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ORIGINAL ARTICLE
Year : 2014  |  Volume : 10  |  Issue : 4  |  Page : 1033-1039

Potent chemopreventive effect of mangiferin on lung carcinogenesis in experimental Swiss albino mice


1 Department of Medical Biochemistry, Dr. ALM Postgraduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, India
2 Department of Pharmacology and Environmental Toxicology, Dr. ALM Postgraduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, India
3 Department of Biochemistry NPO International Laboratory of Biochemistry, Uchide, Nakagawa ku, Nagoya, Japan

Date of Web Publication9-Jan-2015

Correspondence Address:
Dhanapal Sakthisekaran
Department of Medical Biochemistry, Dr. ALM PG Institute of Basic Medical Sciences, Universityof Madras, Taramani Campus, Chennai 600 113
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.137966

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 > Abstract 

Aim of the Study: In the present study the effects of mangiferin were tested against lung cancer-bearing mice in both the pre-initiation and post-initiation periods.
Materials and Methods: Healthy male Swiss albino mice (6-8 weeks old) were used throughout the study. The animals were treated with mangiferin (100 mg/kg body weight dissolved in corn oil) two weeks before (pre-initiation) and the twelfth week after (post-initiation) the establishment of B (a) P (50 mg/kg body weight)-induced lung carcinoma.
Results: The body weight decreased and the lung weight and levels of xenobiotic and liver marker enzymes markedly increased in the carcinogen-administered animals; and mangiferin treatment brought the values of these parameters back to the near-normal ones. The activities of lysosomal enzymes in the animals with B (a) P-induced experimental lung carcinogenesis were also assessed. In these animals there was an increase in the activities of lysosomal enzymes such as acidphosphatase, β-glucuronidase, N-acetyl glucosaminidase, and β-galactosidase.
Conclusion: Supplementation with mangiferin attenuated all these alterations, thus indicating its anticancer effect. Overall, the above data showed that the anticancer effect of mangiferin as a chemopreventive agent was pronounced.

 > Abstract in Chinese 

芒果苷对实验瑞士白化小鼠肺癌的潜在的化学防癌作用,

摘要

研究目的:本研究中测试了芒果苷对于肺癌小鼠在预启动和启动后的作用。

材料与方法:在整个研究过程中使用健康雄性瑞士白化小鼠(6-8周龄)。用芒果苷诱导这些小鼠产生肺癌,用芒果苷100毫克/公斤体重,溶于玉米油于前2周(启动前)和50毫克/公斤体重于以后的12周(启动后)。

结果:这些致癌物注射的动物中,体重下降,肺的重量、致癌物质水平和肝标记标记酶的水平显着增加;芒果苷治疗使这些参数的值返回到接近正常。对这些苯并(a)芘诱导的肺癌病变的溶酶体酶的活性也进行了评估。在这些动物中溶酶体酶的活性增强,如酸性磷酸酶,β葡萄糖醛酸,N乙酰氨基葡萄糖苷酶,β半乳糖苷酶。


结论:补充芒果苷减弱这些变化,从而表明芒果苷的抗癌效果。总体而言,上述数据表明,芒果苷作为化学预防剂预防肿瘤的效果是明显的。

关键词:苯并(a)芘,肺癌,溶酶体酶,芒果苷

Keywords: Benzo(a)pyrene, lung cancer, lysosomal enzymes, mangiferin


How to cite this article:
Rajendran P, Rengarajan T, Nishigaki I, Ekambaram G, Sakthisekaran D. Potent chemopreventive effect of mangiferin on lung carcinogenesis in experimental Swiss albino mice. J Can Res Ther 2014;10:1033-9

How to cite this URL:
Rajendran P, Rengarajan T, Nishigaki I, Ekambaram G, Sakthisekaran D. Potent chemopreventive effect of mangiferin on lung carcinogenesis in experimental Swiss albino mice. J Can Res Ther [serial online] 2014 [cited 2020 Mar 28];10:1033-9. Available from: http://www.cancerjournal.net/text.asp?2014/10/4/1033/137966


