine the expression levels of p53, Bax, Bcl-2 and Fas, RT-PCR was performed using a Qiagen Rotor-Gene Q real-time thermal cycler (Valencia, CA, USA) in accordance with the manufacturer’s instructions. The cells were treated with P. vulgaris var. lilacina extracts and cultured for 24 h. Thereafter, cDNA was synthesized from the total RNA isolated from cells. The PCR reaction was performed using 2× SYBR Green mix (Qiagen, Valencia, CA, USA). All results were normalized to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) expression. The following primer sequences were used for the real-time RT-PCR: GAPDH, 5′-CGG AGT CAA CGG ATT TGG TCG TAT-3′ (forward), 5′-AGC CTT CTC CAT GGT GGT GAA GAC-3′ (reverse); p53, 5′-GCT CTG ACT GTA CCA CCA TCC-3′ (forward), 5′-CTC TCG GAA CAT CTC GAA GCG-3′ (reverse); Bax, 5′-ATG GAC GGG TCC GGG GAG-3′ (forward), 5′-TCA GCC CAT CTT CTT CCA-3′ (reverse); Bcl-2, 5′-CAG CTG CAC CTG ACG-3′ (forward), 5′-ATG CAC CTA CCC AGC-3′ (reverse); Fas, 5′- TCT AAC TTG GGG TGG CTT TGT CTT C -3′ (forward), 5′- GTG TCA TAC GCT TTC TTT CCA T-3′ (reverse).
Gas chromatography-mass spectrum analysis (GC-MS)
GC-MS analysis was carried out using an Agilent 6890 gas chromatograph equipped with a DB-5 ms capillary column (60 m × 0.25 mm; coating thickness 1.4 μm) and an Agilent 5975 MSD detector (Loveland, CO, USA). Analytical conditions were as follows: injector and transfer line temperatures of 250°C; oven temperature was programmed from 50°C to 150°C at 10°C/min, from 150°C to 200°C at 7°C/min, and from 200°C to 250°C at 5°C/min; carrier gas helium at 1 mL/min; and split ratio 1:10. Identification of the constituents was based on comparison of the retention times with those of authentic samples.
Statistical analysis was performed with SPSS (version 17.0; SPSS Inc., Chicago, IL, USA). Descriptive statistics were used to calculate the mean and standard error of the mean (SEM). One-way analysis of variance was performed, and when the significance (p < 0.05) was determined, the differences of the mean values were identified using Duncan’s multiple range tests.
Results and discussion
The yield of the extract and each fraction obtained from dry plant material was measured (Additional file 1: Table S1). The highest solid residue yields were obtained using butanol as the extraction solvent.
Total phenolic content
Total phenolic contents of various solvent fractions obtained from the ethanol extract of Prunella vulgaris var. lilacina
Total polyphenoles1)(mg GAE/g)
303.66 ± 3.61a
109.31 ± 4.08c
242.03 ± 6.16b
124.45 ± 0.24c
322.80 ± 15.12a
Antioxidant capacities of prunella vulgaris var. Lilacina
Total antioxidant capacities of various solvent fractions of the ethanol extract of Prunella vulgaris var. lilacina
DPPH RH50 1) (ug/ml)
FRAP value2) (m M/g)
ABTS RC50 3) (ug/ml)
SOD activity4) (%)
73.05 ± 10.3c
1.07 ± 0.08ab
60.08 ± 3.19
87.74 ± 3.42
1402.96 ± 194a
0.48 ± 0.09c
1469.12 ± 10.1a
23.80 ± 0.53
83.52 ± 7.01c
0.95 ± 0.09bc
61.13 ± 4.23c
92.54 ± 0.32
521.58 ± 8.10b
0.65 ± 0.02bc
153.04 ± 0.58b
72.75 ± 3.91
64.26 ± 2.22c
1.24 ± 0.12a
53.78 ± 2.60c
87.51 ± 3.20
12.82 ± 1.33
15.0 ± 26
7.54 ± 0.13
99.64 ± 2.45
Correlation coefficients between the antioxidant capacity and phenolic content of various solvent fractions of the ethanol extract of Prunella vulgaris var. lilacina
Intracellular ROS scavenging activity
Cell cytotoxicity activity
Real-time RT-PCR analysis
The present study determined that P. vulgaris var. lilacina extract and its fractions have strong antioxidant and anticancer activities in vitro. The correlation coefficients between antioxidant capacity and the phenolic content were very strong, and phenolic compounds were a major contributor to the antioxidant capacities of P. vulgaris var. lilacina.
In addition, we confirmed the presence of 7 major components of P. vulgaris var. lilacina. However, further studies to study the mechanisms of these compounds and find the root of their antioxidative and anticancer activity are underway. On the basis of these results, P. vulgaris var. lilacina appears to be a good source of natural antioxidant and anticancer agents and could be of significance in the food industry and for the control of various human and animal diseases.
2, 2′-Azinibis 3-ethyl benzothiazoline-6-sulfonic acid
Ferric-reducing antioxidant power
Gallic acid equivalent
Reactive oxygen species
2, 4, 6-tris(2-pyridyl)-s-triazine.
This study was carried out with support from the “Research Program for Agricultural Science & Technology Development (Project No. PJ008521)”, National Academy of Agricultural Science, RDA, Republic of Korea.
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