|Year : 2012 | Volume
| Issue : 3 | Page : 210-216
Radiosensitizing effect of sesamol on human cervical carcinoma cells
Mohana Shanmugham, Nagarajan Rajendra Prasad
Department of Biochemistry and Biotechnology, Annamalai University, Annamalai Nagar, India
|Date of Web Publication||8-Aug-2012|
Nagarajan Rajendra Prasad
Department of Biochemistry and Biotechnology, Annamalai University, Annamalainagar - 608 002, Tamil Nadu
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Aim: To determine the radiosensitizing effect of sesamol in cervical carcinoma cell line (HeLa) in vitro. Materials and Methods: Sesamol-pretreated (10 μg/ml) HeLa cells were exposed to 4 Gy γ-radiation and the cellular changes were estimated by lipid peroxidation, changes in the enzymatic and non-enzymatic antioxidant status, oxidative DNA damage, % of growth inhibition, and morphological changes in the irradiated and/or sesamol-treated HeLa cells. Results: Sesamol treatment prior to irradiation significantly increased the levels of thiobarbituric acid reactive substances, (TBARS), lipid hydroperoxides (LPH), and conjugated dienes (CD) in HeLa cells. On the other hand, sesamol treatment before irradiation significantly decreased the levels of reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase activities (GPx). Further, we observed increased % tail DNA, tail length, and tail moment in sesamol plus γ-irradiated cells when compared to irradiation alone. The % of cell death was also increased in sesamol plus γ-irradiated cells, particularly at 48 h incubation. Conclusion: Sesamol pretreatment prior to irradiation enhances the radiation effects in HeLa cell line. This study supports the use of dietary phytochemicals such as sesamol in practical radiotherapy.
Keywords: Cervical cancer, HeLa cells, radiosensitization, sesamol
|How to cite this article:|
Shanmugham M, Prasad NR. Radiosensitizing effect of sesamol on human cervical carcinoma cells. Int J Nutr Pharmacol Neurol Dis 2012;2:210-6
|How to cite this URL:|
Shanmugham M, Prasad NR. Radiosensitizing effect of sesamol on human cervical carcinoma cells. Int J Nutr Pharmacol Neurol Dis [serial online] 2012 [cited 2020 Jan 21];2:210-6. Available from: http://www.ijnpnd.com/text.asp?2012/2/3/210/99472
| Introduction|| |
Cancer of the uterine cervix is the second leading cause of death from cancer in women worldwide.  Radiotherapy is an important treatment modality for cervical cancer, particularly for locally advanced tumors, and is known to induce cell death in tumorous tissue.  Radiotherapy fails in the later stages of cancer due to the radio resistant tumor cells. It is most important in radiobiology to increase the oxidative damage of the tumor cells by using a tumor-selective cytotoxic agent.  The study of such radiation response modifiers is a prime requirement in cancer therapeutics.
Radiosensitizers are intended to enhance tumor cell killing while having much less effect on normal tissues. Most of the radiosensitizers are chemical compounds which exhibit toxicity.  Natural products have proved to be an infinite source as remedies for diseases since ancient times. A large number of dietary phytochemicals have shown potential effects in a variety of pathological situations when used alone or together with radiation.  Phytochemicals can act as radiosensitizers under in vitro and in vivo conditions in a variety of cancer cell lines.  Presence of phytochemicals during irradiation amplifies their effects by several mode including toxic reactions of free radicals, overriding cell cycle arrest, and by inducing apoptosis. Phenolic phytochemicals exhibits pro-oxidant activity which contributes to their therapeutic functions. 
