Suppression of colorectal carcinogenesis by naringin
Graphical abstract
Introduction
Colorectal cancer appears in the large intestine and mostly affects older adults. It occurs as small, benign clumps of cells (polyps) inside the colon, which subsequently becomes malignant (Memariani et al., 2020). Colorectal cancer is considered as the third most malignant neoplasm in the world (Shike et al., 1990). Despite advancements in therapy, the survival rates of colorectal cancer patients did not significantly improve during the past years (Mbah et al., 2020). The mortality rate and incidence of colon cancer continue to increase in most countries, especially in US, European and Asian countries. Colorectal carcinogenesis is multifactorial, including dietary and genetic factors as well as a lack of physical activity (Center et al., 2009). Preventive measures are the best means for the reduction of mortality rates related to colorectal cancer. Excessive amounts of fat and calories are promoters, while high intake of fibers, calcium and micronutrients are suppressants of colorectal carcinogenesis (West and Cairns 1980; Slattery et al., 1988). Dietary modifications decrease the mortality rates of non-hereditary colorectal cancer (Vargas and Alberts 1992). Natural bioactive substances with diverse chemical structures such as phenolic acid containing flavonoids (Sanatkar et al., 2021), and sesquiterpenes including galbanic acid (Sajjadi et al., 2019) now have fundamental potential to influence various types of cancer. Different phytochemicals such as auraptene (Charmforoshan et al., 2021), apigenin (Madunić et al., 2018), genistein, and ferutinin (Naji Reyhani Garmroudi et al., 2021), showed remarkable activity against cancer cells, lipid peroxidation, and bacterial infections . Vegetables and fruits contain high amounts of fibers and several other compounds, which reduce the risk of colorectal carcinogenesis (Fig. 1). High intake of these foods effectively decreased the development of colonic lesions (Espín et al., 2007). The dietary intake of flavonoids such as for prevention, treatment and control of carcinogenesis remains controversial, because of the complex and not fully understood metabolism of flavonoids in the human body (Spilsbury et al., 2012). Flavonoids are important bioactive polyphenolic compounds (Khan et al., 2012). They consist of a chemical scaffold containing 15 carbons with three rings, two of which are benzene rings connected by a three carbon chain (Croft 1998). There are more than 4000 different flavonoids, including flavanones, flavonoids, isoflavonoids, flavones, and catechins in a large variety of plants (Ueng et al., 1999; Ghasemzadeh and Jaafar 2013). Flavonoids are important constituents of the human diet. Typical dietary sources for flavonoids are coffee, tea, juices, cocoa-derived products, fruits, vegetables, and wine (Kris-Etherton et al., 2002; Macready et al., 2014). The amount of flavonoids present in daily diet is approximately 1 g (Di Carlo et al. 1999). In recent years, the interest in bioactive plant compounds has increased due to reported health benefits, including cardioprotective (Cook and Samman 1996), antioxidant (Asgary et al., 1999), anti-hyperglycemic (Rauter et al., 2010), analgesic (Picq et al., 1991), and other pharmacological effects (Gorinstein et al., 2005). Several biologically active flavonoids such as chrysin in nanoliposomes improved antioxidant mineral deposition in the liver (Beyrami et al., 2020). Apigenin-based silver nanoparticles have been suggested as anticancer agent (Zarei et al., 2021).
Various flavonoids, such as naringin, naringenin, catechins, procyanidines, flavonones, flavones, flavonols, isoflavonones, myricetin revealed cytotoxic activity towards cancer cells (Moon et al., 2006; Theodoratou et al., 2007; Pierini et al., 2008). Flavones effectively inhibited growth of transformed colonocytes and induced programmed cell death and differentiation in HT-29 colon cancer cells (Wenzel et al., 2000). The isoflavone genistein encapsulated in chitosan significantly stopped the growth and proliferation of colorectal cancer cells (Rahmani et al., 2020).
The chemical designation of naringin is 4, 5, 7-trihydroxy flavonone 7-rhamnogluco-side (Viswanatha et al., 2017) (Fig. 2). Its molecular sum formula is C27H32O14 and has a molecular weight of 580.4 g/mol. Naringin is a biflavone glycoside discovered in 1857 by De Vry in grape fruit flowers from Java, although De Vry did not published his research work at that time (Rangaswami et al., 1939). The word naringin is likely derived from the Sanskrit language, where narangi means “orange” (Sinclair 1972). The compound is extremely bitter (Braverman 1949) unless converted to 1,3-diphenylpropan-1-one by treatment with a strong base, such as potassium hydroxide, which is approximately 300–1800 times sweeter than sugar with a refreshing taste of menthol (Tomasik 2003). The antioxidant potential of Orange juices appears to be mostly determined by the concentration of anthocyanin in orange juices, because of their overall phenol levels and ability to interact with the biomembrane (Karimi et al., 2012). Naringin is the major component responsible for the bitter taste of grapefruit. Naringin and hesperidin are both flavanone rhamnosyl glucosides with several common features in their structures (Horowitz and Gentili 1969). Naringin is moderately soluble in water and present in the form of chiral isomers, which vary in their amount dependent on the fruit maturity and purification methods (Wilcox et al., 1999).
