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Year : 2020  |  Volume : 16  |  Issue : 6  |  Page : 1500-1505

The inhibitory effect of melatonin on the proliferation of irradiated A549 cell line

1 Department of Radiology, Faculty of Paramedical, Tehran University of Medical Sciences, Tehran, Iran
2 Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
3 Department of Radiology and Nuclear Medicine, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran
4 Department of Immunology, School of Medicine, Tehran University of Medical Sciences; MS Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
5 Department of Medical Physics and Biomedical Engineering, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran

Date of Submission01-Sep-2019
Date of Decision12-Jan-2020
Date of Acceptance06-May-2020
Date of Web Publication18-Dec-2020

Correspondence Address:
Alireza Shirazi
Department of Medical Physics and Biomedical Engineering, Faculty of Medicine, Tehran University of Medical Sciences, Tehran
Maryam Izad
Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_682_19

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 > Abstract 

Background: Lung cancer is the leading cause of cancer-related deaths worldwide. The high resistance of this type of cancer to radiotherapy and chemotherapy is the greatest challenge for the complete eradication of cancer cells. Although the combination of chemotherapeutic agents has some promising results, severe side effects may limit the received tumor dose. The current study aimed at evaluating the possible synergic effect of melatonin on radiation-induced apoptosis and cell proliferation inhibition.
Materials and Methods: A549 cells were incubated with melatonin or vehicle and then irradiated with a single dose of 0, 0.5, 2, or 8 Gy X-rays. The cells were incubated with 1 nM of melatonin or vehicle for 1 week and then treated with 1 mM of melatonin or vehicle 1 h before irradiation. Cell proliferation was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and apoptosis was assessed using flowcytometry detection of annexin V.
Results: Irradiation of the cells with different X-ray doses had no significant impact on MTT results. However, the administration of 1 mM of melatonin 1 h before irradiation significantly reduced the cell proliferation. Nonetheless, there was no significant difference between this treatment group and 1 mM melatonin group. Moreover, the administration of melatonin in combination with irradiation did not show any significant effects on radiation-induced apoptosis.
Conclusion: The current study results indicated that the treatment of A549 cells with melatonin could suppress cell proliferation, whereas it did not mediate the induction of apoptosis.

Keywords: A549 cells, apoptosis, melatonin, radiation, radiotherapy

How to cite this article:
Kahkesh MH, Salehi Z, Najafi M, Ghobadi A, Izad M, Shirazi A. The inhibitory effect of melatonin on the proliferation of irradiated A549 cell line. J Can Res Ther 2020;16:1500-5

How to cite this URL:
Kahkesh MH, Salehi Z, Najafi M, Ghobadi A, Izad M, Shirazi A. The inhibitory effect of melatonin on the proliferation of irradiated A549 cell line. J Can Res Ther [serial online] 2020 [cited 2021 Nov 27];16:1500-5. Available from: https://www.cancerjournal.net/text.asp?2020/16/6/1500/303897

 > Background Top

About 80% of all lung cancer cases are non-small cell lung cancers (NSCLC), which is the leading cause of cancer-related deaths worldwide.[1] Smoking, family history, lifestyle, and exposure to radon or asbestos are the main risk factors of lung cancer. Above 50% of lung cancer patients die in the 1st year of diagnosis, and the 5-year survival is about 17.8%. Patients with lung cancer may receive one or a combination of different treatment methods, including surgery, adjuvant therapy, chemotherapy, or radiotherapy.[2],[3]

Radiotherapy is the first-line treatment for patients with inoperable NSCLC; it is also used as an adjuvant treatment before or after surgery. One of the most critical issues to treat NSCLC is the high radioresistance of this type of cancer, which limits radiotherapy efficiency.[4] The enhancement of therapeutic ratio via the increasing response of tumor cells to radiotherapy is one of the essential objectives in radiobiology, which can help to improve the survival rate and quality of life in patients.[5]

So far, various strategies have been proposed to sensitize tumor cells to chemotherapy or radiotherapy.[6] In addition, the combination of chemotherapy and radiotherapy improves the treatment response.[7] Randomized trials exhibited that the combination of chemotherapy and radiotherapy has a higher survival rate in comparison with radiotherapy alone. One method to combine chemotherapy and radiotherapy is the application of single-agent chemotherapy as a radiosensitizer.[8],[9]

