Farnesol attenuates 1,2-dimethylhydrazine induced oxidative stress, inflammation and apoptotic responses in the colon of Wistar rats
Introduction
Colon cancer is the major health hazard related with high mortality and it is the second most common cause of cancer-related death [1]. Colon carcinogenesis is a multistep process and is thought to arise by the accretion of genetic alterations involving a variety of oncogenes and tumor suppressor genes that transform normal colonic epithelium into an invasive carcinoma [2]. Colon cancer is frequently a pathological consequence of persistent oxidative stress and inflammation [3], [4]. Oxidative stress is a state which occurs when the balance between the productions of reactive oxygen species (ROS) overcomes the endogenous antioxidant defense system and inflammation is a complex biological response of tissues to pathogens and damaged cells [5].
Several epidemiological studies suggest that diet is considered as one of the major factor associated with increased risk for colon cancer incidence and mortality [6], [7], [8]. Many experimental animal models have supported the idea that high fat diet augments the incidence of colon carcinogenesis [9], [10], [11] whereas low fat and high fiber (present in fruits and vegetables) diet, decreases the risk of colon cancer [12]. Many natural products present in the high fiber diets have been reported to possess chemopreventive properties against cancer [13]. Therefore, chemoprevention is a logical and current strategy to reduce the mortality from colon cancer because numerous chemopreventive agents are present in the diet [14].
Farnesol is a 15-carbon naturally occurring sesquiterpene and it may be endogenously generated in the cells by enzymatic dephosphorylation of farnesyl pyrophosphate, a metabolic precursor of squalene yielding sterols and other isoprenoid compounds [15], [16]. Dietary sources of farnesol are the plant products [17] including fruits and berries such as apricots, peaches, plums, blueberries, cranberries, raspberries and strawberries, vegetables such as tomatoes [18], herbs such as lemon grass and chamomile [19] and it is also obtained from the essential oils of ambrette seeds, and citronella [20]. Studies from our laboratory have revealed that farnesol is a potent antioxidant and protects the kidneys and lungs against oxidative damage induced by Ferric-Nitrilo Tri Acetate (Fe-NTA) and Cigarrette Smoke Extract (CSE), respectively [21], [22]. Previous studies also have been shown that farnesol exhibits significant anti-tumor and anti-carcinogenesis effects in vivo that might be due to the inhibition of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase [23], [24], [25], [26], [27]. Thus farnesol results in the inhibition of cholesterol formation due to HMG CoA reductase inhibition and may alter the cell/mitochondrial membrane integrity thereby leads to the apoptosis favorably in tumor cells as compared to normal cells [26], [28], [29], [30], [31]. Tumor cells are highly proliferating cells requiring high levels of cholesterol to maintain the cell/mitochondrial membrane integrity [25], [26]. Apoptosis, is one of the forms of programmed cell death, characterized by chromatin condensation, nuclear fragmentation, membrane blebbing, cytoskeletal rearrangement and cell shrinkage. It is involved in many physiological and pathological processes and helps to regulate tissue homeostasis by eliminating potentially deleterious cells [32]. Oxidative stress is known to be involved in the induction of apoptosis and antioxidants have been reported to diminish the extent of apoptotic tissue damages [33], [34].
1,2-Dimethylhydrazine (DMH) is a colon specific carcinogen and it has been widely used to induce colon cancer in rodents [35]. DMH undergoes metabolism mainly in the liver and to some extent also in the colon and the ultimate metabolite thus formed in the liver is delivered to the colon via, blood or bile, as glucoronide conjugates [36], [37]. In vivo transformation of DMH results in the formation of azomethane and N-oxidation of azomethane leads to the formation of azoxymethane. Further, hydroxylation of azoxymethane leads to the formation of methyazoxymethanol which is an unstable compound and readily yields highly reactive electrophilic methyldiazonium ion. The latter leads to the formation of methyl free radicals and DMH also generates hydroxyl radical or hydrogen peroxide in the presence of metal ion which are known to elicit oxidative stress due to imbalance between the production of ROS and endogenous antioxidants [38], [39]. It has been reported earlier that these ROS are mainly responsible for the damaging effects of the DMH in colonic tissue [38]. DMH also causes covalent modification of DNA by 8-hydroxy-2′-deoxyguanosine (8-OHdG) adduct formation which is a marker of oxidative DNA damage [40] and it has been well accepted that oxidative DNA damage plays an important role in carcinogenesis [41], [42]. DMH-induced colon tumorigenesis reflects many of the same cell kinetic and similar molecular and histopathological alterations to the sporadic colon tumors of humans [43], [44], [45], [46].
The present study was intended to explore the anticipatory effects of farnesol against DMH induced oxidative stress, inflammation and apoptotic responses in the colon of Wistar rats.
Section snippets
Chemicals
Reduced glutathione (GSH), oxidized glutathione (GSSG), nicotinamide adenine dinucleotide phosphate reduced (NADPH), flavin adenine dinucleotide (FAD), ethylene diamine tetra acetic acid (EDTA), nicotinamide adenine dinucleotide reduced (NADH), thiobarbituric acid (TBA), trichloroacetic acid (TCA), bovine serum albumin (BSA), 5,5’-dithiobis-(2-nitrobenzoic acid) (DTNB), 1-chloro-2,4-dinitrobenzene (CDNB), 1,2-dimethylhydrazine (DMH), glutathione reductase were obtained from Sigma (Sigma
Effect of prophylactic treatment of farnesol on the activities of glutathione dependent enzymes in colonic tissue
The activities of GPx, GR and GST decreased significantly (p < 0.001) in Group II as compared to Group I. Farnesol pretreatment at the dose of 50 mg/kg body weight significantly increased the activities of GPx (p < 0.01), GST (p < 0.001), and GR (p < 0.01) in Group III as compared to Group II. Higher dose of farnesol (100 mg/kg body weight) also showed significant increase in the activities of GPx (p < 0.001), GST (p < 0.001), and GR (p < 0.01) in Group IV as compared to Group II. However, the activities of
Discussion
A current upsurge in classifying natural products as cancer chemopreventive agents is gaining much attention of many investigators because natural products like fruits, vegetables, medicinal plants, and herbs have many pharmacological properties and have potential to fight against numerous human diseases associated with oxidative stress. Several natural compounds of dietary sources have been reported to inhibit various diseases including cancer [57], [58] and farnesol is one of them, belongs to
Conclusion
The precise mechanism of chemopreventive action of farnesol against colon carcinogenesis remains to be elucidated but the plausible mechanism of the protection of farnesol may be through the induction of the antioxidant enzymes. From the findings of the current study it can be concluded that farnesol supplementation effectively suppressed the initial phases of colon carcinogenesis probably by reducing the oxidative damage, inflammatory and apoptotic responses induced by DMH in rats. The results
Conflict of interest statement
None declared.
Acknowledgment
We are thankful to the University Grants Commission (UGC) Government of India for the financial support to the first author.
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