Research ArticleExperimental Studies

Mangosteen Inhibits Growth and Survival of Cervical Cancer Cells

NATHAN T. GIVENS, LEI ZHAO, ZIWEN ZHU, MARCO LEQUIO, HUAPING XIAO, BRADLEY D. JOHNSON, QIAN BAI, MARK R. WAKEFIELD and YUJIANG FANG
Anticancer Research June 2022, 42 (6) 2903-2909; DOI: https://doi.org/10.21873/anticanres.15772

Abstract

Background: Cervical cancer is the most common cancer of the female reproductive system. Late-stage cervical cancer treatment has been largely unsuccessful, and urgent anti-cancer therapy is needed. Mangosteen, a tropical fruit, has been studied and found to be rich in xanthones, known anti-cancer compounds. This study was designed to investigate the effect of mangosteen extract (ME) on SiHa cervical cancer cells and to explore the underlying molecular mechanisms. Materials and Methods: Clonogenic survival assay, Quick Cell Proliferation Assay, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) staining, and caspase-3 activity kits were used to investigate the in vitro role of ME treatment in SiHa cervical cancer cell growth. We further investigated the possible molecular mechanisms using RT-PCR. Statistical analysis was done with unpaired two-tailed Student’s t-test and significance at p-value <0.05; each experiment was repeated three times. Results: Our study found that the growth and proliferation of SiHa cervical cancer cells was inhibited by ME. ME also induced apoptosis in SiHa cervical cancer cells. The anti-proliferative effect of ME on cervical cancer cells was associated with statistically significant (p<0.05) down-regulation of the pro-proliferative molecules cyclin B, cyclin D and cyclin E. The pro-apoptotic effect of ME was associated with statistically significant (p<0.05) down-regulation of the anti-apoptotic molecules flice-like inhibitory protein (FLIP) and survivin. Conclusion: ME impedes the growth and survival of SiHa cervical cancer cells by down-regulating cyclin B, cyclin D, cyclin E as well as FLIP and survivin. ME may be a promising strategy for targeted cancer immunotherapy development.

Key Words:

Cervical cancer is the most common reproductive tract cancer in women (1). There were over 550,000 cases and more than 300,000 deaths from cervical cancer in 2018 with 90% of the incidence occurring in developing countries (1, 2). Overall 5-year survival rate for patients with stage III disease is less than 40% (3, 4). First line treatment of cervical cancer typically includes surgical excision and immunotherapy. Advanced stage cervical cancer has been increasingly treated with radiation and chemotherapeutic interventions with very limited success rates, with as low as 10-25% response rates for checkpoint immunotherapy (1, 3, 4). Despite numerous studies on radiosensitization of cervical cancer, there remains to be seen a therapeutic approach that is cost-effective, efficacious, and without associated side effects (5-7). Some potential side effects seen most commonly after radiation therapy include insomnia, urinary frequency, rectal bleeding, small intestinal perforation, and urinary tract obstruction (7, 8). These lethal side effects, coupled with steep financial cost may be ameliorated with mangosteen extract.

Mangosteen extract (ME) has many anti-oxidant and anticancer compounds, including the bioactive α-mangostin and gartanin, which are both part of the chemical group of xanthones (9). Prior studies have shown the potential for α-mangostin and gartanin to exert effects on multiple cancer cell lines including breast, lung, skin, cervical, liver, and oral cancers (9-11). In addition, the cytotoxic potential of mangosteen extract isolates on HeLa cervical cancer cell lines has been studied using a Water Soluble Terazolium assay (10). While previous studies have shown mangosteen extract’s potential anti-tumorigenic effects on HeLa cervical cancer cell lines (10, 12), mangosteen extract has not been tested on the well-studied SiHa cervical cancer cell line. This study is designed to explore the hypothesis that mangosteen extract can exhibit anti-tumor activities on human SiHa cervical cancer cell line via alterations in cell apoptosis and proliferation and investigate the underlying molecular mechanisms responsible for this effect

Materials and Methods

Cell culture. The human cervical cancer cell line, SiHa, was acquired from the American Type Culture Collection (Manassas, VA, USA). Cells were cultured in DMEM and supplemented with 10% heat-inactivated FBS (stain buffer) and 1% penicillin-streptomycin (Invitrogen, Carlsbad, CA, USA) at 37°C in CO2 humidified incubators (Fisher Scientific, Pittsburgh, PA, USA). Cells were cultured to 70% confluence prior to performing experiments.

