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ORIGINAL ARTICLE
Year : 2021  |  Volume : 17  |  Issue : 1  |  Page : 242-247

Hypericin induces apoptosis in K562 cells via downregulation of Myc and Mdm2


1 Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
2 Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
3 Department of Molecular and Cellular Science, Faculty of Advanced Sciences and Technology, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran

Date of Submission04-Oct-2019
Date of Decision10-Apr-2020
Date of Acceptance04-May-2020
Date of Web Publication15-Mar-2021

Correspondence Address:
Hesam Adin Atashi
Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_826_19

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 > Abstract 


Background: Nowadays, some studies have shown the effect of hypericin on cancer cells. However, considering the cytotoxicity of this plant and signs of anticancer activity in the plant, unfortunately, there is still no proper treatment for leukemia cancer cells. Therefore, the present study aims to evaluate the anticancer effect of hypericin in the treatment of leukemia cancer and its possible mechanism of action.
Methods: In this study, the K562 cell line was treated with different concentrations of hypericin for 24 and 48 h. Detection of cell death was performed by 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2-tetrazolium bromide assay. The rate of cell apoptosis was measured by Annexin V/propidium iodide assay using flow cytometry. The expression of Bax, Bcl2, Myc, Mdm2, and P53 genes was evaluated by real-time polymerase chain reaction test, and immunocytochemistry (ICC) analysis was used for further evaluation of P53.
Results: The results showed that hypericin has a dose-dependent cytotoxic effect on the K562 (in much less dose compared with cisplatin). According to flow cytometry results, cell apoptosis after exposure to hypericin for 24 h was 53%, and ICC analysis on p53 confirmed this. Furthermore, after 24 h of exposure to hypericin with IC50 concentration, the expression of P53 and Bax genes increased and the expression of the Bcl2, Myc, and Mdm2 gene decreased.
Conclusion: The results showed that hypericin exerts its cytotoxicity on K562 cancer cells by downregulating Mdm2 and Myc. Based on the data acquired from the present study and many investigations till now, hypericin can be a good option for leukemia cancer cells treatment.

Keywords: Herbal medicine, hypericin, K562, Mdm2, Myc


How to cite this article:
Arani HZ, Olya M, Mirahmadi AS, Saleki H, Atashi HA, Marzouni HZ, Hoseinian M, Javidi MA, Zabolian A. Hypericin induces apoptosis in K562 cells via downregulation of Myc and Mdm2. J Can Res Ther 2021;17:242-7

How to cite this URL:
Arani HZ, Olya M, Mirahmadi AS, Saleki H, Atashi HA, Marzouni HZ, Hoseinian M, Javidi MA, Zabolian A. Hypericin induces apoptosis in K562 cells via downregulation of Myc and Mdm2. J Can Res Ther [serial online] 2021 [cited 2021 Nov 28];17:242-7. Available from: https://www.cancerjournal.net/text.asp?2021/17/1/242/311072




 > Introduction Top


The use of herbs in terms of side effects has always been a concern. Medicinal plants are being used for treating various diseases.[1],[2] According to the WHO, 80% of the world population depends on indigenous medicinal plant remedies. Several plants have been identified for the treatment of certain diseases so far.[3],[4] Nowadays, the number of discovered medicinal plants available in nature, which have confirmed anticancerous properties, is increased.[5] Identification of anticancer and antimetastatic effects of medicinal plants has always been considered.[6] Some studies have indicated the cytotoxic effects of hypericin in Hypericum perforatum plant.[7] This plant is a member of Hypericaceae species, which is commonly found in the wheat and corn fields.[7],[8],[9],[10],[11]

Hypericin, has a characteristic naphthodianthrone construction and is the main active part of Hypericum species; usually known as H. perforatum or St. John's wort.[7] Recently, hypericin has been exploited in medical treatment for different disorders including viruses and depression disorders. Studies demonstrated that hypericin at low concentrations could induce apoptosis mediated by 1O2; and at high concentrations, by affecting reactive oxygen species (ROS) accumulation it tends to induce necrosis.[9],[10],[12] We can find various studies which have demonstrated that hypericin has cytotoxicity specifically on tumor cells and at the same time does have minimum side effect, although the way in front to be applicable in clinics should be paved.[3],[7] Various studies have been carried out on the effects of this extract in the treatment of some diseases, such as depression.[13] However, the identification of other therapeutic effects of this plant's extract can be highly valuable.[7]

