Suppression of colorectal carcinogenesis by naringin

Abstract

Background

Colorectal cancer is the third most malignant cancer worldwide. Despite novel treatment options, the incidence and mortality rates 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 lacking physical activity. Vegetables and fruits contain high amounts of secondary metabolites, which might reduce the risk for colorectal carcinogenesis. Flavonoids are important bioactive polyphenolic compounds. There are more than 4,000 different flavonoids, including flavanones, flavonoids, isoflavonoids, flavones, and catechins in a large variety of plant.

Hypothesis

Among various other flavonoids, naringin in Citrus fruits has been a subject of intense scrutiny for its activity against many types of cancer, including colorectal cancer. We hypothesize that naringin is capable to inhibit the growth of transformed colonocytes and to induce programmed cell death in colon cancer cells.

Results

We comprehensively review the inhibitory effects of naringin on colorectal cancers and address the underlying mechanistic pathways such as NF-κB/IL-6/STAT3, PI3K/AKT/mTOR, apoptosis, NF-κB-COX-2-iNOS, and β-catenin pathways.

Conclusion

Naringin suppresses colorectal inflammation and carcinogenesis by various signaling pathways. Randomized clinical trials are needed to determine their effectiveness in combating colorectal cancer.

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).