 > Introduction Top


Cancer chemoprevention can be defined as the prevention, inhibition or reversal of carcinogenesis by administration of one or more chemical entities, either as individual drugs or as naturally occurring constituents of the diet. [1],[2] Lung cancer is a major cause of morbidity and mortality worldwide in both men and women, accounting for 29% of all types of cancer. The incidence of lung cancer still remains very high. Tobacco smoke contains over 60 established carcinogens. Among the constituents of smoke, polycyclic aromatic hydrocarbons (PAHs) such as benzo (a) pyrene, play a major role in lung carcinogenesis. [3] Plants, vegetables, herbs, and spices used in folk and traditional medicine have been accepted currently as one of the main sources of cancer chemopreventive agents. [4] Polyphenols are dietary compounds largely present in the human diet, found in fruits, vegetables, tea, wine, and so on. [5] Epidemiological studies have shown that there is an inverse relationship between the intake of fruits and vegetables and the incidence of cancer. Several antioxidants and several phenolic compounds are now being therapeutically used as antioxidants. There is an increased interest in the pharmacological activity of natural polyphenols, with respect to their efficacy against oxidative stress. Polyphenols reduce oxidative stress by preferentially neutralizing the reactive free radicals, as their reaction with several damaging free radicals produces radicals that are less reactive toward biomolecules. [6],[7],[8],[9]

Mangiferin, chemically termed as 1, 3, 6, 7-tetrahydroxyxanthone-C2-β-D glucoside (C-glycosylxanthone), is a naturally occurring polyphenol. It is widely distributed in plants of the Anacardiaceae and Gentianaceae families (e.g. Mangiferaindica, mango), especially in the fruit, leaves, bark, and bark root. [10] In the Philippines, mango leaves are used in the preparation of a tea; and the juice of the leaf is considered to be useful against bleeding dysentery. [11]

In Cuba, an extract of this plant is produced on an industrial scale, for use as a nutritional supplement, cosmetic, and phytomedicine. [12] The bark and seeds also act as astringents. [13] In the traditional Indian system of medicine, mangiferin is also used for the treatment of melancholia and nervous debility. [14] Furthermore, one of the traditional Chinese medicines, sann-joongkuey-jian-tang, also includes mangiferin. [15] Mangiferin is also reported to possess antitumor, antiviral, antidiabetic, anti- bone resorption, immunological modulator, and antioxidant activities. [16],[17] Of late, Leiro et al. (2003), has reported that mangiferin inhibits the expression of iNOS and TNF-a genes and has a therapeutic potential in the treatment of inflammatory and neurodegenerative disorders. [18] In the present study we examined the effect of mangiferin in both the pre-initiation and post-initiation periods, in B(a)P-induced lung carcinogenesis.


 > Materials and methods Top


Chemicals

Benzo(a)Pyrene, bovine serum albumin, and mangiferin were purchased from the Sigma Chemical Company, USA. All other chemicals used were of analytical grade.

Animals

Male Swiss albino mice (7-8 weeks old) weighing about 23-26 g were purchased from the King Institute of Preventive Medicine, Chennai, India. The animals were housed under standard conditions of humidity, temperature (25 ± 2°C), and light (12-hour light/12-hour dark cycle). They were fed the standard rat pellet diet and had free access to water.

Experimental design

The animals were divided into five groups, each consisting of six animals. Group I served as the control and these animals received corn oil as the vehicle. Group II animals were treated with benzo(a)pyrene (50 mg/kg b.wt, given orally twice a week, for four consecutive weeks, from the second to sixth week). Group III animals were subjected to pre-initiation treatment with mangiferin (100 mg/kg b.wt, dissolved in corn oil, given orally) from the first week to the eighteenth week, twice a week. B(a)P was administered to these animals simultaneously from the second week to sixth week for the induction of lung cancer. Group IV animals were treated post-initiation with mangiferin (100 mg/kg b.wt, dissolved in corn oil) starting from the twelfth week of the experiment (B(a)P was given as in group II) up to the end of the experimental period. Group V animals were treated with mangiferin alone (as above) for 18 weeks.

