Phytoestrogens for Cancer Prevention and Treatment
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biology Review Phytoestrogens for Cancer Prevention and Treatment Margalida Torrens-Mas 1,2 and Pilar Roca 1,2,3,* 1 Grupo Multidisciplinar de Oncología Traslacional, Institut Universitari d’Investigació en Ciències de la Salut, Universitat de les Illes Balears, 07122 Palma, Spain; [email protected] 2 Instituto de Investigación Sanitaria Illes Balears, 07010 Palma, Spain 3 Ciber Fisiopatología Obesidad y Nutrición (CB06/03), Instituto Salud Carlos III, 28029 Madrid, Spain * Correspondence: [email protected]; Tel.: +34-971-17184 Received: 30 October 2020; Accepted: 25 November 2020; Published: 27 November 2020 Simple Summary: Phytoestrogens are compounds derived from plants that have a similar structure to human sex hormones. This has led to the observation that phytoestrogens have comparable effects to these hormones in our cells. Some beneficial effects of phytoestrogens include the improvement of menopausal symptoms and the prevention of several diseases. In fact, the consumption of soy and soy foods among the Asian population has been associated with a decrease in the incidence of some types of tumors. However, there are some concerns about whether these compounds may also have harmful effects, such as interfere with cancer treatments. In this review, we collect data on the reported effects of phytoestrogens alone or in combination with anti-cancer treatments and discuss the controversy around using these compounds. Abstract: Phytoestrogens are a large group of natural compounds found in more than 300 plants. They have a close structural similarity to estrogens, which allow them to bind to both estrogen receptors (ER), ERα and ERβ, presenting a weak estrogenic activity. Phytoestrogens have been described as antioxidant, anti-inflammatory, anti-thrombotic, anti-allergic, and anti-tumoral agents. Their role in cancer prevention has been well documented, although their impact on treatment efficiency is controversial. Several reports suggest that phytoestrogens may interfere with the effect of anti-cancer drugs through the regulation of oxidative stress and other mechanisms. Furthermore, some phytoestrogens could exert a protective effect on healthy cells, thus reducing the secondary effects of cancer treatment. In this review, we have studied the recent research in this area to find evidence for the role of phytoestrogens in cancer prevention and therapy efficacy. Keywords: phytoestrogens; cancer prevention; cancer treatment; antioxidants 1. Introduction Phytoestrogens are naturally occurring compounds in plants and are characterized by a close structural similarity to estrogens. This allows them to act as weak estrogenic factors and interfere with hormonal signaling. Several reports suggest that phytoestrogens may have a positive effect on the prevention of menopausal symptoms, type 2 diabetes, cardiovascular disease, obesity, and cancer. These health benefits are presumably linked to their anti-inflammatory, anti-tumoral, anti-allergic, antioxidant, anti-thrombotic, and hepatoprotective properties [1]. The interest in phytoestrogens and cancer began after the observation that the consumption of soy and soy-derived foods was correlated with a decreased incidence of breast [2], ovarian [3], and prostate cancer [4]. In fact, the levels of genistein, the main soy isoflavonoid, and other phytoestrogens in plasma are inversely correlated to the risk of developing several types of cancer [5–8]. Phytoestrogens have been extensively tested in vitro and in vivo as anti-cancer treatments, although they have also been studied as adjuvant treatments to improve the response to chemotherapy, Biology 2020, 9, 427; doi:10.3390/biology9120427 www.mdpi.com/journal/biology Biology 2020, 9, 427 2 of 19 Biology 2020, 9, x 2 of 18 hormonotherapy, and radiotherapy. However, some studies alert that phytoestrogen consumption consumption may interfere with cancer treatments and be harmful to patients. In this review, we may interfere with cancer treatments and be harmful to patients. In this review, we analyze the analyze the current knowledge of the anti-tumoral properties of phytoestrogens and discuss their current knowledge of the anti-tumoral properties of phytoestrogens and discuss their potential use potential use as agents for cancer prevention and treatment. For this, we have searched the Pubmed as agents for cancer prevention and treatment. For this, we have searched the Pubmed (https: (https://pubmed.ncbi.nlm.nih.gov/), Google Scholar (https://scholar.google.es/), and Scopus //pubmed.ncbi.nlm.nih.gov/), Google Scholar (https://scholar.google.es/), and Scopus databases (https: databases (https://www.scopus.com/home.uri) for articles regarding phytoestrogens and cancer from //www.scopus.com/home.uri) for articles regarding phytoestrogens and cancer from the last 25 years the last 25 years (1995–2020). To study the combination of phytoestrogens and anti-cancer treatments, (1995–2020). To study the combination of phytoestrogens and anti-cancer treatments, especially the last especially the last six years (2014–2020) were considered. We also searched clinical trial databases to six years (2014–2020) were considered. We also searched clinical trial databases to include those trials, include those trials, finished or ongoing, using phytoestrogens for cancer patients. finished or ongoing, using phytoestrogens for cancer patients. 