K562 cells are the erythroleukemia type and were the first immortalized human myelogenous leukemia line that have been established.[14],[15] About morphological aspects, these cells are rounded and not adherent, they are BCR: ABL fusion gene positive, and have somehow proteomic similarities to erythrocytes and undifferentiated granulocytes.[16] The K562 cell line has attained widespread use as a highly sensitive in vitro target for the natural killer assay.[17],[18] Studies suggested that Myc and Mdm2 overexpression might be a mechanism of over-reproduction and not apoptosis in K562 cell line; this may be in some parts because of Myc and Mdm2 genes role in cell cycle progression and cellular transformation.[19],[20],[21]

Considering the cytotoxicity of this plant and signs of anticancer activity in the plant, unfortunately, there is still no proper treatment for this type of cancer cell line.[10],[11] Therefore, it seems necessary to find a proper treatment for the disease, which may effectively destroy cancer cells without imposing significant side effects on the normal cells.[7] Thus, this study was conducted to investigate the therapeutic effects of hypericin to destroy K562 cells.


 > Methods Top


Materials and reagents

To culture K562 cell line (obtained from Pasteur Institute of Iran), we used Roswell Park Memorial Institute plus 10% fetal bovine serum, streptomycin (100 mg/ml), and penicillin (100 U/ml) (all from Gibco, USA). The medium of the above cells was replaced with a fresh medium every 4 days. Cisplatin, hypericin, and 3- [4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2-tetrazolium bromide (MTT) assay kit were purchased from Sigma Aldrich (USA). To further confirm that whether the cellular death was a kind of apoptosis, Annexin V/propidium iodide (Annexin V/PI) test was performed by the aim of Annexin V/PI apoptosis assay kit from Roche (Switzerland). For immunocytochemistry (ICC), rabbit polyclonal anti-p53 antibody and goat anti-rabbit IgG Fc (FITC) were utilized; furthermore, to stain cells' nuclei, we used PI (all from Abcam, UK). Other reagents used in this study were purchased from Sigma Aldrich (USA).

Defining cellular activity and immunocytochemistry

To investigate how in which dose hypericin and cisplatin can induce 50% cellular death (IC50), MTT assay was performed as described previously.[22] 10000 and 12000 cells were seeded in each well of 96 well plates, for 24 h and 48 h MTT assay, respectively. These cells were treated with a concentration range of hypericin or cisplatin for 24 or 48 h. After these times, MTT assay was performed. Formazan crystals were dissolved in dimethyl sulfoxide, and resulting purple solutions' absorptions were revealed at 570 nm utilizing Biotek ELX800 microplate reader.

By employing the ICC test, the expression level of Bax protein was studied in different samples. Briefly, cells were fixed by 4% paraformaldehyde after 24 h treatment with IC50 dose of hypericin for 24 h (normal/untreated samples did not treat with hypericin). Then, these cells were incubated with antibody against Bax protein overnight at 4°C (secondary antibody contained FITC). To stain cell nuclei, we used PI.

Real-time polymerase chain reaction and statistical analysis

We further studied the important apoptotic gene expression level in different samples. To achieve these data, we first extracted total RNAs by TRIzol reagent (Invitrogen). cDNA synthesis was performed for the same amount of RNAs from each sample by cDNA synthesis kit (Takara, Japan). Primers were designed to specifically amplify Myc, Mdm2, Bax, Bcl2, and P53 mRNAs. Real-time polymerase chain reaction (PCR) program included (1) holding stage: 95°C/5 min; (2) cycling stage: denaturing step: 95°C/15 s, followed by annealing step 60°C/30 s and amplification step 72°C/20 s (number of cycles: 40); and (3) melt curve stage. All statistical analyses were performed by GraphPad Prism software and P < 0.05 was considered as the significant level.


