The Role of Micrornas in the Chemopreventive Activity of Sulforaphane from Cruciferous Vegetables
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nutrients Review The Role of MicroRNAs in the Chemopreventive Activity of Sulforaphane from Cruciferous Vegetables Christopher Dacosta and Yongping Bao * ID Norwich Medical School, University of East Anglia, Norwich NR4 7UQ, UK; [email protected] * Correspondence: [email protected]; Tel.: +44-1603-591778 Received: 13 July 2017; Accepted: 15 August 2017; Published: 19 August 2017 Abstract: Colorectal cancer is an increasingly significant cause of mortality whose risk is linked to diet and inversely correlated with cruciferous vegetable consumption. This is likely to be partly attributable to the isothiocyanates derived from eating these vegetables, such as sulforaphane, which is extensively characterised for cytoprotective and tumour-suppressing activities. However, its bioactivities are likely to extend in complexity beyond those currently known; further insight into these bioactivities could aid the development of sulforaphane-based chemopreventive or chemotherapeutic strategies. Evidence suggests that sulforaphane modulates the expression of microRNAs, many of which are known to regulate genes involved at various stages of colorectal carcinogenesis. Based upon existing knowledge, there exist many plausible mechanisms by which sulforaphane may regulate microRNAs. Thus, there is a strong case for the further investigation of the roles of microRNAs in the anti-cancer effects of sulforaphane. There are several different types of approach to the wide-scale profiling of microRNA differential expression. Array-based methods may involve the use of RT-qPCR or complementary hybridisation probe chips, and tend to be relatively fast and economical. Cloning and deep sequencing approaches are more expensive and labour-intensive, but are worth considering where viable, for their greater sensitivity and ability to detect novel microRNAs. Keywords: broccoli; cancer; cruciferous vegetable; microRNA; sulforaphane; isothiocyanate 1. Colorectal Cancer Colorectal cancer is a major and increasingly common cause of morbidity and premature death. Its global incidence was 1.4 million in 2012, according to the World Health Organization, and is rising, making it the third most commonly diagnosed cancer [1]. In 2015, 774,000 mortalities were directly attributable to colorectal cancer—a figure 58% higher than in 1990 [2]. It is rare for tangible symptoms of colorectal cancer to present until it has already progressed to an advanced (usually terminal) stage, at which currently available treatments are unable to provide a cure [3]. Therefore, strategies for limiting the disease burden from colorectal cancers must include improvements to early-stage diagnosis in asymptomatic individuals, as well as new preventive initiatives. Reported incidence correlates positively with economic development and/or the adoption of “Western” dietary patterns [4]. Increasing rates of chronic diseases such as cancers are inevitable in countries experiencing rising living standards, partly due to reduced rates of premature death from communicable diseases. Economic development also tends to facilitate improvements to public and/or affordable private healthcare, leading to improved diagnosis. Nevertheless, there is compelling evidence to suggest that commonly associated dietary and lifestyle changes have a significant impact upon the development of colorectal cancer [5]. Particularly, one’s risk of developing colorectal cancer is believed to be increased by obesity and a high intake of red meat and/or alcohol and reduced by a fibre-rich diet abundant in fruits and vegetables and a physically active lifestyle, according to Nutrients 2017, 9, 902; doi:10.3390/nu9080902 www.mdpi.com/journal/nutrients Nutrients 2017, 9, 902 2 of 19 guidelines published by Bowel Cancer UK [6]. The apparently strong connections between diet and colorectal cancer risk are unsurprising, given the inevitable exposure of the colorectal tissues to ingested compounds and products of the gut microbiota. The apparently protective effects of diets rich in plant-based foods are believed to be largely attributable to the phytochemicals found in them, many families of which have been studied regarding their direct biological (often cytoprotective) activity—both in vitro and in vivo—since the middle of the twentieth century. Nutrients 2017, 9, 902 2 of 18 2. Cruciferous Vegetables active lifestyle, according to guidelines published by Bowel Cancer UK [6]. The apparently strong Epidemiologicalconnections between studies diet have and colorectal revealed cancer a particular risk are unsurprising, inverse given correlation the inevitable between exposure the intake of of the colorectal tissues to ingested compounds and products of the gut microbiota. The apparently cruciferous vegetablesprotective effects and of colorectaldiets rich in cancerplant‐based risk; foods one are stronger believed to than be largely that attributable between theto the latter and the intake of otherphytochemicals vegetables found [7,8 in]. them, Cruciferous many families vegetables of which referhave been to those studied of regarding the Brassicaceae their direct family and include broccoli,biological cabbage, (often cytoprotective) and Brussel activity sprouts.