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Volume 27, Issue 3 (Summer 2021)                   Intern Med Today 2021, 27(3): 418-433 | Back to browse issues page


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Lotfi Z, Morovati-Sharifabad M, Salehi E, Sarkargar F, Pourghanbari G. Evaluation of Anti-Cancer Effects of Alcoholic Extract of Ginger on SORT1 Gene Expression and Viability of the A2780s Ovarian Cancer Cell Line. Intern Med Today 2021; 27 (3) :418-433
URL: http://imtj.gmu.ac.ir/article-1-3683-en.html
1- Department of Basic Sciences, Faculty of Veterinary Medicine, Ardakan University, Ardakan, Iran.
2- Department of Basic Sciences, Faculty of Veterinary Medicine, Ardakan University, Ardakan, Iran. , mmorovati@ardakan.ac.ir
3- Expert Laboratory of Genetic, Meybod Genetic Research Center, Meybod, Iran.
4- Department of Clinical Sciences, Faculty of Veterinary Medicine, Ardakan University, Ardakan, Iran.
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1. Introduction
Epithelial ovarian cancer is the most common cause of death among gynecological cancers in the United States, and less than 40% of patients with ovarian cancer recover [1]. The highest prevalence rate has been reported in the United States, Northern Europe, and lower prevalence in Japan and developing countries [2]. Ovarian cancer is the 8th most common cancer and the 12th leading cause of death in Iran [3]. Most malignant ovarian tumors are the result of genetic instability. These tumors typically proliferate and are strongly invasive. Because these tumors quickly spread out of the ovaries, especially peritoneum and fallopian tubes, they are usually diagnosed when they involve other parts in addition to the ovary [4]. Epithelial ovarian cancer is the most common ovarian malignancy because they remain asymptomatic until metastasis, with more than two-thirds of patients in advanced stages of the disease when diagnosed [5]. Epithelial ovarian cancer occurs commonly between the ages of 56 and 60. The prevalence of this disease increases with age [6]. Hormones, diet, family history, environmental pollutants, job position, and genetic mutations are also risk factors for ovarian cancer [7].
SORT1 gene is an NTR3/sortilin encoder with 22 exons in humans and is located on the short arm of chromosome 1, close to the centromere (1p21.3-p13.1). This gene encrypts a copy of 7028 nucleotides (NM002959.4), from which a protein with 831 amino acids and a weight of 100 kD (NP002950.3) is translated.
In 1997, Petersen et al. showed that copies of the SORT1 gene are present in the thyroid, heart, brain, skeletal muscle, spinal cord, placenta, and testicles but not in ovarian tissue [8]. Gene expression profiles in ovarian cancer tissue have shown a fourfold increase in SORT1 gene expression compared to non-malignant ovarian tissue [9].
The ginger plant, scientifically named Zingiber officinale, belongs to the Zingiberaceae family. This medicinal plant is widely used worldwide as an important spice and in traditional medicine. Its essential oil contains more than 46 different compounds such as shogaol, gingerol, gingerdion, terpene, and sesquiterpene, which often have antioxidant properties [10]. The therapeutic properties of this plant include rheumatism, fever, hypertension, vomiting, pain, infection, asthma, diabetes, neurological diseases, digestive problems, inflammation, cancer, and improving sexual health [11].
Gingerol inhibits the growth and proliferation of cancer cells through normal cell death. Ginger’s anti-inflammatory capacity is associated with its ability to inhibit cancer by reducing oxidative stress and inducing normal cell death [12]. Quercetin, as one of the flavonoids in ginger, plays a cellular immune role against oxidative stress due to its potent antioxidant activity. It seems that this compound not only protects cells from free radical damage due to its antioxidant effect but also causes programmed cell death through oxidative activity and prevents tumorigenicity [13]. The active compounds of this plant, such as gingerol and shogaol, are well capable of inhibiting the production of inflammatory prostaglandins, nitric oxide inhibitors, and even interleukins involved in inflammation [14]. Cyclooxygenases play a role in all stages of malignant tumorigeneses, such as increased cell proliferation, reduction of apoptosis, angiogenesis, and mobility of cancer cells. Cyclooxygenase enzymes are an important factor in developing ovarian cancer [15]. Gingerol and gingerdion are potent inhibitors of prostaglandins by inhibition of cyclooxygenase enzymes [11]. The anti-cancer effect of ginger extract has been reported on cell lines of cancers, such as colon [16], skin [17], liver, breast [18], prostate [19], endometrium [20], and ovary [21]. This study aimed to evaluate the anti-cancer effects of ginger extract on SORT1 gene expression and viability of the A2780s ovarian cancer cell line.
2. Materials and Methods 
Preparation of extract

