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Review
. 2019 May 5;12(2):68.
doi: 10.3390/ph12020068.

Flaxseed Lignans as Important Dietary Polyphenols for Cancer Prevention and Treatment: Chemistry, Pharmacokinetics, and Molecular Targets

S Franklyn De Silva  1 , Jane Alcorn  2
Affiliations
Review

Flaxseed Lignans as Important Dietary Polyphenols for Cancer Prevention and Treatment: Chemistry, Pharmacokinetics, and Molecular Targets

S Franklyn De Silva et al. Pharmaceuticals (Basel). .

Abstract

Cancer causes considerable morbidity and mortality across the world. Socioeconomic, environmental, and lifestyle factors contribute to the increasing cancer prevalence, bespeaking a need for effective prevention and treatment strategies. Phytochemicals like plant polyphenols are generally considered to have anticancer, anti-inflammatory, antiviral, antimicrobial, and immunomodulatory effects, which explain their promotion for human health. The past several decades have contributed to a growing evidence base in the literature that demonstrate ability of polyphenols to modulate multiple targets of carcinogenesis linking models of cancer characteristics (i.e., hallmarks and nutraceutical-based targeting of cancer) via direct or indirect interaction or modulation of cellular and molecular targets. This evidence is particularly relevant for the lignans, an ubiquitous, important class of dietary polyphenols present in high levels in food sources such as flaxseed. Literature evidence on lignans suggests potential benefit in cancer prevention and treatment. This review summarizes the relevant chemical and pharmacokinetic properties of dietary polyphenols and specifically focuses on the biological targets of flaxseed lignans. The consolidation of the considerable body of data on the diverse targets of the lignans will aid continued research into their potential for use in combination with other cancer chemotherapies, utilizing flaxseed lignan-enriched natural products.

Keywords: Cellular/molecular targets; Chemopreventive; Chemotherapeutic; Dietary polyphenols; Flaxseed lignans; Hallmarks of cancer; Pharmacokinetics; Phytochemicals; Quality of life.

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Conflict of interest statement

The authors declare no conflicts of interest. The funders had no role in the design of the study, in the collection, analyses or interpretation, in the writing of the manuscript, or in the decision to publish this review.

Figures

Figure 1
Figure 1
Polyphenolic phytochemicals (e.g., lignans) block and suppress carcinogenesis. Carcinogenesis is a multistage process of initiation, promotion, and progression. Carcinogens may initiate carcinogenesis by causing the conversion of a normal cell into an “initiated cell”, a process that is irreversible and involves genetic mutations. Initiated cells further transform into pre-neoplastic cells during the stage of promotion, and subsequently progress into neoplastic cells. Polyphenolic phytochemicals are capable of interfering with cellular and molecular processors in various stages of carcinogenesis. Phytochemicals may block cancer initiation through inhibition of procarcinogen activation into electrophilic species and their subsequent interaction with DNA. Alternatively, phytochemicals can stimulate carcinogen detoxification and their subsequent elimination from the body. Phytochemicals may suppress cancer by interfering with cancer promotion (a reversible process that involves nongenetic changes) or by regulating cancer progression, a complex process that involves both genetic and nongenetic changes as well as cell survival. Some polyphenols can act as blocking agents; others act as both blocking and suppressing agents, and some function as suppressing agents to modulate autophagy, cell cycle, and differentiation, thus affecting cancer cell proliferation. Adapted from references [3,4,67].
Figure 2
Figure 2
Chemical composition of flaxseed. (a) Schematic representation of the lignan macromolecule. The principal flaxseed lignan, secoisolariciresinol diglucoside (SDG), exists as a macromolecule in the flaxseed hull. This polymer complex is composed of five SDG structures held together by four hydroxy-methylglutaric acid (HMGA) residues with the hydroxycinnamic acids, p-coumaric glucoside (4-O-β-d-glucopyranosyl-p-coumaric acid or linocinnamarin) (CouAG), and ferulic acid glucoside (4-O-β-d-glucopyranosyl ferulic acid) (FeAG) as end units linked to the glucosyl moiety of SDG. The backbone moieties of this macromolecule are represented by the circles. The overlapping circles represent the linker molecule HMGA and the squares represent the terminal units. The terminal unit can be CouAG/FeAG or HMGA. (b) Postulated structure of the lignan oligomer. The SDG–HMGA polymer complex is converted into its monomer units—3-HMGA and SDG—by hydrolysis (average size, n = 3). Flaxseed contains high levels of the lignan oligomer (with ester linkages to HMGA, cinnamic acid, and other phenolic glucosides), which undergoes conversion to its aglycone, secoisolariciresinol (SECO), with further biotransformation into mammalian lignans by the action of the colonic bacteria in mammalian systems. Adopted from references [234,302,348,371,372].
Figure 3
Figure 3
Lignan chemical structure and metabolites. Plant lignans are converted to various metabolites including the mammalian lignans (enterolactone (ENL) and enteroldiol (ED)) and their phase II metabolites such as glucuronide conjugates. The conversion of plant lignan secoisolariciresinol diglucoside (SDG) into the mammalian lignans can by separated into four catalytic reactions in order of O-deglycosylation (SDG to the its aglycone, SECO), O-demethylation (SECO to 2,3-bis (3’-hydroxybenzyl)butyrolactone/2,3-bis(3,4-dihydroxybenzyl)butane-1,4-diol), dehydrogenation (2,3-bis(3,4-dihydroxybenzyl)butane-1,4-diol to ED), and dihydroxylation (ED to ENL). Adopted from references [42,380,381,384].
Figure 4
Figure 4
Flaxseed lignan absorption, first-pass metabolism, and enterohepatic recycling. The flaxseed lignan, secoisolariciresinol diglucoside (SDG), is biotransformed by bacteria in the gastrointestinal tract upon oral intake. Due to their lipophilicity, the aglycones and mammalian lignans may cross biological membranes via passive diffusion. With permeation into the enterocyte a portion of the aglycone and mammalian lignans undergo first-pass metabolism by phase II enzymes (e.g., UDP-glucuronosyltransferases (UGT), sulfotransferases (ST)). The polar, water-soluble glucuronide and sulfate conjugates require transport across the basolateral membrane of the intestinal epithelium by active transporters to gain access to the portal blood supply. Unmetabolized aglycone and mammalian lignans enter the hepatocyte by passive diffusion and undergo phase II metabolism by UGTs and STs. The conjugated metabolites are actively transported into the bile and can be reintroduced into the gastrointestinal tract. Here, they can be deconjugated and undergo reabsorption, a process called enterohepatic recirculation (EHR). The various lignans and their corresponding metabolites may elicit biological responses upon entering the systemic circulation by interacting with various enzymes, transporters, and other cell signaling macromolecules. Elimination of the conjugated metabolites can occur through either fecal or renal excretion. Adopted from reference [403].
Figure 5
Figure 5
Protective health benefits of lignans. Lignans are polyphenolic phytochemicals that have varying biological activities under several contexts. Lignan containing diets or supplements can support general health as well as target many diseases.
Figure 6
Figure 6
The cellular and molecular targets of lignans. Flaxseed lignans have the ability to target multiple pathways in cancer given the evidence from both in vitro and in vivo evaluations (Table 2). Cancer metastases can be inhibited by the modulation of the cytoskeleton and cell motility processors. Modulation of cell growth and differentiation as well as cell cycle arrest interfere with tumor proliferation and survival. Starving tumors by targeting angiogenesis as well as triggering apoptosis leads to inhibition of progression and survival. Interfering with different cell signaling pathways linking AKT and ERK modulates cell metabolism and disfavors progression and survival.
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