Treatment of SiHa with mangosteen extract. The 70% confluent SiHa cells were treated for 72 h with 50 μg/ml mangosteen extract (Badmonkey Botanicals, Tacoma, WA, USA) or medium alone (13-17). The concentration for mangosteen extract and the duration of its incubation with cells were based on our pilot experiments and our previous studies (18-20).

Clonogenic survival assay. Seventy-two hours after mangosteen extract treatment, clonogenic survival assay was performed as outlined in previous studies (14-16). One thousand cells were plated in 60 mm Petri dish (Corning, Tewksbury, MA, USA) and incubated at 37°C in a humidified 5% CO2 incubator, in triplicate. Fresh media was added on day 5 after seeding, then 9 days after incubation, cells were fixed with 10% formaldehyde and stained with 0.05% crystal violet. The number of colonies was counted and expressed as a percentage of total colonies in controls.

Determination of proliferation using the quick cell proliferation assay kit. Quick Cell Proliferation Assay Kit from BioVision, Waltham, MA, USA was used to assess SiHa cervical cancer cell proliferation in the presence or absence of mangosteen extract according to the manufacturer’s instructions. Increased mitochondrial dehydrogenase activity from proliferating cells increases formazan dye, which can be detected by spectrometry.

Reverse transcriptase polymerase chain reaction. Mangosteen extract-treated and control cells were washed with phosphate-buffered saline (PBS) and homogenized in TRIzol (Invitrogen). Once the RNA was extracted from these cells, the RNA concentrations were determined by Nanodrop. Reverse transcription of 1 μg of RNA and the primer sequences for glyceraldehyde 3-phosphate dehydrogenase, p18, p21, p27, p53, cyclin B, cyclin D, cyclin E, and cyclin dependent kinase-2 were reverse transcribed as previously documented (15-18).

Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining. Apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining (TUNEL) assay using an Apoptag kit (Chemicon) as previously described (18-20). To quantify the number of apoptotic cells, all cells in 3-5 randomly selected high-power fields (magnification: ×400) were manually counted using image analysis software MetaMorph version 6.3r6 (Molecular Devices Analytical Technologies, Sunnyvale, CA, USA). TUNEL+ cells were expressed as a percentage of total cells.

Measurement of caspase-3 activity. Cellular caspase-3/CPP32 colorimetric assay kit (BioVision) was utilized, as previously documented (14-16), to measure apoptosis of SiHa cells via caspase-3 activity relative to the control. In short, 50 μg of protein was diluted to 50 μl with lysis buffer, and the lysate was mixed with 50 μl 2× reaction buffer (containing 10 mM dithiothreitol), and 200 μM DEVD-paranitroanilide. The reaction was performed at 37°C for 2 h. The cleaved paranitroanilide, with a light emission at 400 nm, was quantified using a spectrophotometer.

Results

Mangosteen extract inhibits the growth of SiHa cervical cancer cells. To investigate if mangosteen extract has any effect on the growth of cervical cancer cells, SiHa cells at 70% confluence were treated for 72 h with 50 μg/ml mangosteen extract or medium alone, and cell survival was evaluated by clonogenic survival assay. The percentage of colonies in the mangosteen extract-treated group was significantly reduced compared to the percent of colonies treated with medium alone (Figure 1A, p<0.05). Optic density (OD) values were obtained using a Quick Cell Proliferation Assay to analyze cell proliferation and further reinforced the clonogenic survival assay results (Figure 1B, p<0.05). Anti-proliferative effects of mangosteen extract were further evaluated by mRNA expression levels of proliferating cell nuclear antigen (PCNA). mRNA expression levels of PCNA were significantly decreased after treatment with mangosteen extract and this was consistent with results from the clonogenic survival assay and the Quick Cell Proliferation Assay (Figure 1C, p<0.05). Taken together, these results strongly indicate that mangosteen extract exerts a negative effect on the survival and proliferation of SiHa cells.

Figure 1.
Figure 1.