About 500 g of fresh and coarse rhizome of ginger (Zingiber officinale) was prepared in autumn. This species was approved by the expert of the Herbarium Laboratory of Yazd Faculty of Agriculture and Natural Resources, Yazd City, Iran. After washing, some of it was peeled and cut into thin pieces. The ginger plant was dried in an oven at 50°C and ground. Ethanol 80% was added to the resulting powder. The solution was completely mixed for 3 days using a magnetic device. It was then flattened with Whatman 42 filter paper. To smooth and prepare raw alcoholic extracts, a Buchner funnel was used, and all fine particles were taken. The obtained liquid was placed in the rotary (78°C) to distillation, and the alcohol in it was separated. The extract was stored in autoclave capped glass at 4°C [22].
Cell culture
In this study, the A2780s cell line (Pasteur Institute, Iran) was used. The cells were cultured in RPMI1640 (Inoclon, Iran) containing 10% FBS (Gibco, the USA) and 1% Pensterep antibiotic (Inoclon, Iran), and they were incubated at 37°C with a 5% CO2.
Every 48 hours, the culture medium was replaced. After reaching 70% density level, the passage was performed. At first, the culture medium of the cells was slowly poured out and washed with PBS. To separate the cells from the flask surface, trypsin was added. After isolation of cells, some culture medium with FBS was added to neutralize the effect of trypsin. After centrifugation (1200 rpm for 5 minutes), the upper medium was discarded, and the new medium was added. Finally, 10 μL of the solution was poured on the Neubauer slide for counting.
Viability assay
After counting, 25×104 cells were cultured in each well of a 24-well plate. After 24 hours of incubation under optimum conditions, for calculating IC50 (half maximal inhibitory concentration), the medium containing ginger extract with concentrations of 40, 60, 80, and 100 μg/mL were added to the wells, and the cells were incubated for 24 hours. To calculate the time, a culture medium containing ginger extract with appropriate concentration (according to the viability percentage of cells in each concentration) was added to the wells. Then, the cells were incubated for 24, 48, and 72 hours. The wells of the control group were treated with a culture medium for 24 hours.
After the desired time, the cells were separated from the plate surface by PBS and trypsinization. After centrifugation, 10 μL of cell suspension was poured on the Neubauer slide for counting.
It should be noted that the RPMI1640 medium was used as a solvent to prepare desired concentrations. All experiments have been repeated at least three times.
RNA extraction
One million cells were cultured into each well of a 6-well plate. The cells were treated with 60 μg/mL of ginger extract for 24 and 48 hours. The control group was treated with a culture medium for 24 hours. Cells were centrifuged after separation from plate surface, and cell plaques were quickly transferred to nitrogen tank to maintain RNA. The extraction of RNA was performed according to the High Pure RNA Isolation Kit (Roche) guidelines. Electrophoresis was performed on an agarose gel to ensure the quality of the extracted RNA. The presence of two clear bands on the gel confirmed the health of the extracted RNA. For quantitative investigation of extracted RNA, an optical absorption ratio of 260/280 and 260/230 nm was obtained by NanoDrop. This ratio was between 1.7 and 1.9 in all samples, indicating the high purity of extracted RNA.
c-DNA synthesis
cDNA synthesis was performed based on the Thermo Scientific Kit protocol. About 1 μL RNA, 1 μL Random Hexamer, and 6 μL DEPCE water were mixed, spun, and incubated in a thermal cycler for 5 min at 65°C. About 4 μL 5x reaction buffer, 2 μL dNTP, and 1 μL RT enzyme were added to it and reached the final volume of 20 μL with D.D.W. The temperature-time program was performed as follows: 25°C for 10 min, 42°C for 60 min and 65°C for 10 min. Using the NanoDrop device, the synthesized cDNA quality was ensured.
Real-time PCR
Sequences of SORT1 and GAPDH genes were obtained from the NCBI website. Dedicated primers were designed by the gene runner program and blasted by NCBI (Table 1).