Sesamol [Figure 1] is a phenolic derivative with a methylenedioxy group and is a constituent of processed sesame oil. Sesamol is formed from the decomposition of sesamolin during the processing of sesame oil. It exhibits powerful inhibitory effects on lipid peroxidation.  An in vitro study indicated that sesamol inhibits mutagenicity.  Sesamol also attenuates the production of nitric oxide, hydrogen peroxide, and reduces monoamine oxidase (MAO) activity in glial astrocyte cells.  It is not known if sesamol has a differential effect on normal and malignant cells. It is important to screen natural compounds which can enhance the radiation effects in cancer cells in order to obtain maximum cancer cell killing. In the present study, we analyzed the effect of sesamol as a sensitizer against γ-radiation mediated cellular changes in human cervical cancer cell lines in vitro .
|Figure 1: Structure of sesamol. 1,3-Benzodioxol-5-ol; 3,4-methylenedioxyphenol; 3,4-(methylenedioxy)phenol; oxyhydroquinone, methylene ether; 5-hydroxy-1,3-benzodioxole; methylene ether of oxyhydroquinone. Molecular formula C7H6O3|
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| Materials and Methods|| |
HeLa cells was obtained from National Centre for Cell Science (NCCS), Pune, India. The cells were grown as monolayer in Dulbecco's Modified Eagle's Medium (DMEM) with 10% Fetal Bovine Serum (FBS), 1% glutamine, and 1% penicillin-streptomycin at 37°C in 5% CO 2 atmosphere. Stocks were maintained in 25 cm 2 tissue culture flasks. After the cell numbers were counted, cells were seeded at 5 × 10 4 cells per well in 24-well plates. Cells were harvested by trypsinization after 3 days of culturing. Before irradiation, the medium was replaced by small amounts of complete medium to avoid drying during irradiation.
HeLa cells were treated with sesamol (10 μg/ml) 1 hour prior to γ-irradiation (4 Gy). Irradiation was carried out using Phonex Teletherapy Unit (Cobalt 60) in G. V. N. Cancer Hospitals, Trichy, India, at a dose rate of 1.6 Gy/min.
Group I: HeLa cells (untreated)
Group II: HeLa cells + sesamol (10 μg/ml)
Group III: HeLa cells + γ-radiation (4 Gy)
Group IV: HeLa cells + sesamol (10 μg/ml) + γ-radiation (4 Gy)
The cells were harvested by trypsinization. The pellet obtained was suspended in phosphate buffered saline (PBS) and aliquots were taken for biochemical estimations. The supernatant was taken for enzymic and other estimations. The levels of thiobarbituric acid reactive substances (TBARS),  conjugated dienes (CD),  lipid hydroperoxides (LPH),  superoxide dismutase (SOD),  catalase (CAT),  glutathione peroxidase (GPx),  and reduced glutathione (GSH),  were determined in the supernatant according to the procedures described elsewhere.
Cell proliferation assay
The 3-(4,5-dimethyl-2-thiaozolyl)-2,5-diphenyl-2H tetrazolium bromide (MTT) test, a colorimetric non-radioactive assay, was used for measuring cell proliferation as described elsewhere.  HeLa cells (2 × 10 4 cells/ml) were seeded in 96-well plates. Cells were incubated for different time periods. Cells were washed with DMEM and resuspended in fresh medium. MTT (0.5 mg/ml) was added to the cells followed by incubation for 4 h at 37°C (+5% CO 2 ). The formazan crystals formed were solubilized by adding dimethyl sulfoxide (DMSO) to the cells. Absorbance was measured at 570 nm.
DNA damage was estimated by alkaline comet assay according to the method of Singh et al., with slight modifications as described earlier.  The extent of DNA damage was estimated by fluorescence microscope attached to a digital camera and analyzed by image analysis software, CASP.  Briefly, for each sample, 100 cells were analyzed and classified visually into one of five classes according to the intensity of fluorescence (DNA) in the comet tail. DNA damage was quantified by the tail moment (product of the tail length and the fraction of total DNA in the tail), tail length (distance of DNA migration from the body of the nuclear core and it is used to evaluate the extent of DNA damage) and Olive tail moment [(tail mean − head mean) × tail % DNA/100]. 
Morphological study of apoptosis
Propidium iodide (PI) is a membrane-permeable fluorescent dye. It is specific for apoptotic cell death and does not significantly stain necrotic cells.  Apoptotic nuclei exhibiting typical changes such as nuclear condensation and segmentation were stained by PI. To confirm the cytotoxic effects of sesamol, the morphological study of PI staining was carried out. The cells (2 × 10 4 /well) were seeded into six-well plate and grown to approximately 85% confluence, for a specified duration. PI stained cells were observed under a fluorescence microscope using a red filter.