Although over half of all patients with lung cancer receive radiotherapy, there is still a need to find an agent that can sensitize lung cancer tissue to radiotherapy with low damage to normal tissue. On the other hand, severe side effects such as fibrosis and pneumonitis limit the received dose of radiotherapy and chemotherapy. Therefore, the administration of other agents with less toxicity can enhance therapeutic efficacy without severe reactions.[10]

During recent years, several studies have been conducted to find some adjuvant agents in order to sensitize cancer cells. Some studies found that inhibition of cell proliferation and angiogenesis, and induction of apoptosis, can be triggered by some agents such as metformin, curcumin, melatonin, and celecoxib in cancer cells.[11],[12],[13] Although celecoxib has been investigated in clinical trials, concerns remain regarding its long-term effects.[14] Studies to offer agents or compounds with less side effects and higher antitumor activity are underway.

Melatonin is an indolamine that shows great potential to prevent the side effects of radiation therapy, such as damage to normal tissue.[15],[16],[17] Besides, melatonin presents some anticancer properties on different cancer cells due to its radiomodulatory potential.[18],[19] Studies approve that melatonin can inhibit cell proliferation, migration, invasion, angiogenesis and induce cell cycle arrest.[20],[21] In addition, melatonin shows pro-apoptotic properties in some cancer cells through cytochrome c release, p53 upregulation, and bax/bcl-2 balancing. Furthermore, melatonin is used as a therapeutic agent because of its low toxicity and ease of penetration in different cell types, which make it a potential radiosensitizer to use in clinical radiotherapy.[22] The current study aimed at evaluating the possible anti-proliferative and apoptotic effects of melatonin in combination with irradiation on NSCLC cell lines.

 > Materials and Methods Top

Cell culture

Human lung cancer cell line A549 was purchased from Pasteur Institute of Iran (Tehran, Iran). The cells were cultured in 75-cm2 flasks, and Dulbecco's modified Eagle's medium high-glucose (DMEM high G) (Biowest, Nuaillé, France) was supplemented with 10% fetal bovine serum (FBS; Biowest, Nuaillé, France), 100 U/mL of penicillin, 100 μg/mL of streptomycin (Biowest, Nuaillé, France), and 2 mM of stable glutamine (Biowest, Nuaillé, France) containing 1 nM of melatonin – that is the physiological concentration of melatonin – or 96% alcohol as vehicle. The cells were incubated for 1 week in 5% CO2 and humidified air at 37°C. After the incubation time, the cells were seeded into culture plates in DMEM with 10% FBS and incubated for 24 h to allow for cell attachment before irradiation. Then, 1 hour before irradiation, the cells were treated with 1 mM of melatonin – that is the common pharmacological concentration of melatonin – or alcohol. The cells were irradiated with 0, 0.5, 2, or 8 Gy at room temperature. Control cells were placed for the same period into the radiation field without irradiation. After irradiation, the cells were incubated for 3 days in the old medium.

Ionizing radiation

A549 cells were irradiated using an ELEKTA Compact medical accelerator 6 MV (Elekta, Stockholm, Sweden) at room temperature. A single dose of 0, 0.5, 2, or 8 Gy in an 11.5 cm × 18 cm field size was delivered to the cells, with 100 cm source-to-skin distance and a dose rate of 1 Gy/min. 2 Gy radiation is the standard dose used in fractionated radiotherapy; 0.5 Gy was chosen for low-dose evaluation and 8 Gy was chosen for high-dose evaluation to investigate the radioresistance of A549 cells.

MTT assay

For proliferation assay, 2.5 × 104 cells/well were seeded in a 96-well cell culture plate, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed based on the manufacturer's instructions (Sigma-Aldrich, St. Louis, Missouri, USA). The absorbance was measured at 570 nm with a reference filter of 650 nm in a microplate photometer (BioTek PowerWave XS2, Winooski, Vermont, USA). These experiments were repeated three times.

