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 Table of Contents  
REVIEW ARTICLE
Year : 2016  |  Volume : 7  |  Issue : 3  |  Page : 71-78

Ellagic acid radiosensitizes tumor cells by evoking apoptotic pathway


1 Centre for Cellular and Molecular Biology, Deakin University, Melbourne, Australia
2 Foundation for Education and Research, India and BM International Research Centre, Mumbai, Maharashtra, India

Date of Web Publication10-Jan-2017

Correspondence Address:
K P Mishra
Foundation for Education and Research, India and BM International Research Centre, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-0168.197973

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  Abstract 

Cancer causes millions of deaths each year globally. In most patients, the cause of treatment failure is found associated with the resistance to chemotherapy and radiotherapy. The development of tumor cell resistance evokes multiple intracellular molecular pathways. In addition, the limitation in treatment outcome arises due to unintended cytotoxic effects of the synthetic anticancer drugs to normal cells and tissues. Considerable focus of research is, therefore, devoted to examine plant-based herbal compounds which may prove potential anticancer drug for developing effective cancer therapy. Research results from our laboratory have shown that ellagic acid (EA), a natural flavonoid displays enhanced tumor toxicity in combination with gamma radiation to many types of cancers in vitro as well as in vivo. Studies on the underlying mechanisms of toxicity suggest that EA employs the cellular signaling pathways in producing the observed effects. This paper gives an account of molecular mechanisms of EA-induced apoptosis process in tumor cytotoxicity. It is suggested that EA acts as a novel radiosensitizer for tumors and a radioprotector for normal cells which may offer a novel protocol for cancer treatment.

Keywords: Apoptotic sensitivity, cancer, ellagic acid, radioprotection, radiosensitizer


How to cite this article:
Ahire VR, Mishra K P. Ellagic acid radiosensitizes tumor cells by evoking apoptotic pathway. J Radiat Cancer Res 2016;7:71-8

How to cite this URL:
Ahire VR, Mishra K P. Ellagic acid radiosensitizes tumor cells by evoking apoptotic pathway. J Radiat Cancer Res [serial online] 2016 [cited 2019 Jul 23];7:71-8. Available from: http://www.journalrcr.org/text.asp?2016/7/3/71/197973


  Introduction Top


Being a powerful antioxidant, ellagic acid (EA) exhibits a variety of health benefits. It is found in pecans, walnuts, cranberries, raspberries, and some other fruits and vegetables. It is believed to target free radicals throughout the body and acts as an antioxidant reflected in the slowing down of tumor growth. Italian researchers were the first to perform human clinical studies in 2005 showing that EA reduced side effects of chemotherapy in patients with advanced cancer. [1] Research in laboratory has shown that EA is a novel and potent radiosensitizer to tumor. It acts by increasing the oxidative stress in tumor cells and drives them to undergo apoptosis process. On the other hand, EA has been found to protect normal cells against radiation. In this review, we have attempted to investigate the mechanism of EA-induced sensitization of tumor to gamma radiation. It is found that EA exerts its cytotoxic effects on tumor cells by inducting apoptosis pathway involving reactive oxygen species (ROS). The opposite response of EA in normal cells is attributed to the low threshold level of cytosolic oxidative status.


  Ellagic Acid-Mediated Therapeutic and Biological Health Benefits Top


Mechanism of EA-induced toxicity to tumor cells has been subject of studies in many laboratories. [Figure 1] explains the various therapeutic beneficial effects EA elicits in humans. In heart patients, it has been found to reduce the risk of heart disease. It also mitigates liver-related problems, especially in breaking and removing the carcinogens from blood. Ellagitannins are also known to be antibacterial due to their gyrase inhibition activity that is required for bacterial growth. In the stomach, it fights the Helicobacter pyroli bacteria which is associated with the incidence of ulcers. [2] In rat model, EA has been found to prevent the long-term brain injuries due to a significant reduction in hippocampal discrepancies and brain inflammation. Other than being a natural polyphenol and a potent antioxidant, EA has several health benefits of being an antimutagenic, antiviral, and anticarcinogenic properties. [3] [Figure 2] and [Figure 3] describe the effect of EA on growth and metastasis of tumor cells involving various cellular proteins. It can reduce the activation of carcinogenic substances through its antioxidant ability and the ability to decrease the cytochrome P450 activity. [4] It also prevents the cellular oxidative DNA damage by reducing the metabolic activation of carcinogenic substances. [5],[6] EA is known to be a scavenger of ROS and a DNA protector from the injury of alkylating agents. [7]
Figure 1: Ellagic acid mediated therapeutic effects