Effect of mangosteen extract on proliferation in SiHa cervical cancer cell line. (A) Clonogenic survival assay of SiHa cells treated with mangosteen extract (50 μg/ml) or medium alone for 72 h. The colony numbers were counted and expressed as a total percentage of colonies in the controls (medium alone). (B) Representative result evaluated with a cell proliferation kit between control and Mangosteen extract 50 μg/ml group. These results represent three independent experiments and are expressed as the mean OD + SEM for each group. (C) Relative ratios of PCNA+ SiHa cells to GAPDH (housekeeping gene for comparison) in the mangosteen extract (50 μg/ml) treated group compared to controls (medium alone). Experiments were done in triplicate and results were expressed as the mean ratio of molecule densitometric Units/GAPDH + SEM (×100). The * symbol indicates significant differences in the PCNA to GAPDH ratio or OD values in the mangosteen extract-treated vs. control group (p<0.05).

Mangosteen extract down-regulates the expression of the pro-proliferative molecules cyclin B, cyclin D and cyclin E. Cell proliferation plays a critical role in cell growth and p18, p21, p27, and p53 are important anti-proliferative molecules whereas cyclin B, cyclin D, cyclin E, and cyclin dependent kinase 4 are crucial pro-proliferative molecules. To investigate the mechanism by which mangosteen extract inhibits growth and decreases survival of SiHa cervical cancer cells, RT-PCR was utilized to measure mRNA expression of these crucial anti-proliferative and pro-proliferative molecules (Figure 2, p<0.05). The expression of mRNA levels in cyclin B, cyclin D, and cyclin E significantly decreased in the mangosteen extract-treated group in comparison to the control group (Figure 2, p<0.05). Overall, the results suggest that the down-regulation of cyclin B, cyclin D, and cyclin E correlated with the inhibitory effect of mangosteen extract in the survival of SiHa cervical cancer cells.

Figure 2.
Figure 2.

Effect of mangosteen extract on expression of pro- and anti-proliferative molecules evaluated using RT-PCR. Experiments were done in triplicate and results were expressed as the mean ratio of molecule densitometric Units/GAPDH + SEM (×100). Significant differences in mRNA expression of mangosteen extract-treated group (50 μg/ml) vs. control group for 72 h are designated by the * symbol (p<0.05).

Mangosteen extract promotes apoptosis of SiHa cervical cancer cells. To investigate the contribution of apoptosis to mangosteen extract-mediated inhibitory effect on the survival of SiHa, TUNEL staining was performed (Figure 3A). In the mangosteen extract treatment group, TUNEL+ cell percentage was 19.50±6.90%, a significant increase compared to the control group at 1.96±0.80% (Figure 3B, p<0.05). This indicates that mangosteen extract promotes apoptosis of SiHa cells. Further analysis of apoptosis was also performed by finding the relative caspase-3 activity of SiHa cells. In line with the TUNEL staining findings, the relative caspase-3 activity in SiHa cells was significantly increased in the mangosteen extract treatment group (Figure 3B, p<0.05). Taken together, these results indicate that mangosteen extract promotes apoptosis in SiHa cells, contributing to the overall reduction in cell survival.

Figure 3.
Figure 3.

Effect of mangosteen extract on apoptosis in SiHa cervical cancer cell line. *indicates a statistically significant difference in TUNEL+ cells and relative caspase-3 activity in the mangosteen extract treated group compared to the control group (p<0.05). (A) TUNEL staining images of SiHa cells treated with mangosteen extract and cells treated with medium only are displayed at original magnification (×400). (B) TUNEL+ cell percentage was determined through MetaMorph image software analysis of 3-5 randomly selected high-power fields of three slides. * Indicates the significant difference in the relative caspase-3 activity between the control medium and the mangosteen extract treated SiHa cervical cancer cells (p<0.05). Relative caspase-3 activity was measured as described in the methods section and the results are expressed as mean caspase-3 activity relative to controls (+ SEM). Assays were completed in triplicate.