Statistical analysis was performed by one-way analysis of variance (ANOVA) on SPSS/PC (Statistical Package for Social Sciences, personal computer) and the group means were compared by Duncan's Multiple Range Test (DMRT) taking P < 0.05 to test the significant difference between groups.
| Results|| |
Effect of sesamol and radiation on lipid peroxidation, enzymatic and non-enzymatic antioxidants in HeLa cells
Levels of lipid peroxidation such as TBARS, CD, and LPH in untreated, γ-irradiated, and sesamol-pretreated HeLa cells are shown in [Figure 2]. There was a significant increase in the levels of TBARS, CD, and LPH in sesamol-pretreated, γ-irradiated, and sesamol plus γ-treated HeLa cells in comparison to the untreated cells. Sesamol pretreatment alone (Group II) and γ-irradiation alone (Group III) increased the levels of lipid peroxidation in HeLa cells. The sesamol pretreatment and irradiation (Group IV) caused a further significant increase in TBARS levels when compared to γ-irradiation or sesamol pretreatment alone.
|Figure 2: Effect of sesamol on the levels of TBARS, CD, and LPH in untreated, g-irradiated, and sesamol-pretreated HeLa cells. Values are given as mean ± SD of six experiments in each group. Values not sharing a common superscript differ significantly at P < 0.05 (DMRT)|
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Levels of enzymatic and non-enzymatic antioxidants are shown in [Figure 3]. Sesamol treatment alone (Group II) and γ-irradiation alone (Group III) decreased the levels of enzymatic and non-enzymatic antioxidants in HeLa cells. Sesamol treatment and irradiation (Group IV) caused a further depletion in antioxidant status when compared to γ-irradiation or sesamol treatment alone.
|Figure 3: Effect of sesamol on the levels of (a) SOD, (b) CAT, (c) GPx, and (d) GSH in untreated, ?-irradiated, and sesamol-pretreated HeLa cells. Values are given as mean ± SD of six experiments in each group. Values not sharing a common superscript differ significantly at P < 0.05 (DMRT). The x axis is unit per mg of protein|
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Effect of sesamol and radiation on DNA damage in HeLa cells (comet assay)
[Figure 4] and [Figure 5] show the changes in the levels of DNA damage in the untreated HeLa cells, sesamol-pretreated, γ-irradiated, and γ-irradiated plus sesamol-pretreated HeLa cells. γ-irradiation (Group III) increased DNA damage in HeLa cells. Sesamol treatment and radiation (Group IV) further increased the % DNA damage when compared to γ-irradiation alone group (Group III).
|Figure 4: Changes in the levels of DNA damage in untreated, ã-irradiated, and sesamol-pretreated HeLa cells. (a) HeLa control, (b) HeLa + sesamol (10 ìg/ml), (c) ã-radiation (4 Gy), (d) ã-radiation (4 Gy) + sesamol (10 ìg/ml)|
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|Figure 5: Effect of sesamol on DNA damage (% tail DNA, tail length, tail moment, Olive tail moment) in untreated, g-irradiated, and sesamol-pretreated HeLa cells. Values are given as mean ± SD of six experiments in each group. Values not sharing a common superscript differ significantly at P < 0.05 (DMRT)|
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Effect of sesamol and γ-irradiation on cell proliferation in HeLa cells
Effects of sesamol and γ-irradiation on cell proliferation in HeLa cells were determined by MTT assay. HeLa cell proliferation was significantly inhibited by both sesamol and radiation treatment (10 μg/ml). The inhibitory effect started at 24 h and reached a maximum at 48 h of incubation. [Figure 6] shows the changes in the levels of cell proliferation inhibition in the untreated HeLa cells, sesamol-pretreated, γ-irradiated, and γ-irradiated plus sesamol-pretreated HeLa cells. Sesamol pretreatment alone (Group II) and γ-irradiation alone (Group III) increased the proliferation inhibition in HeLa cells. Sesamol treatment and irradiation (Group IV) caused significantly increased proliferation inhibition when compared to γ-irradiation alone or sesamol treatment alone.