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Figure 2: Effects of ellagic acid on the growth of tumor cells. Anticancer effect can be seen in various cancer associated processes such as proliferation, angiogenesis, expression of pro-inflammatory cytokines and the synthesis of estrogen

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Figure 3: Effects of ellagic acid on tumor metastasis. Ellagic acid by several inhibitory mechanisms assists cancer cells to undergo the epithelial mesenchymal transition, chemotaxis, and cell migration. It aids in the maintenance of cell adhesion molecule

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Pomegranate oligomers (composed of gallic acid, EA, and glucose units) accelerate the growth of probiotic bacteria. [8] Oral suspension of EA has a hypolipidemic action, i.e., lowering glucose level in rats that had high-fat diet-induced hyperlipidemia. [9] EA protects endothelial cells from oxidized low-density lipoprotein-induced apoptosis. [10] Cells treated with EA showed a significant increase in glutathione levels, total thiols, and augmented biosynthesis of metallothionein protein. It aids in the repair mechanism of the protein sulfhydryl, safeguarded from the DNA damage associated with oxidative stress, reduction of intracellular calcium, and inhibition of the lipid peroxidation. [11] Researchers have also found that the dietary intake of EA reverses the gene expression markers linked with cancer formation and development thereby proving to be novel in cancer therapy. [12]

EA nanoparticulate formulations at three times lower dose prevented cyclosporin A-induced nephrotoxicity. [13] EA showed antiangiogeneic effects when chelated with zinc. This inhibited the activity of the matrix metalloproteinase (MMP)-2 and migration of the vascular endothelial cells. [14] Cells treated with EA (60 mg/kg body weight [b.w.] dose) were able to effectively modulate the oxidative stress. This was seen by the improved antioxidant status and decreased thiobarbituric acid reactive substances (TBARS), nitric oxide, liver marker enzymes (gamma-glutamyl transferase and alkaline phosphatase), and hydroperoxides when compared with the effect of alcohol-induced oxidative stress. [15] EA administration at 50 mg/kg b.w. considerably declined the hepatic marker enzymes activities compared to the 12.5, 25 mg/kg b.w. doses of EA. In liver, the levels of enzymatic and nonenzymatic antioxidants significantly improved on treatment with EA, but the levels of TBARS and hydroperoxides were significantly decreased. [16] In cholestatic rats, EA modulates the Cu and Zn in the serum and liver at the dose of 60 mg/kg/day. [17] Hence, EA can serve as a crucial compound in the development of hepatoprotective drugs. [18]

Topical EA administration prohibited collagen damage and inflammatory responses triggered by ultraviolet (UV)-B. Hence, dietary and pharmacological involvements with berries rich in EA can prove to be encouraging treatment approaches associated with skin wrinkling and inflammation linked with prolonged UV exposure leading to photoaging. [19] Owing to inhibition of nuclear factor kappa B (NF-κB), EA exhibits anti-inflammatory property by inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, tumor necrosis factor-alpha, and interleukin (IL)-6 downregulation. [20] Its oral administration (50 and 100 mg/kg b.w.) caused reduction in micronuclei formation, restoration of antioxidant enzyme activity, reduction in DNA fragmentation, and serum toxicity marker enzymes such as lactate dehydrogenase, urea, and creatinine that had augmented after treatment with cyclophosphamide-induced renal injury, DNA damage, and genotoxicity. [21] In addition, when administered orally at dose 7.5 or 15 mg/kg can act as cardioprotective and used for treatment of the infracted heart by decrease of the infarct size, regulation of the apoptotic gene expressions, and enhancement of the activities of mitochondrial respiratory marker enzymes and cell viability. [22] EA has shown antiplasmodia activity in vivo and potentiates the action of existing antimalarial drugs such as chloroquine, mefloquine, artesunate, and atovaquone. [23] It possesses antiplasmodial activities in the upper nanomolar range by inhibiting glutathione S-transferases. [24] [Figure 1] explains the various therapeutic beneficial effects of EA elicits in humans.