Mangosteen extract down-regulates anti-apoptotic molecules FLIP and Survivin in SiHa cervical cancer cells. To investigate the mechanism by which mangosteen extract induces apoptosis in SiHa cells, mRNA expression levels of the pro-apoptotic molecules [Fas, Fas ligand (FasL), TNF-related apoptosis inducing ligand (TRAIL), and TRAIL receptor 1 (TRAILR1)] in addition to the anti-apoptotic molecules [flice-like inhibitory protein (FLIP), B-cell lymphoma 2 (Bcl-2) and surviving] were measured with RT-PCR in the mangosteen extract-treated group and control group. The expression of these pro- and anti-apoptotic molecules are comparable except Fas, FasL, TRAIL, and Bcl-2 (Figure 4). The mRNA levels of TRAILR1, FLIP, and survivin were significantly lower in the mangosteen extract-treated vs. the control group (Figure 4, p<0.05). It was surprising that the mRNA expression levels of the pro-apoptotic molecule TRAILR1 were lowered in the mangosteen extract-treated group compared to the control group. Most notably, the anti-apoptotic molecules FLIP and survivin were found to be significantly decreased in SiHa cells treated with mangosteen extract (Figure 4, p<0.05). The results showed that the possible mechanisms by which mangosteen extract induced apoptosis of SiHa cells involved the down-regulation of the anti-apoptotic molecule survivin.

Figure 4.
Figure 4.

Effect of mangosteen extract on mRNA expression of pro- and anti-apoptotic molecules in SiHa cells. GAPDH was used as the housekeeping gene for comparison. Experiments were conducted in triplicate and the results are shown as the mean ratio of pro- and anti-apoptotic molecule densitometric Units/GAPDH + SEM (×100) and are representative of three independent experiments. * Indicates significant differences in mRNA expression between cells treated for 72 h with mangosteen extract (50 μg/ml) vs. medium only (p<0.05).

Discussion

Our study revealed that mangosteen extract inhibited the survival of SiHa cells by down-regulating the pro-proliferative molecules cyclin B, cyclin D, and cyclin E, as well as the anti-apoptotic molecules survivin and FLIP. To our knowledge, this was the first study to demonstrate the anti-tumor effects of mangosteen extract on disrupting the proliferation and bolstering apoptosis of SiHa cervical cancer cells. This is also the first study to uncover the molecular mechanisms underlying these findings. Furthermore, this study expands the applications of mangosteen extract in cancer treatment and deepens scientific understanding of anti-cancer compounds.

It is well established that flux through the cell cycle depends on a crucial balance between pro-proliferative and anti-proliferative molecules at different checkpoints (21, 22). Cyclin B, which was shown to be decreased by mangosteen extract, serves as an M phase regulator (23). Cyclin B forms a complex with CDK1 (cyclin dependent kinase 1), which triggers the onset of mitosis from G2 phase (24). Decreased levels of cyclin B caused by mangosteen extract effectively halts passage into mitosis. Cyclin B overexpression has been implicated in the pathogenesis of non-small-cell lung cancers, colorectal cancer, gastric cancer, breast cancer, and cervical cancer (24). These cancers may be potential future areas of interest for mangosteen extract’s therapeutic application.

Cyclins D and E are also important regulators of the cell cycle. They both serve as G1/S-phase checkpoint molecules (21, 25-27). Cyclin D complexes with CDK4, another pro-proliferative molecule (25). Cyclin D overexpression is seen commonly in patients with human papilloma virus (HPV) 16, a malignant form of cervical adenocarcinoma (26). Cyclin E binds to CDK2 in G1 and phosphorylates retinoblastoma (Rb) to promote G1 transition to S phase (27). Decreases in cyclin D and cyclin E caused by mangosteen extract prevent abnormal DNA replication in G1 phase and thus halt cancer progression (25-30).

It has been shown that DNA contents parallel the amount of cellular proliferation. In our study, we found decreased proliferation of the mangosteen extract treated cervical cancer cell group due to down-regulation of Cyclins, B, D, and E. It would be very interesting to compare the DNA contents of the mangosteen extract treated cells and control cells. One study showed higher DNA content in inner intestinal crypt cells of mice embryogenic fibroblastic cells when the replication origin regulators Cdc6 and Cdt1 were overexpressed in vivo (28). Another recent study showed that higher UVB exposure in the elderly leads to higher levels of PCNA, which increases DNA content and predisposes keratinocytes to carcinogenesis (29). This study is a very promising future direction and to further confirm our initial findings, we plan to study DNA contents in our subsequent studies.