—both in Particular vitro and in vivo to this—since plant the middle family of the are twentieth glucosinolates—a century. group of compounds endogenously synthesised and derived from glucose and amino acid residues. Upon the rupture2. Cruciferous of plant Vegetables cells—such as occurs from the consumption of the vegetables or from parasitic attack—theEpidemiological glucosinolates studies have are revealed able to a beparticular hydrolysed inverse correlation by endogenous between the myrosinase intake of enzymes. Intact plantcruciferous tissue separates vegetables glucosinolatesand colorectal cancer from risk; one myrosinase stronger than enzymes that between by the compartmentalising latter and the the intake of other vegetables [7,8]. Cruciferous vegetables refer to those of the Brassicaceae family and former in S-cellsinclude [ 9broccoli,] and thecabbage, latter and in Brussel myrosin sprouts. cells Particular [10]. to Only this plant upon family cell are rupture glucosinolates are the—a myrosinase enzymes ablegroup to of hydrolyse compounds the endogenously glucosinolates. synthesised Several and derived types from ofglucose compound and amino areacid potentiallyresidues. formed, including isothiocyanates,Upon the rupture of thiocyanates, plant cells—such and as occurs nitriles from [11 the]. consumption of the vegetables or from parasitic attack—the glucosinolates are able to be hydrolysed by endogenous myrosinase enzymes. Intact plant tissue separates glucosinolates from myrosinase enzymes by compartmentalising the 3. Sulforaphaneformer in S‐cells [9] and the latter in myrosin cells [10]. Only upon cell rupture are the myrosinase enzymes able to hydrolyse the glucosinolates. Several types of compound are potentially formed, Isothiocyanatesincluding isothiocyanates, are to date thiocyanates, the most-studied and nitriles and[11]. best-characterised of known glucosinolate- hydrolysis-derived products in terms of their bioactivity. They are believed to play a defensive role in the3. plants Sulforaphane via their cytotoxic effects on microorganisms and small parasitic animals, but to be directlyIsothiocyanates beneficial are to to date human the most health‐studied and via best broad‐characterised anti-inflammatory of known glucosinolate and‐ antioxidant hydrolysis‐derived products in terms of their bioactivity. They are believed to play a defensive role effects, andin thusthe plants are via able their cytotoxic to help effects inhibit on microorganisms the development and small parasitic of cancers animals, [ 12but], to cardiovascularbe diseases [13],directly and beneficial osteoarthritis to human [ health14,15 via]. broad Broccoli anti‐inflammatory is particularly and antioxidant high in effects, a particular and thus are glucosinolate called glucoraphanin,able to help inhibit whose the development myrosinase-mediated of cancers [12], cardiovascular hydrolysis diseases generates [13], and an osteoarthritis isothiocyanate called [14,15]. Broccoli is particularly high in a particular glucosinolate called glucoraphanin, whose sulforaphanemyrosinase (SFN, 1-isothiocyanato-4-(methylsulfinyl)butane),‐mediated hydrolysis generates an isothiocyanate called the structuresulforaphane of which(SFN, 1 is‐ depicted in Figure1. isothiocyanato‐4‐(methylsulfinyl)butane), the structure of which is depicted in Figure 1. Figure 1. FigureThe molecular1. The molecular structure structure of of 1-isothiocyanato-4-(methylsulfinyl)butane),1‐isothiocyanato‐4‐(methylsulfinyl)butane), also known as also known as sulforaphane.sulforaphane. A multitude of experiments in vitro and in vivo reportedly demonstrate the ability of SFN to A multitudeboth defend of experiments healthy cells againstin vitro chemicaland in and/or vivo radiationreportedly‐induced demonstrate carcinogenesis the [16–18] ability and ofto SFN to both inhibit the proliferation, migration, invasive potential and survival of tumour cells [19–21]. It is likely defend healthy cells against chemical and/or radiation-induced carcinogenesis [16–18] and to inhibit that the former, cytoprotective function of SFN is largely attributable to the induction of nuclear factor the proliferation,(erythroid migration,‐derived 2)‐like invasive 2 (Nrf2), potential resulting from and the survivalseparation of of cytoplasmic tumour Nrf2 cells from