Apoptosis assay

The rate of apoptosis in the irradiated cells was measured using an annexin V-fluorescein isothiocyanate (FITC) apoptosis detection kit (BioVision Inc., Milpitas, California, USA), according to the manufacturer's instructions. In short, 2 × 105 of A549 cells were suspended in 100 μL of binding buffer and then incubated in the dark with annexin-V FITC and propidium iodide (PI) for 15 min at room temperature. After the incubation, 400 μL of the binding buffer was added to the cells, and then 104 cells of each experiment were analyzed by flow cytometry in a BD-FACSCalibur 2009 (BD Biosciences, San Jose, CA, USA). These experiments were repeated three times.

Data analysis

The data were expressed as a mean ± standard error of the mean. The difference between the groups was analyzed using one-way analysis of variance and Tukey's post hoc test. P < 0.05 was considered statistically significant.

 > Results Top

Antiproliferative effects of melatonin on A549 cells

To determine the effect of melatonin and radiation on the proliferation of human NSCLC A549 cells, the MTT assay was performed. As depicted in [Figure 1], when cells were cultured with melatonin alone, the physiological concentrations (1 nM) of melatonin had no effects on the cells compared with the untreated controls. In contrast, pharmacological concentrations (1 mM) significantly decreased the cell proliferation (P < 0.001).
Figure 1: Effects of radiation and melatonin on cell proliferation in A549 cells; 1 mM melatonin increased cytotoxicity in comparison to untreated cells. Error bars expressed as mean ± standard error of the mean. a: P < 0.001 versus those of the control; b: P < 0.001 versus 1 nM of melatonin alone

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Irradiation of cells with different X-ray doses did not affect cytotoxicity. The administration of 1 nM of melatonin 1 week before the irradiation did not change the effect of radiation on the cells. When 1 mM of melatonin was used 1 h before the irradiation, cell proliferation significantly declined compared with that of the control group (P < 0.001). However, there was no significant difference between this group and the 1 mM melatonin-alone group. The administration of 1 mM of melatonin had similar effects on A549 cells when administrated with different doses of X-ray irradiation. Two concentrations of melatonin together or in addition to radiation showed the same cytotoxicity as 1 mM of melatonin alone or in combination with radiation.

Radiation increased apoptosis induction in A549 cells

The annexin V/PI staining was employed to evaluate the impact of melatonin on radiation-induced apoptosis. The percentage of annexin V-stained cells in the combination treatment compared with each treatment alone [Figure 2]. The obtained results showed that radiation alone (0.5, 2, or 8 Gy) increased apoptosis induction in the cells (P < 0.001), but not in a dose-dependent manner. The results also indicated that the administration of melatonin (1 nM, 1 mM) with radiation had no significant effects on radiation-induced apoptosis.
Figure 2: Effects of radiation and melatonin on apoptosis in A549 cells; radiation increased apoptosis induction in the cells, but not in a dose-dependent manner. Melatonin has shown no pro-apoptotic effect on A549 cells. (a) Error bars expressed as mean ± standard error of the mean. (a) P < 0.001 versus those of the control; (b) the horizontal axis represents annexin-V staining, and the vertical axis represents propidium iodide staining

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 > Discussion Top

Poor response to radiotherapy is the main feature of NSCLC, which results in low therapeutic efficacy for this method of lung cancer treatment. So far, several studies have been conducted to investigate the radioresistance mechanisms of NSCLC, which may help to find some strategies to overcome this problem. Some studies proposed that radioresistance may be induced by some signaling pathways such as Akt and calcium signaling.[23] However, it seems that the upregulation of factors such as microRNA-21 is involved in this pathway.[4] Yang et al. showed that the upregulation of COX-2 following exposure to radiation is one of the main properties of A549 cells, which leads to radioresistance in NSCLC cells.[24] The inhibition of COX-2 sensitizes A549 cells via the induction of apoptosis.[25] In addition, using COX-2 inhibitors can increase the survival of patients with lung cancer undergoing radiotherapy.[26],[27],[28] Stimulation of antioxidant enzymes following exposure to ionizing radiation is one of the other proposed mechanisms for the resistance of lung cancer cells.[29] Another reason for the radioresistance of this type of cancer cells may be related to their cell cycle distribution. Li et al. ascribed that the proportion of cells in G2-M cell cycle arrest in radioresistant A549 cells was higher compared with that of the radiosensitive cells. They proposed that CDC25C plays a central role in the distribution of cell cycle in this cell type.[30] Results of the current study proved that exposure of A549 cells to X-rays could not lead to significant suppression of cell proliferation.