  Preclinical Studies on Tumors Top


[Figure 4] gives a brief overview of several cellular signaling pathways influenced by EA through molecular targets in various cancer types.
Figure 4: A brief overview of several cellular signaling pathways influenced by ellagic acid through molecular targets in various cancer types

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Liver cancer

Tanaka et al. showed that EA exhibited cancer inhibitory properties. They induced hepatocarcinogenesis ACI/N rates (200 ppm N-2-fluorenylacetamide [FAA] +400 ppm EA) for 4 months. EA was fed before and after for a week during this treatment. After termination of the carcinogen diet, animals were sacrificed for up to 20 weeks at regular intervals. Using gamma-glutamyl transpeptidase reaction, neoplasms and liver-altered foci were identified. The frequency of incidence of hepatocellular neoplasms was 100% and a significant number of altered foci were observed at the end of 36 weeks after FAA exposure. Interestingly, the altered foci number was lower at all the different time points in the group receiving the EA and FAA treatment. The frequency of hepatocellular neoplasms (30%) was found to be reduced. [25]

Colon cancer

Narayanan and Re showed that EA acted as an antioxidant in colon cancer cells, SW 480, when given at a concentration of 10 − 5 M for 48 h. EA induced the downregulation of insulin such as growth factor (IGF)-II, mediated an accumulative effect on G1/S transition phase, activated p21 (waf1/Cip1), and subsequently caused apoptotic cell death. This study reveals that EA inhibits cancer cell growth by damaging cellular DNA, prompt p53 to activate p21, and alter the expression of growth factor that can eventually result in downregulation of IGF-I. [26]

Prostate cancer

Narayanan et al. characterized the alterations in prostate cancer associated with EA treatment. They used human cDNA microarrays with 2400 clones consisting of 17 prosite motifs. After 48 h, exposure of LNCaP cells to EA revealed more than a 2-fold difference in expression in 593 genes. Differential expression of certain genes from the cDNA microarrays was confirmed and authenticated by quantitative reverse transcription polymerase chain reaction. Further data analysis proposed the stimulations of various growth inhibition signaling pathways in the LNCaP cells, some of them being p53 responsive and PPAR families of genes. [27]

Breast cancer

EA inhibited the proliferation of MCF-7 cells by arresting them in the G0/G1 phase of the cell cycle. The gene expression profile of EA-treated (6, 12, and 24 h) cells revealed > 2-fold change in 1738 genes after 24 h treatment. Two thousand five hundred and forty-seven were downregulated and 2191 were upregulated and 16 genes belonged to that TGF-β/Smads signaling pathway. It was observed that cells' cyclins (cyclin A2 and cyclin E2) were downregulated, but cyclin-dependent kinase inhibitors (p21Cip1, p15, and p19) were upregulated. During mid-G1 phase, cdk4 and cdk6 interact with D-type cyclins to form heterodimer kinase complex. This event follows the interaction of cyclin E with cdk2 to phosphorylate Rb in the late G1 phase. [28],[29],[30],[31]

EA also seems to exert both estrogenic and antiestrogenic effects in breast cancer cells. EA increased the hTERT α + β + mRNA whereas when given in the presence of 17 β-estradiol, EA significantly reduced the 17 β-estradiol-induced increase in hTERT α + β + mRNA. [32] EA also exhibited antiangiogenic effect in breast cancer cells by targeting the VEGFR-2 and its associated signaling pathways. In Chick embryo chorioallantoic membranes model, it inhibited the blood vessel formation. In MDA-MB-231 × enograft model, it suppressed the tumor growth and reduced the microvessel density. [33]

