MicroRNA targeting by quercetin in cancer treatment and chemoprotection
Graphical abstract
Introduction
Cancer is a serious health issue across the globe and is the primary cause of mortality worldwide as published in World Health Organization (WHO) report 2018. According to recent statistics from the WHO, cancer is the second primary cause of death in the world that account to 9.6 million deaths in 2018 [1]. The most prevalent was lung cancer (1.76 million) followed by liver, colorectal, stomach and breast cancer [1]. Based on statistics compiled by the International Agency for Research on Cancer for the year 2012, the global incidence of new cases of cancer was 14.1 million [2]. 1,735,350 new cancer cases and 609,640 cancer deaths are expected to occur in the United States in 2018 [3]. The speculated global cancer incidence by the year 2030 is reported to increase by 68%. [4]. Furthermore cancer is one of the most significant financial burdens to the affected families and society as the healthcare becomes to be sophisticated and modern approaches to cancer treatment are expensive [5]. The WHO estimated that the total economic cost of cancer for the year 2010 was a staggering 1.16 trillion USD [1] and the Agency for Healthcare research and Quality (AHRQ) estimated that the direct economic cost for cancer in the United States of America for the year 2015 was 80.2 billion USD [6].
Combination of mutations in oncogenes or tumor suppressor genes as well as epigenetic changes in DNA, represented by altered methylation can result in the development of cancer [7]. Up-to-date knowledge of the cancer mutations and concurrent availability of therapeutic agents targeting the altered genes or corresponding biochemical pathways are required for a personalized therapeutic approach in treatment of cancer [8]. Tumors when possible are removed surgically and remaining cells can be eradicated by radiotherapy, chemotherapy and immunotherapy [9]. Unfortunately, when metastases occur, the treatment options become very limited. The failure of the chemotherapy is associated mainly with poor accessibility of anti-neoplastic agents to the tumor mass. The subsequent requirements of high doses of chemotherapeutics cause severe toxicity due to the relative low selectivity of these agents [10]. Despite some recent advances, nausea, vomiting, gastrointestinal toxicity, alopecia, chemotherapy-related myelosuppression, immunosuppression, neurotoxicity, sterility, and other debilitating side effects are still common.
Plant-derived natural products play an essential role in the human diet as antioxidants and cancer chemopreventive agents [11]. Natural compounds or their derivatives serve as cytostatics, e.g. Vinca alkaloids (vincristine, vinblastine), taxanes (paclitaxel, docetaxel), camptothecins (irinotecan, topotecan), and epipodophyllotoxins (etoposide, teniposide) [12]. Having favorable safety profiles and bioavailability, phytochemicals from a wide range of natural sources have been used for prevention and treatment of cancer based on traditional medicine practices [[13], [14], [15], [16]]. Many of these phytochemicals exert their anti-cancer activities through multiple pathways and mechanisms [[17], [18], [19]], and the relative contribution of each mechanism to anti-cancer effect varies with a stage of cancer, in other words in initiation, promotion, or progression. For example we can notice the antioxidant β-carotene showing stage-dependent effects [20], while quercetin having well-documented effects in early (onset) and late (proliferation) stages of tumorigenesis.
Due to their inhibitory effects on multiple signaling pathways associated with cancer stem cells growth and development, naturally occurring phytochemicals including curcumin, resveratrol, sulforaphane and green tea polyphenols have gained phenomenal attention in recent years [[21], [22], [23]]. In this context, phytochemical’s regulation of microRNAs (miRNAs) involved in pathogenesis of cancer has also been gradually documented [[24], [25], [26]] and the ability of anti-cancer compounds to target miRNAs is of great interest as a single miRNA can modulate the expression of several proteins in the cell [27].
Many phenolic compounds with potent antioxidant potential are suitable candidates to be used for preventing and treating disorders pathogenically connected to oxidative stress, such as cardiovascular disorders, cancer, diabetes mellitus and neurodegenerative illnesses [[28], [29], [30], [31]]. Vegetables, fruits, some berries and beverages like wine grapes, and tea are the primary sources of such phenolics [32]. The most common phenolics are phenolic acids and flavonoids which are also found as dietary components of fruits, vegetables, chocolate, tea and other plant sources [[33], [34], [35], [36], [37]]. Flavonoids, the diverse group of natural products with over 6000 compounds identified, can be structurally categorized into six main subgroups: flavanols (catechins), flavones, flavanones, flavonols, anthocyanidins and isoflavones. Among those known for chemopreventive efficacy in various cancers, luteolin, kaempferol, quercetin, genistein, epigallocatechin 3-gallate, silymarin, apigenin and daidzein are widely studied [38]. Their anti-cancer effects are attributed to different mechanisms including a direct and indirect antioxidant activity, anti-inflammatory effects, a control of progression of cell cycle, inhibition of proliferation of cancer cells, a negative regulation of activation of carcinogens, a positive regulation of detoxification of carcinogens, an induction of apoptosis, an inhibition of activation of oncogenes and modulation of activity of hormones or growth factors [39].