 > Results Top


Defining cellular activity and immunocytochemistry

MTT assay demonstrated that the IC50 dose for hypericin in 24 h was 2 (μg/ml) and that of cisplatin was 150 (μg/ml). The IC50 dose of hypericin in 48 h was revealed to be 1 (μg/ml) and that of cisplatin was 100 (μg/ml) [Figure 1] and [Figure 2]. The results showed no effect of this drug on fibroblast cells even at high doses.
Figure 1: 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2-tetrazolium bromide assay results revealed that hypericin could induce 50% cellular death in K562 cells at the concentration of 2 (μg/ml) and 1 (μg/ml) for 24 h (left diagram) and 48 h (right diagram), respectively

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Figure 2: 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2-tetrazolium bromide assay results for the treatment of K562 cells with different doses of cisplatin. The results demonstrate that 150 (μg/ml) and 100 (μg/ml) of cisplatin after 24 h (left diagram) and 48 h (right diagram), respectively, induces 50% cellular death in K562 cells

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Flow cytometry (Annexin V/propidium iodide)

Annexin V/PI flow cytometry test demonstrated that treatment of cells with an IC50 dose of hypericin for 24 h induced about 53% apoptosis [Figure 3].
Figure 3: Annexin V/PI results. After treatment of K562 cells with 2 (μg/ml) of hypericin for 24 h, about 53% of cells underwent apoptosis (right diagram/right up and down quadrant) compared to untreated cells (left diagram)

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Expression important genes involved in apoptosis in different samples

After treatment of K562 cells with IC50 dose of hypericin for 24 h, proapoptotic gene expression level (including Bax and P53) increased; furthermore, Bcl2 antiapoptotic gene expression decreased significantly compared to untreated K562 cells [Figure 4]. The results demonstrated that treating cells with hypericin would result in downregulation of the oncogene Myc (which is one of the characteristics of chronic myeloid leukemia cell line K562) and Mdm2. The latter downregulation will result in P53 upregulation [Figure 4].
Figure 4: Real-time polymerase chain reaction results demonstrated that the treatment of K562 cells with the IC50 dose of hypericin upregulates the expression of P53 and Bax genes and downregulates that of Myc, Mdm2, and Bcl2 genes

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The ICC test revealed that after treatment of cells with an appropriate IC50 dose of hypericin for 24 h, p53 protein expression level increased [Figure 5].
Figure 5: Immunocytochemistry results for treated (a-c) and untreated (d-f) cells with the IC50 dose of hypericin for 24 h. Cells nuclei are stained with DAPI (a and d). Staining cells with an antibody against the p53 protein (b and e). The merged picture of whether a + b (c) or d + e (f). The red dots show the expression of p53 protein. If we compare c and/or b with f and/or e, we realize that the expression of p53 protein is increased after treatment of K562 cells with hypericin

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 > Discussion Top


Cancer is one of the common diseases, and due to the vital role of the liver organ in the body, liver cancer can lead to permanent complications.[23],[24] Physiologically, apoptosis or programmed cell death (PCD) is essential in removing damaged and aging cells. Disruption in PCD is involved in expansion and tumorigenesis; moreover, cells lose their capability to undergo PCD due to a change of ecological and genetic factors.[6] Thus, furthermore limiting cancer cell proliferation and metastasis, stimulating cancer cell apoptosis is also an effective method of cancer therapy.[11]

Treatment of cancer is done commonly through surgery, radiotherapy, and chemotherapy; furthermore, in some cases, other approaches including targeted therapy are utilized. Considering that resistance to radiotherapy and chemotherapy is always a common problem, the identification and development of anticancer drugs is always a vital requirement.[25],[26] Some studies have reported the positive effects of hypericin in the treatment of some of the cancer cases.[9],[23] However, the mechanism of hypericin in treating cancer cells is not clear, but it is believed that this active ingredient affects a number of essential cellular pathways that contribute to the survival and death of cell.[23] It has been indicated that apoptosis, secondary to the enhancement in ROS, is a conquering mechanism of action in hypericin, and it has been recommended that the mitochondrial-mediated and death receptor-mediated pathways are involved in PCD induced by hypericin treatment.[11],[13],[27],[28]

The results of this study demonstrated that hypericin has significant cytotoxic effects on K562 cancer cells. IC50 for this extract was 2 μg/ml, 24 h after exposure, and it was 1 μg/ml, 48 h after exposure, much less compared with cisplatin (150 and 100 μg/ml for 24and 48 h, respectively). One important point in the results of this study is that the results showed no effect of this drug on fibroblast cells even at high doses. This indicates that this substance has no effects on healthy cells.