At the end of the experimental period, the animals were killed. Blood, as well as lung and liver tissues were collected and the tissues were immediately weighed and then homogenized in Tris-HCl buffer 0.1 M (pH 7.4). Analysis of the total protein in the serum and tissue homogenates was conducted by the method of Lowry et al. (1951). [19]

Biochemical assays

The aryl hydrocarbon hydroxylase (AHH) assay was modified from the method of Mildred et al.(1981). [20] The enzyme activity was expressed as the amount of phenolic metabolite formed/minute/milligram of protein. The activity of γ-glutamyltranspeptidase (γ-GT) was estimated according to the method of Rosalki and Rao (1972). [21] The amount of p-nitroaniline in the supernatant was measured at 410 nm. The activity of γ-GT was expressed as μmoles of p-nitroaniline formed/minute/milligram of protein. 5'Nucleotidase (5'-ND) was assayed by the method of Luly et al. (1972). [22] The enzyme activity was expressed as nmoles of inorganic phosphorus liberated/minute/milligram protein. The activity of lactate dehydrogenase (LDH) was assayed by the method of King (1965), with the activity expressed as μmoles of pyruvate liberated/minute/milligram of protein. [23] Adenosine deaminase (ADA) was assayed by the method of Baggott (1986). [24]

Serum aspartate and alanine transaminase (AST and ALT) activitieswere estimated by the method of King (1965). [23] Alkaline phosphatase (ALP) activity was assayed by the method of King (1965), using disodium phenyl phosphate as the substrate. [25] The enzyme activity was expressed as mmoles of phenol liberated/(min/mg/protein). [25] β-Glucuronidase was assayed by the method of Kawai and Anno (1971). [26] The substrate for the enzyme reaction was p-nitrophenyl β -d-glucuronide and the enzyme activity was assessed in terms of mmoles of nitrophenol liberated/(hour/mg/protein). N-Acetyl glucosaminidase activity was assessed by the method of Marhun (1976), using 4-nitrophenyl-N-acetyl glucosaminide as the substrate; and its activity was expressed as mmoles of p-nitrophenol formed/(h/mg/protein). [27] The activity of β-galactosidase was assessed by the method of Rosenblit (1974), with 4-nitrophenyl-N-acetyl galactopyranoside as the substrate; and its activity was expressed as mmoles of p-nitrophenol liberated/(h/mg/protein). [28]

Statistical analysis

For statistical analysis, one-way analysis of variance (ANOVA) was used, followed by the Newman-Keuls multiple comparison test. Differences with P < 0.001, P < 0.01, and P < 0.05 were considered statistically significant.


 > Results Top


[Figure 1] depicts the activities of xenobiotic and liver marker enzymes (AHH, LDH, γ-GT, 5ͲNucleotidase) in the lung and serum samples from the control and experimental animals. These activities were significantly (P < 0.001) increased in the cancer-bearing Group II animals when compared to those from the Group I control animals. These increased enzyme activities were decreased significantly (P < 0.001) in Group III (pre-initiation) and Group IV (post-initiation; (P < 0.001, P < 0.01, and P < 0.05) mangiferin-treated animals, when compared to those in the Group II lung carcinoma-bearing animals. The mangiferin treatment in Group III and Group IV mice caused reversion of these activities to nearly normal, but this reversal in Group III animals was more effective than that in group IV ones. There seemed to be no significant difference between the animals treated with mangiferin alone (Group V) and the control (Group I) animals.
Figure 1: Effect of mangiferin on the levels of serum and lung xenobiotic and liver marker enzymes in control and experimental animals. Each value is expressed as the mean ± SD for six mice in each group. AHH-ƒÊmoles of fluorescent phenolic metabolites formed/minute/mg/protein; LDH-μmoles of pyruvate liberated/minute/mg/protein; γ-GT nmoles of p-nitroaniline formed/minute/mg/protein; 5'nucleotidase-nmoles of Pi liberated/minute/mg/protein. Group I: Control animals; Group II: Cancer-bearing animals; Group III: Mangiferin pre-initiation, B(a)p-treated; Group IV: Mangiferin post-initiation, B(a) p-treated; and Group V: Treated with mangiferin alone. Statistical significance: *P < 0.001, #P < 0.01, @P < 0.05 and NS ot significant. (a) As compared with Group ; (b) As compared with Group I; (c) as compared with Group II