Section snippets
Botanical sources of naringin
Naringin has been isolated from different plant families and genera (Table 1). Naringin was detected by UPLC-MS/MS in high amount in branches and leaves of Carissa carandas (El-Desoky et al., 2018). Naringin is predominantly found in the juice of grapefruit (Citrus paradisi) (Jourdan et al., 1985) and orange (Citrus sinensis) (Kuhnau 1976). Naringin is also present in other Citrus plants such as C. nobilis, C. junos, C. unshiu, C. tachibana (Guadagni et al., 1973), Artemisia stolonifera,
Therapeutic potential of naringin
Naringin reduced inflammation (Manthey et al., 2001; Chen et al., 2011) as determined by the expression of inflammatory signaling factors such as inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), interleukin-8 (IL-8), TNF-α, nuclear factor erythroid 2-related factor 2 (NRF2) (Habauzit et al., 2011). In chronic bronchitis induced in guinea pigs, naringin decreased the concentrations of leukotriene B4 and IL-8, myeloperoxidase activity in BALF (bronchoalveolar lavage fluid) and lung
Metabolism and absorption of naringin
Naringin is hydrolyzed in the large intestine into six glycosides, and small amounts of naringenin are metabolized by bacterial enzymes (Kuntz et al., 1999; Shimoda et al., 2010). Upon oral administration, naringin is rapidly absorbed into the blood with two peak concentrations at 15 min and 3 h. Naringin could not be detected 480 min after dosing (Li et al., 2013). After administration of naringin (600 and 1000 mg/kg) through a duodenal cannula, its average Cmax in portal plasma was reached
Acute toxicity studies of naringin
Several toxicity studies showed that naringin is relatively nontoxic and safe (Additives and Feed 2011). Various marketed dietary products recommended a daily intake of 200–1000 mg naringin (Jung et al., 2003). The maximum orally tolerated dose in rats was 16 mg/kg naringin without any harmful effects (Li et al., 2013). Chronic and sub-chronic toxicity studies for 24 and 13 weeks, respectively, demonstrated that doses up to 1250 mg/kg did not cause organ toxicity, but decreased body weight and
Anticancer activity of naringin
Several biologically active polyphenols including flavonoids have proven anticarcinogenic activity (Moon et al., 2006). Naringin has been studied in various types of cancer cells. So and colleaguesstudied naringin along with other flavonoids in human MDA-MB-435 breast carcinoma cells and rodent DMBA-induced mammary tumors. Naringin inhibited the proliferation of both these cells types (So et al., 1996). Froufe and coworkers reported the inhibition of estrone sulfatase by naringin in silico and
Naringin in colorectal cancer
Recent publications with well-designed experimental in vivo protocols demonstrated the protective effect of vegetables and fruits against colorectal carcinogenesis (Vanamala et al., 2006). Scalbert and Williamson calculated that 1250 ml grapefruit and orange juices contain 690 mg Naringin (Scalbert and Williamson 2000). Naringin and its secondary metabolite naringenin (a glucuronide and sulfated form of Naringin) were found in blood and urine of rats upon oral application. Furthermore,
Mechanisms of chemoprevention in colorectal cancer
Polyphenols emerged as promising chemopreventive agents for colorectal cancer because of their ability to target various molecular pathways such as metastasis, angiogenesis, apoptosis, proliferation and inflammatory cytokines (Ramos 2008).
Conclusion
Naringin is one of the most prevalent flavonoids in Citrus species. Naringin has shown profound efficacy against several cancers and including colorectal cancer. Naringin suppressed several cellular pathways involved in colorectal carcinogenesis. Furthermore, Naringin reduced the toxicity if combined along with other therapeutic agents. Hence, it may be considered as a safe agent against colorectal cancer. On the basis of the current data available for Naringin, it is worthwhile to conduct both
CRediT author statement
Bushra Ansari and Yaseen Hussain collected the literature, wrote the paper draft and drew the figures.
Haroon Khan supervised the project and designed the concept of this paper.
Thomas Efferth and Michael Aschner corrected and finalized the writing of the paper.
All data were generated in-house, and no paper mill was used. All authors agree to be accountable for all aspects of work ensuring integrity and accuracy.
Declaration of Competing Interest
The authors declare that there is no conflict of interest.
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