Cervical cancer

EA is used against the prevention and treatment of human papillomavirus-induced cervical cancer as it exhibits the antitumor as well as antiviral properties. It inhibits a protein kinase CK2 that seems to be a promoter of tumorigenesis. EA induced a dose- and time-dependent cell cycle arrest and caspase-mediated apoptosis in HeLa cells. It effectively repressed the E6 and E7, viral oncogene expression and the phosphorylation of CK2, decrease in cyclin A, and an increase in p53 expression. The subsequent cytochrome C releases in the cytosol, and activation of caspase-3 induced the poly (ADP-ribose) polymerase (PARP) fragmentation. Hence, blocking the cell signaling pathways that induce cancer by stalling the CK2 can assist in the reactivation of dormant cells' defense machinery. In vivo studies reported that EA-treated mice survived longer as they showed to inhibit the cervical cancer xenograft growth as compared to control mice which exhibit its antitumor and antiviral properties. [34]

Bladder cancer

When human bladder cancer cells, TSGH8301 cells were treated with different doses of EA, it induced a G0/G1 phase arrest, morphological changes, and eventually apoptosis. EA has been supposed to have worked by exerting oxidative stress by the production of ROS and Ca (2 + ) and decreasing the mitochondrial depolarization that stimulated the activities of caspase-9 and -3. Experimental data clearly indicated that the EA promoted DNA damage and induced apoptosis in TSGH8301 cells. EA upregulated the p53 and p21 whereas decreased the CDC2 and WEE1. This leads to the cell cycle arrest in the G0/G1 phase, promoting the expression of BAD, AIF and Endo G, cytochrome c, caspase-9 and -3 for leading to apoptosis in TSGH8301 cells. [35]

EA also induces apoptosis in cancer cells by activating a cascade of molecular events like that of cell cycle arrest, apoptosis, etc., In human bladder cancer cells T24, EA induced apoptosis by activating events of molecular cascade. It arrested the cell cycle in the G0/G1 phase causing decrease in CDK2 and increase in p53 and p21, reducing cell viability, and promoting caspase-3 activity that eventually pushed the cells to apoptosis. [36]

Ovary cancer

When treated with EA (10-100 μM), ovary cancer cell lines ES-2 and PA-1exhibited inhibition of cell proliferation in dose- and time-dependent manner. The cells were arrested in the G1 phase of the cell cycle with elevated p53 and Cip1/p21. There was a decrease in the cyclin D1 and E levels. EA also increased the Bax: Bcl-2 ratio that subsequently induced apoptosis through the caspase-3 mediation and restored anoikis in the ovarian cancer cells. [37]

Pancreatic cancer

Studies have shown that EA can prevent pancreatic cancer growth, angiogenesis, and metastasis. It does so by effectively over powering the Akt, Shh, and Notch pathways. PANC-1 cells were injected subcutaneously into Balb c nude mice and tumor-bearing mice were treated with EA. Treatment of PANC-1 × enografted mice with EA caused substantial inhibition of tumor growth. This was due to the suppression of cell proliferation, activation of caspase-3, and induction of PARP cleavage. EA induced Bax expression but inhibited the expression of other significant proteins such as CDK2, CDK6, cyclin D1, and Bcl-2 in tumor tissues as compared to the control. Angiogenesis and metastasis markers such as IL-6 and IL-8, vascular endothelial growth factor, vascular endothelial growth factor receptor, COX-2, HIF1α and MMP-2, MMP-9, respectively, were also inhibited. EA-treated mice also significantly showed inhibition in the phospho-Akt, Gli1, Gli2, Notch1, Notch3 proteins. EA upregulated E cadherin, inhibited the Snail, MMP-2, and MMP-9 that subsequently reversed the epithelial mesenchymal transition. [38] In human pancreatic adenocarcinoma, EA (10-50 mmol/L) decreased proliferation and kindled apoptosis by mitochondrial depolarization leading to release of cytochrome C and activation of caspases. EA associated dose-dependent decrease in the NF-κB binding activity was also seen. [39]