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[Figure 2] shows the activity of adenosine deaminase (ADA) in the serum, lung, and liver samples of the control and experimental animals. There was an increase in the level of this enzyme in Group II (P < 0.001) B (a) P-treated animals, as compared to its level in the Group I control animals. This increase was significantly decreased in Group III (P < 0.001) and Group IV (P < 0.01 and P < 0.05) mangiferin-treated animals, when compared with its value in Group II B(a)P-treated animals. Group V showed no significant difference in the activityof this marker enzyme when compared with the Group I control animals.
Figure 2: Effect of mangiferin on the activities of ADA in serum, lung, and liver of control and experimental animals. Each value is expressed as the mean ± SD for six mice in each group. Groups are defined in the legend of Figure 1. Statistical significance: *P < 0.001, #P < 0.01, @P < 0.05 and NS ot significant. (a) As compared with Group I; (b) As compared with Group II; (c) As comparedwith Group III

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[Table 1] shows the effect of mangiferin on the activities of xenobiotic and liver marker enzymes (AHH, LDH, γ- GT, and 5'nucleotidase) in the livers of the control and experimental animals. The levels of these enzymes in Group II animals were significantly increased (P < 0.001) when compared to those for the Group I control animals. This increase was significantly decreased in the Group III (P < 0.001) and group IV (P < 0.001 and P < 0.05) mangiferin-treated animals. Group V mice showed that there was no significant difference in the activities of the xenobiotic and liver marker enzymes between Group V and Group I animals.
Table 1: Effect of mangiferin on the activities of xenobiotic and liver dysfunction marker enzymes in the liver of the control and experimental animals

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[Figure 3] shows that the activities of aspartate, alanine transaminases, and alkaline phosphatase were significantly higher in the serum, lungs, and livers of B(a)P-treated mice than in those in the control animals, and lower in the animals treated with B(a)P as well as mangiferin, when compared with the values for the B(a)P-treated animals. The animals treated with mangiferin alone showed no significant change.
Figure 3: Effect of mangiferin on transaminaseactivities in the serum, lung, and liver of control and experimental animals. Each value is expressed as mean ± SD 6mice in each group. Statistical significance: *P < 0.001, #P < 0.01, @P < 0.05 and NS ot significant. (a) As compared with Group I; (b) As compared with Group II; (c) As comparedwith Group III. Groups are defined in the legend of [Figure 1]

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In the B(a)P-treated animals, the activities of acidphosphatase, β-glucuronidase, N-acetyl glucosaminidase, and β-galactosidase were significantly higher than those of the control animals. The administration of mangiferin to B(a)P-treated mice considerably and significantly reversed the above changes to the normal levels. The mangiferin pre-initiation Group III showed greater restoration than the post-initiation Group IV. However, there was no significant difference between Group V and Group I.