2. Phytoestrogen Phytoestrogen Structure Structure and and Classification Classification Even though phytoestrogens areare aa largelarge andand heterogenicheterogenic group, group, all all of of them them are are characterized characterized by by a aphenolic phenolic ring ring and and two two hydroxyl hydroxyl groups groups (Figure (Figure1 ),1), which which are are crucial crucial for for the the binding binding toto thethe estrogenestrogen receptors (ER). The agonist or antagonist properties of phytoestrogens depend on their phenolic group [[1]1].. BasedBased on on their their structure, structure, phytoestrogens phytoestrogens are classifiedare classified into threeinto mainthree classes,main classes, which includewhich includeflavonoids, flavonoids, lignans, lignans, and stilbenes and stilbenes [9,10]. [9,10]. Figure 1. Comparison of the chemical structure of the different classes of phytoestrogens and 17β-estradiol. Figure 1. Comparison of the chemical structure of the different classes of phytoestrogens and 17β- 2.1. Flavonoidsestradiol. 2.1. FlavonoidsFlavonoids present the typical structure C6-C3-C6, with two aromatic rings (benzene A and B) joined together by a chain of 3 carbons cycled through an atom of oxygen (Figure1)[ 11]. Flavonoids are commonlyFlavonoids divided present into several the typical sub-classes, structure based C6- onC3 the-C6, connection with two positionaromatic of rings the B (benzene and C rings, A and as well B) joinedas the degreetogether of by saturation, a chain of oxidation, 3 carbons and cycled hydroxylation through an of atom the C of ring oxygen (Figure (Figure1). This 1) subclassification[11]. Flavonoids areincludes commonly isoflavonoids divided into (isoflavones several sub and-classes, coumestans), based on flavones, the connection flavonols, position flavan-3-ols of the B (or and catechins), C rings, asflavanones, well as the chalcones, degree andof saturation, anthocyanins oxidation, [1,11–14 and]. hydroxylation of the C ring (Figure 1). This subclassificationIsoflavonoids includes are compounds isoflavonoids derived (isoflavones from plant and metabolism, coumestans), and flavones, their structure flavonols, consists flavan of-3 a- ols3-phenylchroman (or catechins), flavanones, skeleton. They chalcones, are also and divided anthocyanins into two major [1,11– groups,14]. isoflavones, and coumestans. IsoflavonesIsoflavonoids are flavonoids are compounds in which derived the B ring from is plant linked metabolism to the heterocyclic, and their ring structure at the C3 consists instead of ofa 3the-phenylchroman C2 position (Figure skeleton.1)[ 15 ].They Genistein are also and daidzeindivided into constitute two upmajor to 90%groups, of isoflavones isoflavones found, and in coumestans.soybeans [16 ],Isoflavones and formononetin are flavonoids and biochanin in which Athe are B mainlyring is linked found to in the red heterocyclic clover. Isoflavones ring at the can C3 be insteadfound in of their the freeC2 position form or in(Figure their esterified 1) [15]. Genistein forms [15 and]. Coumestans, daidzein constitute the other up subclass to 90% of of isoflavonoids, isoflavones foundhave a 1-benzoxolo(3,2-c)chromen-6-onein soybeans [16], and formononetin structure and formed biochanin by a benzoxoleA are mainly fused found with a chromen-2-one.in red clover. Isoflavones can be found in their free form or in their esterified forms [15]. Coumestans, the other subclass of isoflavonoids, have a 1-benzoxolo(3,2-c)chromen-6-one structure formed by a benzoxole Biology 2020, 9, 427 3 of 19 One of the most studied coumestans is coumestrol, considered an endocrine disruptor, as it has the potential to bind to both ERs with similar affinity as estradiol, affecting the estrogenic signaling cascade [17]. Although the estrogenic activity of coumestrol is weaker than that of estradiol, it is 30 to 100 times greater than that of other isoflavones [18], due to the position of its two hydroxy groups, which match estradiol. This chemical structure also gives coumestrol the ability to inhibit aromatase and 3α-hydroxysteroid dehydrogenase [19], which are involved in the synthesis of steroid hormones [20]. Flavones are another type of