  Enhancing Ellagic Acid Bioavailability Top


A major limitation of EA is its rapid elimination from the body after being administered. Realizing its potential nutritional and therapeutic benefits researchers have come up with strategies to enhance its bioavailability. Researcher at Jadavpur University prepared a novel formulation with phospholipids that protected the liver from carbon tetrachloride-induced liver damage in rats. Determining the enzymes in the oxidative stress form were used to assess the antioxidant activity of the complex (i.e., equivalent of EA = 25 and 50 mg/kg of b.w.). The complex showed to protect the liver by reinstating the action of superoxide dismutase (SOD), catalase, liver glutathione, and thiobarbituric acid reactive substances with respect to the group treated with carbon tetrachloride. The complex (equivalent to 80 mg/kg of EA) not only exhibited enhanced protection but also was maintained in effective higher concentrations (Cmax = 0.54 μg/mL) in the serum for a longer period than that of pure EA (80 mg/kg) (Cmax = 0.21 μg/mL). This suggested the effective working of EA complex being a hepatoprotective agent compared to the free form due to its potential antioxidant property. [40]

To increase EA bioavailability, it was administered systemically by subcutaneous silastic implants. In the test animals, EA plateaued at 8 weeks showing 1167 ± 171, 1458 ± 302, and 1272 ± 192 ng/ml at 8, 16, and 28 weeks, respectively. A continuous increase of 53 ± 15, 130 ± 30, and 185 ± 72 ng/ml at 8, 16, and 28 weeks, respectively, was observed with the use of silastic implants. A notably high diet of 4 mg/day was required as compared to the silastic implant method that required just 0.03 mg/day. This aided in achieving 7-fold higher plasma EA levels. The oral bioavailability of EA which was just 0.2% increased to 5% when directed by continuous systemic transfer.

In a separate study conducted to evaluate the increase in the oral bioavailability of EA (430 ppm). It was administered in form of ellagitannins in female S/D rats treated with benzo[a] pyrene. Groups of animals were also administered punicalagins and EA through subcutaneous polycaprolactone implants (10% load). The polycaprolactone implant delivery (570 μg/day) resulted in > 150-fold higher plasma EA levels (589 ± 78 ng/ml), resulting in much higher bioavailability (0.85%). EA administration through the diet (5 mg/day) and polycaprolactone implants (about 0.16 mg/day) showed 317 ± 39 and 673 ± 101 ng/ml plasma EA, respectively.

Research reveals that EA, when administered in the diet either as pure compound or as a component of black raspberry, there was no significant difference in the bioavailability of EA; however, sustained systemic delivery enhanced the bioavailability of EA by 25-fold; and oral bioavailability of EA when administered as free EA was much higher than when administered as ellagitannins. [41]


  Radiosensitizing Effect of Ellagic Acid Top


Scientists are now recognizing the enormous potential that herbals can have in the development of an effective radiosensitizer that can be used in the clinics as effective combinatorial cancer treatment modality. Investigations from our laboratory have been focused on elucidating the mechanistic activity of such plant-based anticancer and antioxidant agents such as curcumin, eugenol, triphala, tocopherol succinate, and EA. These phytochemicals present cytotoxic effects when delivered in combination to ionizing radiation. It is also known by now that these compounds modulate the membrane peroxidative damage and the intracellular ROS production which aids in efficient induction of killing cancer cells by the way of programmed cell death.

In cancer cells, EA along with radiation was able to generate substantial amount of ROS. This combinatorial treatment showed a remarkable subsequent drop in the membrane potential of the mitochondria and loss in cell viability in tumor cells from mice. In addition, EA protected the splenic lymphocytes in the mice transplanted with tumor. The levels of cellular antioxidant enzymes such as catalase, SOD glutathione peroxidase, and glutathione reductase (GR) were found to go low after the EA and radiation combined treatment in vivo. There was a significant decrease in the b.w. in tumor bearing mice, suggesting the reduction in the tumor burden. [42]

A significant synergistic tumor cytotoxic effect was observed when breast cancer cells, MCF-7, were irradiated in the presence of EA for radiation dose of 2 and 4 Gy. Data suggest that the radiosensitization effect was as a consequence of modulation the MCF-7 cell cycle and induction of apoptosis. EA heightened cell death and reduced the cell growth potential of MCF-7 cells. Survival and proliferation outcomes absolutely suggest that EA facilitated reproductive cell death in 48 h. MCF-7 cells failed to overcome the radiation insults in terms of DNA damage and were therefore arrested in the G1 phase and subsequently pushed to the apoptotic phase in 48 h. This can also be attributed to the maximum detectable γ-H2AX foci being retained even at 24 h indicating a severe irreparable DNA damage. The cells visibly showed the preapoptotic nuclear and mitochondrial changes in terms of phosphatidylserine externalization and dose-dependent drop in the mitochondrial potential. Protein expression data suggests the induction of apoptosis is complemented by a diminution of Bcl-2 and upsurge in Bax, thus shifting the Bax: Bcl-2 ratio in favor of apoptosis. Increase of PARP was observed due to the radiation insults that caused single-stranded DNA binding protein (SSB) in the DNA.