[Figure 4] shows the histological analysis of the lung section of the control and experimental groups. Lungs from the control (Group I) animals revealed normal architecture cells with small uniform nuclei [Figure 4]a. Lung cancer-bearing animals (Group II) revealed a loss of architecture and alveolar damage, as seen from hyperchromatic and irregular nuclei in the cells of the alveolar wall [Figure 4]b. Cancer-bearing animals pre-treated with mangiferin (Group III) exhibited reduced alveolar damage with near-normal architecture [Figure 4]c. Group IV animals post-treated with mangiferin showed slightly reduced alveolar damage [Figure 4]d. Those treated with mangiferin alone showed no appreciable change from the control animals in the histopathological abnormalities [Figure 4]e.
Figure 4: Histopathological studies of the lung viewed under a light microscope in the control and experimental animals. (a) Control animals showing normal architecture (H and E, ×40). (b) Benzo (a) pyrene-treated animals showing alveolar damage, as seen by the increased number of hyperchromatic, irregular nuclei in the cells of the alveolar wall (H and E, ×40). (c) Mangiferin pre-treated animals showing reduced alveolar damage, as evident from the reduced number of hyperchromatic irregular cells in the alveolar wall (H and E, ×40). (d) Mangiferin post-treated animals showing slightly reduced alveolar damage (H and E, ×40). (e) Animals treated with nangiferin alone showing normal architecture, similar to that of control animals (H and E, ×40)