For real-time PCR, SYBR Green Master Mix (Applied Biosystems, Warrington, UK) was used. About 10 μL SYBR green, 1 μL of forward and reverse primers of each gene, 5 μL cDNA was mixed and reached the final volume of 20 μL with D.D.W. The temperature-time program was performed as follows: 95°C for 1 min, 95°C for 15 s, and 60°C for 60 s. To ensure the specificity of the product, the melting curve was investigated. All experiments in this study were repeated three times. Gene expression was measured by the 2-∆∆Ct method.
Statistical analysis 
After measuring the gene expression by the 2-∆∆Ct method and using Excel software, the obtained data from real-time PCR and viability assay sections were analyzed with 1-way ANOVA and Tukey’s test in SPSS v. 25. The results were calculated as Mean±Standard Deviation, and P<0.05 was considered significant.
3. Results
IC50 assay

The percentage of living cells compared to the control group (Mean±SD) in the treated groups with concentrations of 40, 60, 80, and 100 μg/mL extracts of ginger after 24 hours is shown in Figure 1.

According to the results, ginger extract in different concentrations significantly decreased the percentage of living cells compared to the control group, and the treatment groups also had a significant difference. This diagram shows that ginger extract in a dose-dependent manner reduces the viability of A2780s cells. The IC50 of ginger extract at 24 hours is 76.8 μg/mL. A concentration of 60 μg/mL in which 66% of the cells survived was selected for further investigation.
Investigation of cell viability at different times
Figure 2 shows the percentage of living cells (Mean±SD) in groups treated with 60 μg/mL concentrations of ginger extract at 24, 48, and 72 hours compared to the control group.

Ginger extract at different times, after adding the extract, significantly decreases the percentage of living cells compared to the control group. Treatment groups also showed significant differences. This diagram indicates that ginger extract reduces the viability of A2780s cells in a time-dependent manner.
SORT1 gene expression analysis
Figure 3 shows that SORT1 gene expression level in cells treated with 60 μg/mL concentration of ginger extract decreased significantly at 24 and 48 hours compared to the control group.

Gene expression significantly decreased in cells treated with ginger extract for 48 hours compared to cells treated with ginger extract for only 24 hours. Table 2 compares the reduction of gene expression in different groups.