In a different study, HeLa cells were given a combined treatment of EA and radiation. The results showed the upregulation of p53, increased superoxide, and decrease in the levels of cellular antioxidant enzymes such as SOD and GPx. The induced oxidative stress lead to enhanced caspase-3 activity, increase in the levels of phospholipase C and intracellular calcium, loss in mitochondrial potential. [43]

Biopsies from stage III A and B cervical cancer patient were collected later and prior 24 h after the initial fractionated dose treatment of 2 Gy to evaluate various parameters. Alteration in the membrane fluidity, calcium and SOD levels eventually induced apoptosis. The cells showed a direct correlation with the apoptotic sensitivity after the initial dose of radiation treatment and the treatment outcome in patients after completion of radiotherapy in a clinical setup suggesting apoptotic index may form a basis for prognosis in radiation therapy of the stage III cervical cancer patients. [42]

In a different study on HeLa, EA at a concentration of 10 μM acted as a growth inhibitor and anticancer agent. Before radiation treatment, HeLa cells were treated prior with EA 10 min. This allowed the cells to get sensitized and be receptive to radiation therapy. Hela cells when treated with EA before radiation exhibited significant synergistic toxicity to the cells. The cellular damage was severe, and hence, cell death was augmented as a result of radiation insult. This was quantified in terms of the γ-H2AX foci formed after the radiation treatment and was persistent and irreparable even after 24 h. This resulted in the upsurge of PARP as a result of DNA SSB. Consequently, the cell cycle was halted at the G1 phase. The cells in due course of time also lost their reproductive potential. Downregulation of antiapoptotic Bcl-2 and upregulation of proapoptotic BAD was observed, inducing the cell to the programmed cell death pathway of apoptosis. Since a drop in the mitochondrial membrane potential was observed, it can be concluded that the cells followed the mitochondrial mediated cell death pathway which was effected by the caspase-3, of which PARP is a substrate. PARP gets cleaved and therefore cannot repair DNA DSB further confirming the cell being pushed to apoptosis. The combinatorial treatment of EA and radiation enhanced the oxidative stress-mediated cytotoxicity in tumor cells and increased the apoptotic sensitivity to radiation-induced cell death. [Figure 5] explains the role of EA as a radiasensitizer.
Figure 5: Effects of ellagic acid as a radiosensitizer on tumor cells. When cancer cells are treated with radiation alone, they are killed by the reactive oxygen species generated due to oxidative stress. However, when cells are given a prior treatment of a chemotherapeutic agent such as ellagic acid, it augments the production of reactive oxygen species and eventually leads to enhanced apoptosis

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  Normal Cell Radio-protection Top


Induction of micronuclei and chromosomal aberrations produced by whole-body exposure of gamma radiation (1.5-3.0 Gy) in mice was found to be significantly inhibited by oral administration of natural antioxidant, EA (200 μM/kg/b.w.). EA-induced inhibition of micronucleated polychromatic and normochromatic erythrocytes was comparable with alpha-tocopherol (200 μM) administration. EA was also found to significantly reduce the number of bone marrow cells with chromosomal aberrations and chromosomal fragments as effectively as alpha-tocopherol. Moreover, administration of EA inhibited the DNA strand breaks produced in rat lymphocytes upon radiation as seen from the DNA unwinding studies. These results indicated that antioxidant-like EA provided protection against chromosome damage produced by radiation. [44]