|Figure 6: Effect of sesamol on proliferation inhibition (24 and 48 h) in untreated, γ-irradiated, and sesamol-pretreated HeLa cells. Values are given as mean ± SD of six experiments in each group. Values not sharing a common superscript differ significantly at P < 0.05 (DMRT)|
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Effect of sesamol and γ-irradiation on morphological changes in HeLa cells
[Figure 7] shows the effect of sesamol and radiation on percentage apoptosis in control, γ-irradiated, sesamol-pretreated, and sesamol plus γ-irradiated HeLa cells. The % apoptotic cell death was greater in sesamol plus γ-irradiated cells when compared to sesamol treatment or radiation treatment alone. The occurrence of 80% apoptotic cells was observed in sesamol plus γ-irradiated HeLa cells after 48 h incubation, and at 72 h incubation we observed 100% apoptotic index in sesamol-treated, γ-irradiated, and sesamol plus γ-irradiated HeLa cells.
|Figure 7: Effect of sesamol on quantitative analysis of apoptosis (24 and 48 h) in untreated, g-irradiated, and sesamol-pretreated HeLa cells. Values are given as mean ± SD of six experiments in each group. Values not sharing a common superscript differ significantly at P < 0.05 (DMRT)|
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| Discussion|| |
Radiotherapy is an effective mode of cancer treatment known to induce cell death in tumors.  As the tumor cells proliferate very rapidly, they overgrow their vascular blood supply, resulting in centrally necrotic and hypoxic regions, rendering radiation ineffective in these areas.  To overcome this problem, higher doses of radiation must be delivered to control the tumor. This is clinically not feasible, since the normal tissues surrounding the tumor are well perfused, vascularized, and remain oxygenated, and are therefore prone to radiation damage.  The success of radiotherapy, therefore, depends on increasing the sensitivity of the cancer cells to radiation. 
Previously, we reported that sesamol (10 μg/ml) modulated radiation-induced oxidative damages in normal human blood lymphocytes.  In this study, we investigated its radiation modifying potential in human cervical cancer cell lines. Interestingly, sesamol (10 μg/ml) showed radiosensitizing effects in HeLa cells treated 1 hour before 4 Gy irradiation. Our studies indicate that sesamol and radiation treatment increase lipid peroxidation in HeLa cells. Lipid peroxidation and oxidative stress have been implicated in many pathophysiological conditions.  It has been previously proved that sesamol exhibits pro-oxidant activity and oxidizes oxymyoglobin in bovine and porcine muscle model systems. 
These processes have been known to induce apoptosis in a wide variety of cultured cells and are believed to play a major role in the regulation of apoptosis. It has been described that the pro-oxidant action of plant-derived phenolics may be an important mechanism for their anticancer and apoptosis-inducing properties, as reactive oxygen species (ROS) can mediate apoptotic DNA fragmentation and their pro-oxidant phenoxyl radicals can cause mitochondrial toxicity by altering the mitochondrial membrane potential. 
Ionizing radiation has been shown to enhance the production of ROS in cells.  The generated ROS can be eliminated by antioxidant enzymes such as SOD, CAT, and GPx, which has been associated with radio- and chemoresistance in cells. The susceptibility of tumor cells to radiation is associated with decreased activities of antioxidant enzymes.  It has been proposed that exposure to agents that enhance oxidative stress-induced injury may sensitize cells to the cytotoxic effects of ionizing radiation. In our study, we observed decreased activities of antioxidant enzymes, i.e. SOD, CAT, and GPx, in sesamol plus γ-irradiated HeLa cells. Bhosle et al .  showed that ellagic acid decreased the activities of antioxidant enzymes in mice treated with radiation.