4. Discussion 
The present study results showed that the alcoholic extract prepared from fresh ginger rhizome has a lethal effect on the A2780s ovarian cancer cell line. We found that with increasing the concentration of ginger extract in 24 hours, the cell viability percentage decreased significantly compared to the control group. In addition, the percentage of living cells decreased significantly compared to the control group by increasing the duration of treatment of cancer cells with a concentration of 60 μg/mL of ginger extract. The results of real-time PCR showed that treatment of cancer cells with 60 μg/mL concentration of ginger extract for 24 and 48 hours significantly reduced SORT1 gene expression compared to the control group.
During a study on colon cancer cells, the results showed that ginger extract inhibits proliferation and induces apoptosis in HT29 and HCT116 cell lines by stopping cell cycles in G0/G1 stage and decreasing DNA synthesis [16]. In another study, 6-gingerol, 10-gingerol, 6-shogaol, and 10-shogaol prevented the proliferation of pc3R prostate cancer cell lines by inhibition of GSTλ and MRP1 proteins [19]. In another study, they found that terpenoids in ginger extract induce apoptosis in endometrial cancer cell lines by activating the p53 pathway. Also, treatment of endometrial cancer cells with ginger extract leads to a significant increase in intracellular calcium, a decrease in mitochondrial membrane potential, an increase in caspase-3 expression, and a significant reduction in Bcl-2 expression [20].
Phenolic composition of 6-gingerol inhibits the growth and proliferation of skin carcinoma cells and induces apoptosis, regulates mitochondrial function by ROS through disruption of Bax/BCL-2 ratio, and up-regulation of cytochrome C, caspase-3, and -9, and induces caspase cascades. Therefore, 6-gingerol can effectively treat skin cancer [17]. Kim et al. evaluated the antitumor and anti-angiogenesis activity of ginger rhizome extract on VEGF and MTA1 factors, which played a major role in angiogenesis in cancer cells. They concluded that gingerol in ginger rhizome extract could effectively reduce VEGF and MTA1 inducing cell proliferation [23]. Gingerols are a promising factor in cancer treatment because of their ability to prevent NF-κB activation, induce apoptosis and inhibit proliferation, invasion, metastasis, and angiogenesis. Dose-dependent gingerols increase the fracture levels of caspase -9, -7, -3, and PARP and reduce the expression of BCL2 [24].
6-Shogaol and 6-gingerol effectively inhibit invasion and metastasis of hepatocellular carcinoma through various molecular mechanisms, including inhibition of the MAPK and PI3k/Akt pathways and NF-κB and STAT3 activities to suppress the expression of MMP-2/-9 and uPA and block angiogenesis [25]. Methanolic extract of ginger has significant inhibitory activity against liver cancer cells (HePG2) and breast cancer cells (MCF7). Gingerol and paradol are essential in inhibiting cell growth through oxidation-reduction reaction by trapping free radicals, ultimately reducing reactive oxygen [18]. In another study, the ginger extract inhibited the activity of the MMP-9 enzyme in a concentration-dependent manner and thus inhibited migration in the MDA-MB-231 breast cancer cell line. In this study, the ginger extract inhibited the viability of MDA-MB-231 cells in a concentration-dependent manner [26]. In another study, the researchers used in silico method. They found the beneficial role of 6-gingerol and 6-shogaol compounds as growth inhibitors and modulators of lymphangiogenesis and angiogenesis molecules (VEGF-A, VEGF-C, Nrp2, angiopoietin-2, PDGF-B, KDR, SERPINFI, etc.). They play a role in the metastatic progression of breast cancer [27].
Liang et al. reported that 6-shogaol increased ROS production, increased expression of Bax, caspase-9, and -3, and decreased expression of cyclin D1, PCNA, IL-6, JAK, and Bcl-2 in the A2780 ovarian cancer cell line. They showed that 6-shogaol caused apoptosis by inhibiting STAT-3 transmission in ovarian cancer cells and inhibiting the growth of ovarian cancer cells [21]. Another study was conducted on zerombon, another compound found in ginger. The results showed that zerombon better than cisplatin induces cell death in ovarian and cervical cancer cell lines by stimulating apoptosis. Zerombon inhibits the cellular cycle at the G2/M stage in a dose-dependent manner and significantly decreases IL-6 secretion levels in CAOV-3 and HeLa cell lines [28]. Rhode et al. showed that ginger selectively inhibits the growth of ovarian cancer cells compared to normal ovarian epithelial cells. In addition, ginger inhibits the products of the NF-κB regulatory gene, including IL-8, and VEGF, which are involved in cell proliferation and cellular angiogenesis. According to the results of this study, 6-shogaol is the most active ginger substance tested in ovarian cancer cells [29]. In another study, researchers reported dose- and time-dependent reductions in the number of ovarian cancer cells treated with 10-gingerol. Reduction of cancer cell proliferation was associated with an increase in the percentage of cells in the G2 phase of the cell cycle and a decrease in the percentage of cells in the G1 stage. Ovarian cancer cells showed a decrease in cyclin A, B1, and D3 expression after exposure to 10-gingerol [30]. In another study conducted on ovarian cancer cells, the growth of SKOV-3 cell line cells was significantly inhibited by the ginger extract. This study showed a more than 0.4-fold decrease in Bcl-2 gene expression after treatment with ginger extract, and the p53 gene expression level increased about 7 times in cells treated with ginger extract compared to the control group. Therefore, the researchers concluded that the p53 gene stimulates apoptosis by deleting the Bcl-2 gene [31].
The results of this study confirmed previous research studies on ginger extract as effective anti-cancer plant material and demonstrated its effect on the A2780s cell line.
5. Conclusion
Ginger extract has an inhibitory effect on the survival of the A2780s ovarian cancer cell line in a dose-dependent and time-dependent manner. It also reduces SORT1 gene expression in A2780s cells. The present study confirms previous research studies and promises that ginger extract has a toxic effect on the A2780s ovarian cancer cell line, and this compound can be used to develop ovarian anti-cancer drugs.

Ethical Considerations
Compliance with ethical guidelines

This study was conducted at Cell and Developmental Laboratory of the Basic Sciences Department, Faculty of Veterinary Sciences, Ardakan University (Code: IR.YAZD.REC.1399.035).

Funding
This research did not receive any grant from funding agencies in the public, commercial, or non-profit sectors. 

Authors' contributions
All authors equally contributed to preparing this article.

Conflicts of interest
The authors declared no conflict of interest.

Acknowledgements
The authors want to thank the sincere cooperation of Ardakan University Laboratory Officer, Mr. Mohsen Rashidi.


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Type of Study: Original | Subject: Basic Medical Science
Received: 2021/03/31 | Accepted: 2021/06/15 | Published: 2021/07/1

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