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 > Discussion Top


Polyphenol derivatives, including mangiferin, are present in commonly used folk medicinal preparations around the world. However, little is known about their mechanisms of action or even their toxicological properties. Mangiferin is a polyphenal that consists of glucose as C-glucosylxanthone. Some xanthone derivatives are mutagenic in Salmonella typhimurium TA100 and TA98, but mangiferin is non-mutagenic. Mangiferin is also used in traditional alternative medicine, but its mechanism of action is unclear. Bhattacharya et al. (1972), has reported that the effect of this compound on the central nervous system is related to its ability to inhibit monoamine oxidase activity. [14] Mangiferin also has anti-viral effects on herpes simplex and anti-oxidant action. [1],[2],[3],[4],[5],[6] In addition, mangiferin activates lymphocytes in tumor-bearing mice, and inhibits the growth of ascetic fibrosarcomas in Swiss mice. It also enhances the cytotoxicity of lymphocytes and macrophages against tumor cells and antagonizes the cytopathic effect of human immunodeficiency virus (HIV) in vitro. These activities are somewhat similar to those of other chemopreventive agents such as 10-acetoxychavicol acetate. [1],[2],[3],[4],[5],[6],[7],[8],[9] In the present study, the Group II B(a)P-treated animals have shown a sharp drop in their body weight. This drop may have been due to cancer cachexia. Cancer cachexia results in progressive loss of body weight, which is mainly due to wasting of the host body compartments such as the skeletal muscle and adipose tissue. Weight loss and tissue wasting are observed in cancer patients, which are signs that imply poor prognosis and shorter survival time. [29] Pain et al. (1984), have attributed the drop in body weight to lower food intake and/or absorption, which contribute to muscle wasting in tumor cachexia. [30] As regards the drug treatment (Group III and Group IV), the gradual increase in body weight indicates the antineoplastic property of the drug. The drug control (Group V) animals did not show any significant variations in the parameters tested, thus inferring its non-toxic nature. Analysis of the tumor xenobiotic and liver marker enzymes is an indicator of the cancer response to therapy. Changes in many biochemical, immunological, and molecular properties of the host have been observed in B(a)P-mediated cancers. [31] Marker enzymes such as AHH, γ-GT, 5'ND, LDH, and ADA are specific indicators of liver and lung damage. [32],[33] Chen and Liu (2000), reported that AHH is one of the useful biomarkers for the early diagnosis of lung cancer. [34] This enzyme is responsible for the activation of B(a)P and other PAHs in cigarette smoke, leading to carcinogenesis. [35] The AHH activity is increased in lung cancer-bearing animals. This elevation is found to be significantly inhibited upon mangiferin supplementation, during either the pre-initiation or post-initiation period. γ -GT activity serves as a specific marker for the prognosis of carcinogenic events. γ -GT is not only useful for diagnosis, but also has an extrapolative value in malignancies such as lung cancer and malignant melanoma. An increased level of γ -GT is observed in cancer cells and this elevation may indicate the basic tumor burden. [36] A decreased level of γ -GT is observed in mangiferin-treated animals, when compared with the level in lung cancer-bearing animals without this treatment, thus indicating a decreased tumor burden in the mangiferin- treated animals. Increased activity of 5'ND seems to originate from proliferating tumor cells, and the fast-moving 5'-nucleotide phosphodiesterase is known to be elevated in tumor cells metastasizing from the lung or breast to the liver. [37],[38] In the present study, an elevated activity of 5'ND was observed in the cancer-bearing animals; and on administration of mangiferin, the activity of 5'ND was brought down to near-normal values, indicating its anti-tumor and/or anti-proliferative effect on lung cancer. Lactate dehydrogenase (LDH) is recognized as a potential tumor marker enzyme for assessing the proliferation of malignant cells. LDH is a fairly sensitive marker for solid neoplasms and an elevated activity of this enzyme has been reported in the serum of lung cancer patients. [39] A possible reason for the elevated levels of LDH may be the higher rate of glycolysis under cancerous conditions, as glycolysis is the only energy-producing pathway for uncontrolled proliferating malignant cells. [40] The presently observed decrease in LDH activity, on treatment with Mangiferin, may have protected against abnormal cell growth, by changing the permeability of the plasma membrane or by affecting cellular growth. The increase in ADA activity in the cancer-bearing mice may have been a compensatory mechanism against the accumulation of toxic substrates due to accelerated purine and pyrimidine metabolism in the cancerous tissues and cells. [41] It has been reported that patients with lung cancer have elevated serum ADA levels. [24] In the present study, increased ADA activity has been observed in the lung cancer-bearing animals. Upon mangiferin treatment, the activity of this enzyme was brought back to near normalcy, thus highlighting the antiproliferative/antitumour property of mangiferin. B(a)P undergoes metabolic activation by cytochrome P450 enzymes to become reactive electrophiles that are cytotoxic, mutagenic, and carcinogenic. [42] Serum transaminases are sensitive indicators of hepatic injury. Several reports have shown an increase in the activities of AST and ALT during B(a)P-induced lung carcinogenesis. [43] The elevated activities of serum AST and ALT observed in the B(a)P-treated mice may have been due to B(a)P-induced hepatic damage and subsequent leakage of these enzymes into the circulation. It has been reported that B(a)P is transported through the blood and causes hepatic injury. [44] Administration of mangiferin restores the activities of these enzymes to near normal values, which may be attributed to the chemoprotective role of mangiferin. Lysosomal enzymes are the main factors playing a vital role in tissue injury and repair, inflammation, and phagocytosis; and they participate in pathological processes such as cancer inflammation, degeneration, and rheumatoid arthritis. [45] Changes in lysosomal enzyme activities may result in impaired phagocytic and endocytic activities and in inadequate extracellular matrix turnover and remodeling. These impairments suggest that lysosomal enzyme activities may be involved in the pathogenesis of autoimmune diseases. [46] It is further postulated that lysosomal enzymes are released in inflammatory diseases to stimulate the synthesis of prostaglandins. [47] In this study, the activities of lysosomal enzymes in the plasma, lungs, and liver of B(a)P-treated mice were elevated compared to those in the control group. Mangiferin-induced reduction in the release of lysosomal enzymes proves its beneficial action and indirectly confirms the protective effect of the drug.


 > Conclusions Top


In conclusion, mangiferin showed potential as a chemopreventive agent. Our findings suggested that mangiferin exerted a strong anti-cancer effect. The possible mechanism of mangiferin, especially in relation to the antioxidant property is inhibition of free radical formation and reduced cancer incidence. It was found in the present study that mangiferin was more effective in the initiation-treated group (Group III) than the post-initiation treated group (Group IV). This may be due to the inhibitory action of mangiferin on initiation of the B(a)P activation/detoxification process. In the present study, the mechanism of action of mangiferin in preventing lung cancer is not known. However, further pharmacological investigations at the molecular level are underway to establish the mechanism of action of this drug.

 
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