In a study by Hamilton et al., they confirmed that at low concentrations, hypericin inhibits the growth of pituitary adenoma cells in AtT-20 and GH4C1 cell lines. Furthermore, the effect of this substance on fibroblast cells was confirmed.[29] Kim et al. demonstrated that growth inhibitor concentration in 50% of U-937 cells associated with myeloid leukemia is 0.2 μM.[30] Moreover, in a study by Mirmalek et al. on the cytotoxic and apoptotic effect of hypericin on MCF-7 cell line, they concluded that the substance plays a dose-dependent cytotoxic effect on this cell line. They showed that the LD50 versus cisplatin in hypericin on the MCF-7 cell line was 5 μg/ml versus 20 μg/ml, indicating the effectiveness of this substance at much lower concentrations compared with cisplatin. In their study, they concluded that hypericin has an appropriate cytotoxic effect on the MCF-7 cell line and is an appropriate candidate to be used in the treatment of this type of cancer.[23]

In this study, we used flow cytometry and ICC to determine the level of apoptosis and cytotoxicity induced by exposure to hypericin, and real-time PCR was used to measure the expression of Myc, Mdm2, Bax, Bcl2, and P53 genes.

Myc is a regulatory gene and encodes a transcription factor which is a multifunctional, nuclear phosphoprotein that plays a role in cell cycle progression, PCD, and cellular alteration. Furthermore, Mdm2 is a protein which is an important negative regulator of the P53 tumor suppressor. A mutated version of Myc and Mdm2 is found in many cancers, which causes Myc and Mdm2 to be constitutively expressed.[19],[20],[21]

The results of this study indicate 53% apoptosis induced by 24 h exposure of hypericin to the K562 cell line. In the study of Mirmalek et al., the apoptosis induction rate at a concentration of 5 μg/ml on MCF-7 cell lines was 52%.[23] The ICC results of this study confirmed these findings. Furthermore, the results of this study showed that the expression of P53 and Bax genes was increased after exposure to hypericin for 24 h and the expression of Myc, Mdm2, and Bcl2 genes decreased. These results confirm the induction of apoptosis and cytotoxic activity of hypericin on the studied cell line. These results are in line with the studies of Mirmalek et al. and Acar et al.[23],[31] Acar et al. indicated that hypericin induction increases expression of cell death-inducing genes and ultimately increases apoptosis.[31]

Some studies have examined the mechanism of action of hypericin in the induction of cancer cell apoptosis and its cytotoxic effects, such as in the study of Jendzelovský et al., it was argued that hypericin exposure could increase expression in the multidrug resistance-related protein 1 and breast cancer resistance protein genes. The expression of these two genes can be related to the linkage between proadifen (SKF-525A) and ABC transporter proteins. This relationship increases intracellular oxidative stress and decreases the mitochondrial membrane potential, which is associated with the activation of caspase 9 and then caspase 3 and ultimately leads to apoptosis.[32]

In a study by Eriksson and Eriksson, it is argued that there is the possibility of interactions between hypericin and Ca2 + pump SERCA in terms of the three-dimensional structure. They also managed to show the presence of a proper location of the cell membrane for the binding of hypericin to some parts of the membrane lipid. An important part of this location exists in the endoplasmic membrane.[33] Furthermore, in a study by Barliya et al., it was showed that hypericin plays a key role in the induction of hypoxia-inducible factor 1α, thereby eliminating von Hippel–Lindau protein from cancerous cells and preventing the growth of cancer cells.[34]

The results of this study demonstrated that hypericin prevents cell division and apoptosis in these cells, while several studies confirm the results of this study.[22],[35] However, some studies do not confirm these results.[36]


 > Conclusion Top


The results of this study showed that hypericin is a cytotoxic and apoptosis-inducing substance in K562 cell line. However, hypericin does not have cytotoxic effects on fibroblast cells. It seems that hypericin, with its proper anticancer effects, can be a suitable alternative for the treatment of this disease. It is recommended that in future, the anticancer effects of hypericin be evaluated under in vivo conditions.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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