We also noticed decrease of GSH levels in HeLa cells during radiation plus sesamol treatment. Previous studies showed that phytochemicals depleted intracellular antioxidants, thereby enhancing radiation effects in cancer cells.  Caffeic acid phenethyl ester (CAPE) sensitizes CT26 colorectal adenocarcinoma to ionizing radiation, which may be by depleting GSH and inhibiting nuclear factor (NF)-κB activity. It is suggested that CAPE may deplete GSH and inhibit the recycling of GSH in CT26 cells. Because phytochemicals deplete GSH by increasing its oxidation and inhibiting GSH recycling, it is implicated that sesamol might act with inhibitors of de novo synthesis of GSH to sensitize tumor cells to radiation.
DNA is an important molecular target in radiation killing of tumor cells. The induction of DNA single strand breaks is often used to predict the radiosensitivity of tumor cells.  Polyphenols are known to enhance radiation-induced DNA damage.  In our study, tumor cells showed response to the treatment with either radiation or sesamol, but more pronounced response was seen in cancer cells treated with a combination of radiation and sesamol. A large number of natural compounds have shown cytotoxic effects in a variety of situations, i.e. either alone or together with radiation.  Flavonoids autooxidize in aqueous medium and may generate highly reactive hydroxyl radicals.  Polyphenols may act as substrate for peroxidases and other metalloenzymes, yielding quinone or quinomethide type pro-oxidants.  Sahu and Washington (1992)  showed the effect of curcumin on irradiated cells and indicated that under certain conditions it may serve as a pro-oxidant, thus stimulating radiation damage.
In the MTT assay, % growth inhibition of HeLa cells treated with sesamol and radiation was time dependent. The radiosensitizing action of sesamol was most pronounced after 48 h incubation. Previous reports showed that phenolic phytochemicals enhanced radiation effects.  Plumbagin pretreatment also enhances radiation effects by inhibiting HeLa and SiHa cell proliferation in vitro.  Ursolic acid and oleanolic acid inhibit colon carcinoma cell line HCT15 proliferation.  (−)-Epigallocatechin-3-gallate promotes growth inhibition of T24 bladder cancer cells by inducing apoptosis via modulation of the PI3K/AKt pathway.  Further, phytochemicals modulate mitochondrial membrane potential and cause growth inhibition. This may be one of the reasons for increased cytotoxicity observed in sesamol plus radiation treated cells. It has been reported earlier that 50 and 100 mg/kg body weight of sesamol was effective in Swiss albino mice.  Further, it has been already reported that 10 μg/ml of sesamol was effective against radiation-induced chromosomal aberrations. 
To explore the method of cell death in cervical cancer cells by sesamol and radiation, we observed apoptotic morphology by PI staining. Phytochemicals potently activate the apoptosome by the release of Cyt-C from mitochondria and activate caspases 9, 8, 7, and 3. Ursolic acid and oleanolic acid treatment resulted in apoptotic morphological changes and DNA fragmentation in carcinoma cell lines.  It has been reported earlier that the cell surviving rate significantly decreased as the dosage and duration of the sesamol treatment increased. Sesamol has been reported to induce apoptosis thorough the activation of the caspase pathway in mouse Leydig tumor
cells.  Sesamol tetramer, at a concentration of 10-30 μM, significantly inhibited the growth of K562 cells and the compound at 30 μM greatly increased the cell K562 lethality.  It has been reported that sesamol treatment modulates apoptotic and inflammatory signaling in human skin dermal fibroblasts.  In experimental animals, it has been proven that sesamol blocks tumor necrosis factor (TNF)-α and activates plasminogen in many pathological conditions, thereby preventing endothelial dysfunction and radiation-induced enterotoxicity. Further, sesamol prevented radiation-induced DNA damage in whole-body irradiated Swiss albino mice. 
| Conclusion|| |
Thus, our results summarize that sesamol enhances radiation effects by decreasing cell proliferation and antioxidant status, and increasing lipid peroxidation, DNA damage, and apoptosis in HeLa cells. Identification of more such compounds and elucidating the mechanism through which they act could extend effective protocol for cancer radiotherapy.
| Acknowledgment|| |
The authors gratefully acknowledge the University Grants Commission, New Delhi, for providing financial assistance in the form of Major Research Project.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]