Another important mechanism behind mangosteen extract’s effect on the survival of SiHa cervical cancer cells is the down-regulation of FLIP and survivin, which are critical anti-apoptotic molecules (31). FLIP’s best described function is as a negative regulator of caspase-8 dependent apoptosis (32). FLIP suppression or silencing has been shown to promote p53-induced apoptosis, inducing PUMA (p53 up-regulated modulator of apoptosis) expression (32). A number of studies have found PUMA expression levels to be correlated with different types of cancer including colorectal and medulloblastoma (33, 34). Survivin, also known as baculoviral inhibitor of apoptosis repeat containing 5 (BIRC5), is a well-known cancer therapy target (35). Survivin is at the crossroads of many cancer signaling pathways and there are a plethora of transcription factors, enzymes, proteases, binding proteins and kinases that regulate survivin and are in turn, regulated by survivin (36). There have been Phase II clinical trials with survivin-2B80-88 vaccine, with very low efficacy and effectiveness, along with other methods of survivin therapy including survivin-partner protein interaction inhibitors, survivin homodimerization inhibitors, survivin gene transcription inhibitors, and survivin mRNA inhibitors (36). However, despite over two decades of knowledge about survivin, much more has yet to be discovered about its potential as a cancer immunotherapeutic target. This is the first study in which mangosteen extract’s down-regulation of survivin showed immunotherapeutic potential in cervical cancer.

Our study also showed the down-regulation of the pro-apoptotic death receptor TRAIL-R1 in the presence of mangosteen extract. This decreased TRAIL-R1 expression correlated with an increase in apoptosis in SiHa cells in the mangosteen extract group, as both TUNEL+ cells and caspase-3 activity were increased. This is a paradoxical and unexpected significant decrease in TRAIL-R1 expression because TRAIL-R1 is a critical pro-apoptotic molecule that has traditionally been up-regulated in prior cancer studies (19, 20, 37). One possible mechanism for the down-regulation of TRAIL-R1 is a cellular compensatory response to evade apoptosis by opposing pro-apoptotic signals or the induction of other pro/anti-proliferative molecules whose molecular mechanisms have not yet been uncovered. This mechanism is further supported by recent studies in which TRAIL-R1 down-regulation was found to promote a positive response in lung cancer cells (38, 39). Further study is necessary to elucidate the mechanism and uncover the complex molecular interactions between the pro/anti-proliferative and pro/anti-apoptotic molecules modulating the fate of the SiHa cervical cancer cell line.

In our study, there were a few relevant limitations. Only one well studied cell line for cervical cancer, SiHa, was used. HeLa, another cervical cancer cell line, is currently being studied and further exploration into mangosteen extract’s anti-cancer effects utilizing this cell line will be beneficial in future studies. In addition, only the critical pro/anti-proliferative and pro/anti-apoptotic molecules were investigated in this study. However, it is possible that other pro/anti-proliferative and pro/anti-apoptotic molecules may have played a role in the witnessed effects of mangosteen extract on cervical cancer and further investigation into these molecules would be of value in subsequent studies.

In conclusion, mangosteen extract exhibits anti-tumor activity by promoting apoptosis and inhibiting cellular proliferation in vitro. The results of our study demonstrate potential for the use of mangosteen extract as a treatment for cervical cancer in addition to its well-established anti-cancer effects on melanoma seen in our prior studies. Further studies in the oncology field may shed light on the therapeutic efficacy of mangosteen extract.

Acknowledgements

This study was partially financially supported by the grant from Des Moines University for Yujiang Fang, M.D., Ph.D. (IOER 112-3749).

Footnotes

  • Authors’ Contributions

    Yujiang Fang designed the study. Yujiang Fang, Nathan T. Givens, Lei Zhao, Marco Lequio, Bradley Johnson, Huaping Xiao and Qian Bai performed the experiment. Yujiang Fang, Nathan T.Givens, Lei Zhao, Mark R. Wakefield and Ziwen Zhu analyzed the data. Yujiang Fang, Ziwen Zhu, Nathan T. Givens, Lei Zhao, and Mark R. Wakefield interpreted the data. Nathan T. Givens wrote the draft and Yujiang Fang revised the manuscript.

  • Conflicts of Interest

    The Authors have no conflicts of interest to report.

  • Received March 15, 2022.
  • Revision received April 11, 2022.
  • Accepted April 13, 2022.

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Mangosteen Inhibits Growth and Survival of Cervical Cancer Cells
NATHAN T. GIVENS, LEI ZHAO, ZIWEN ZHU, MARCO LEQUIO, HUAPING XIAO, BRADLEY D. JOHNSON, QIAN BAI, MARK R. WAKEFIELD, YUJIANG FANG
Anticancer Research Jun 2022, 42 (6) 2903-2909; DOI: 10.21873/anticanres.15772
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