Apoptosis, a form of programmed cell death, has two main pathways: the extrinsic or death receptor pathway and the intrinsic or mitochondrial pathway. The extrinsic pathway is triggered following upregulation of dead receptors such as Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand. The intrinsic or mitochondrial pathway of apoptosis occurs through upregulation and mitochondrial penetration of Bax, leading to the release of cytochrome c. A small group of cancer cells shows features correlated with apoptosis after treatment with high concentrations of melatonin. Experimental evaluations show that both apoptosis pathways can be triggered in cancer cells following treatment with melatonin. This is associated with increased phosphorylation of caspase proteins, reduced regulation of Bcl-2, and upregulation of Bax enzyme.[31],[32] Apoptosis is the principal cell death mechanism induced by radiation, too.[33] This investigation confirmed that irradiation significantly increases apoptosis induction in A549 cells. Liu et al. showed that caspase3 protein progression is associated with fractionated radiation-induced apoptosis in A549 cells.[33] Furthermore, irradiation of A549 cells increases reactive oxygen species generation, leading to the release of cytochrome c from mitochondria, which is an incident for radiation-induced apoptosis.[34]

To date, various agents have been studied as radiosensitizers for lung cancer cells. The most common modality for this purpose is a combined modality of chemotherapy and radiotherapy. However, the high toxicity of these treatment modalities may limit receiving the optimal dose of radiation or chemotherapy agents. Thus, the search for low toxic agents for this particular purpose is ongoing. For example, miR-21 silencing results in the suppression of PI3K/Akt signaling pathway, which can sensitize A549 cells via induction of apoptosis.[4]

Melatonin is a potent anti-inflammatory and antioxidant agent studied as a radioprotector for years. However, in recent years, some studies showed that melatonin has some anticancer properties as well. Induction of apoptosis, suppression of DNA repair pathways, inhibition of angiogenesis, and growth of cancer cells are the possible mechanisms for the anticancer effects of melatonin.[18],[19] The combination of radiotherapy and melatonin may amplify apoptosis induction in some cancer types.[35] The current study found that melatonin could inhibit cell proliferation, while it could not induce apoptosis in A549 cancer cells. It demonstrated that melatonin could suppress the viability of cells after treatment with 1 mM, but not 1 nM of melatonin. This indicated that to inhibit A549 cell proliferation significantly, it needed to administer a sufficient dose of melatonin. The dose-dependent response of cancer cell viability to melatonin has also been observed in some previous studies. The reduced viability may be resulting from the suppression of cancer cell proliferation via cell cycle arrest. It seems that the activation of p53 by melatonin is the main cause of the reduction of viability in cancer cells. Melatonin can phosphorylate Akt, leading to degradation of MDM2 and activation of p53.[36] Indeed, melatonin increases the percentage of cells in G1 and G2 phases of the cell cycle following upregulation and activation of p53 and p21.[37] Further studies are required to illustrate the mechanisms of anticancer effects of melatonin on this cell line.

 > Conclusion Top

The results of the current study showed that treatment of A549 cells with melatonin could significantly inhibit their proliferation. Irradiation of cells with different doses of X-rays up to 8 Gy could induce apoptosis but did not lead to inhibition of cell proliferation. However, pretreatment with melatonin could not induce apoptosis. The combination of radiation and melatonin leads to significant apoptosis and inhibition of proliferation. This may prove melatonin as a helpful agent as a radiosensitizer for patients with NSCLC for these patients. However, further in vivo studies are needed to find a radiosensitizer for this cell line.

Financial support and sponsorship

This research has been supported by Tehran University of Medical Sciences & health Services grant 31494.

Conflicts of interest

There are no conflicts of interest.

 > References Top

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