Quercetin, a member of flavonols subgroup, is one of the chief antioxidant flavonoids [40]. The anti-cancer activities of quercetin have been extensively reported from several in vitro and in vivo studies [41], as well as from epidemiology [42,43]. Concerning bioavailability, quercetin supplementation in humans afforded plasma concentrations higher than 1 μM [44] and pharmacokinetics has been improved with oral delivery systems recently tested in animals [45]. Notably, some in vivo metabolites of quercetin such as isorhamnetin also retain miRNA-regulating activity [46], favoring the therapeutic efficacy of the flavonoid. However, reports using mechanistic approach to evaluate particularly the effects of quercetin on miRNA system are very patchy. Some groups have reviewed the ability of natural compounds to regulate miRNA levels [[47], [48], [49]], but the data accumulated specifically for quercetin in the context of cancer and miRNA need a dedicated analysis. The aim of this review is to summarize the impact of miRNA on cancer deregulation, the chemical basis, botanical sources as well as the pharmacological profile of quercetin; clarifying the therapeutic potential of quercetin in cancer by targeting disease-relevant miRNAs.
Section snippets
Basic concepts on the molecular biology of miRNAs
Lin-4 is the first member of miRNA discovered in 1993 in Caenorhabditis elegans [50]. Following this discovery, several miRNAs have been identified [51]. Composed of 21–25 nucleotides, the miRNAs are short non-coding RNAs with regulatory function on gene expression [52]. They regulate more than 60% of the protein-coding genes in the entire human genome [53]. In doing so, they bind to target messenger RNAs (mRNAs), causing degradation of mRNA or inhibiting its translation and thus control gene
The expression of miRNA and cancer
The alteration in the expression of miRNAs is known to be implicated in human disorders, including cancer (Table 1) [70]. An involvement of miRNAs in initiation and progression of cancer of different origin has been supported by results of various studies in breast cancer, hepatocellular carcinoma, lymphoma, lung cancer, leukemia, kidney and bladder cancer, pancreatic tumor, cervical cancer, colorectal cancer, prostate cancer, cancers of thyroid origin, glioblastoma and other brain tumors [27,68
Quercetin: Natural sources and pharmacological profile
Discovered in 1857, quercetin (3,3´,4´,5,7-pentahydroxyflavone, Fig. 2) is one the most studied bioactive flavonoids [115,116]. Its name is derived from the latin word Quercetum meaning oak forest [117] and can be found abundantly in diverse edible and medicinal plants (Table 2). Onion, kale, apple, many berries, citrus fruits and tea are all rich sources of quercetin and its derivatives [118]. It usually occurs in glycosidic form such as rutin, isoquercetrin and hyperoside; nevertheless, it is
Quercetin in prevention and therapy of cancer
The effects of quercetin against different kinds of cancer have previously been reported [144]. Quercetin can be a valid option for a prevention and treatment of cancer. While the amounts of quercetin taken in dietary form would likely fulfil the requirements for cancer prevention, supplementation by other delivery means would be necessary for cancer treatment [145]. In vitro studies indicate that dosing of quercetin in range of 3–50 μM exhibit anti-proliferative effects [146]. An imbalance
Potential roles of miRNAs in chemopreventive effects of quercetin
A chemopreventive agent is able to block initiation, delay or reverse the carcinogenic process [159]. Epidemiological data indicates that quercetin consumption prevents the onset of cancer. Levels of quercetin intake in the form of onions and apples was found to decrease the risk of lung cancer and, remarkably, the effect was dependent on the genotype of CYP1A1, a chief P450 enzyme in the metabolic activation of procarcinogens to their ultimate electrophilic DNA-interacting species [43]. In a
Modulation of miRNA expression by quercetin in cancer models
Since multiple genes are involved in the development of cancer, the capability of natural products, including quercetin to affect miRNAs is an attractive alternative and/or as combined therapeutic approach in cancer therapy. Common dietary compounds such as curcumin, resveratrol, genistein, epigallocatechin-3-gallate and quercetin can down-regulate oncogenic as well as up-regulate tumor suppressive miRNAs [170]. Quercetin has been shown to affect the expression of miRNAs both in cell cultures
Data-driven integrative approaches to microRNAs as biomarker and for drug discovery
Profiling miRNAs can be a meaningful diagnostic tool [75,77,203] with the potential, for example, to evaluate the immune status of patients or classify tumor types by expression analysis of micro vesicle miRNAs [27]. Genomic profiling seems insufficient to capture the complex functional interplay of biological processes in cancer, and drug discovery platforms seek for disease-relevant biomarkers and new pathology modeling options in evaluating target biology and drug efficacy. Top-down holistic
Mechanisms of regulation of microRNAs by quercetin and other polyphenols
The data in the bibliography is clear on the ability of quercetin to modulate the level of highly important cancer-related miRNAs, namely the up-regulation of let-7 family, miR-16 and miR-146a and the down-regulation of oncogenic miR-21 observed in more than one cancer model (Fig. 4). However, the molecular mechanisms by which quercetin operates this regulation have been scarcely studied.
Taking in account the data available on different polyphenols, several modes of action can be put forward.
Conclusions
For a long time, the therapeutic properties of quercetin were claimed to be linked to its antioxidant potential. Quercetin has also been reported to possess numerous other pharmacological activities including anti-inflammatory and organo-protective effects. Numerous studies confirmed the attractiveness of quercetin, as a natural compound occurring in diet, for cancer prevention due to its beneficial anti-mutagenic and anti-proliferative effects, its antioxidant properties and its role in the
Declaration of Competing Interest
The authors declare that there is no conflict of interest.
Acknowledgements
This paper was supported by Konkuk University in 2017.
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