Whole-body irradiation of rats (10 Gy as five fractions) found to produce lung fibrosis within 2 months as seen from increased lung collagen hydroxyproline and histopathology. Oral administration of antioxidants, EA, at a concentration 200 μM/kg b.w. significantly reduced the lung collagen hydroxyproline in these animals. The serum and liver lipid peroxidation which were found to be increased by irradiation were significantly by the antioxidant treatment. The liver SOD and glutathione peroxidase activity were also found to be increased and catalase activity decreased in irradiated control. Superoxide dismutase activity reduced significantly by antioxidant treatment while catalase activity was found to be increased with alpha-tocopherol treatment. The increased frequency of micronucleated polychromatic erythrocytes after whole-body irradiation of mice was found to be significantly reduced with antioxidants. [45]

In the case of normal cells, EA protects them against radiation damage. EA was found to generate ROS in tumor cells, which increased, by an order of magnitude when cells were treated with EA in combination with gamma radiation. The decrease in mitochondrial potential and the loss of cell viability were remarkably greater in tumor cells from mice treated with EA and radiation than alone treatment with either of them. Measurement of antioxidant enzymes, such as SOD, catalase, GSH-Px, and GR, in tumor cells showed decrease after treatment with EA and radiation in vivo. [46]

EA inhibits gamma radiation (hydroxyl radical)-induced lipid peroxidation in rat liver microsomes in a dose- and concentration-dependent manner. Its antioxidant capacity has been estimated using the 1, 1-diphenyl-2-picrylhydrazyl radical assay. To understand the actual mechanisms involved in antioxidant activity and the free radical scavenging ability, a nanosecond pulse radiolysis technique has been employed. [47]

Laboratory studies on NIH3T3 also reveal EA to be a radioprotector. NIH3T3 cells treated with EA and radiation at 24, 48, and 72 h showed cell death to be 7%, 12%, and 18% for 2, 4, and 6 Gy of radiation treatment alone. At 48 h, cell death was found to be 16%, 22%, and 30% for 2, 4, and 6 Gy of radiation treatment, respectively. However, when NIH3T3 cells were pretreated with EA, there was a substantial drop in the cell death at 24 and 48 h. At 24 h, the cell death was 4% and 7% and 7% and 9% at 48 h for 2 and 4 Gy of radiation. The % relative cell growth of EA pretreated cells increased from 93% and 88% to 96% and 93%, respectively, for 2 and 4 Gy at 24 h. At 48 h also, there was a significant increase found from 84% and 78% to 93% and 92% for 2 and 4 Gy treatment. Morphological studies also revealed that the cells were as normal as the control cells. Hence, it can be concluded that EA and radiation combined treatment of 10 μM EA + 2 Gy and 10 μM EA + 4 Gy not only protected NIH3T3 cells from radiation damage but also helped them to repair the damage and survive healthily. [42] [Figure 6] explains the role of EA as a radioprotector.
Figure 6: Effects of ellagic acid as a radioprotector on normal cells. While treating cancer cell with radiation, normal cells also receive the radiation insults. Cells prior treated with ellagic acid are able to overcome the insults readily and are not only able to able to survive better but also grow healthy

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  Conclusion Top


Herbal polyphenols hold promise in therapy due to their smaller or negligible side effects as compared to that of synthetic drugs. Most synthetic drugs are not only killer of cancer cells but also killer of surrounding normal cells which either die off or become abnormal. It is important that researchers have to consider the fact of protecting the normal cells and look into more options of using and evaluating the potential of herbal polyphenols and how they can be brought into a clinical setup. This review has focused on one of the common laboratory chemotherapeutic or chemosensitizer, EA. Its potential has been tried and its efficacy has been effectively tested in a variety of tumors. Cancer cells have altered signaling pathways usually related to cell growth and cell division. One of the strategies to effective cancer therapy would to understand these molecularly altered pathways and plant-derived compounds that can regulate them. In the current review, we have summarized EA-modulated signaling pathways in various cancer types. EA radiosensitization studies also showed that it can sensitize tumor cells like that of the breast and cervix and aid to overcome tumor resistance to cancer therapy. Studies have also shown that EA also protects normal cells and helps them to overcome the radiation damage effectively and aids in healthy normal growth of the cells. Our previous studies have been able to show its effectiveness in breast and cervical cancer as a radiosensitizer. In normal cells, it shows its radioprotective effect. Although EA looks to be a potential radiosensitizer, more work needs to be done in evaluating its mechanism of action.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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