Azrad M, Vollmer RT, Madden J, et al. Flaxseed-derived enterolactone is inversely associated with tumor cell proliferation in men with localized prostate cancer. J Med Food. 2013;16(4):357-360.
Data extraction from previous phase II randomized controlled trial
The study included 161 men with prostate cancer who underwent prostatectomy, 147 of whom had sufficient information for analysis.
Study Medication and Dosage
Data for this study was procured from a previous study in which men were randomized by race (Black vs non-Black) and Gleason score (Gleason ≥7 vs ≤6) into 4 groups: control (n=41), flaxseed (FS; n=40), low-fat diet (LF; n=40), or flaxseed and low-fat diet (FS & LF; n=40). Flaxseed groups consumed 30 g/day and “low fat” diet groups consumed <20% of calories per day from fat. For purposes of the current study both flaxseed groups were combined for the flaxseed group (n=73) and the control and LF groups combined to make the no flaxseed group (n=74). Dietary and flaxseed intervention began approximately 30 days prior to prostatectomy.
Urinary enterolactone, enterodiol, and total lignans (μg/day) at baseline and at time of surgery. Correlations between urinary enterolignans and prostate tumor expression of Ki-67, vascular endothelial growth factor (VEGF), and nuclear factor kappa B (NF-κB) were assessed.
There were significant correlations between plant lignan intake and urinary concentrations of total enterolignans (P<0.0001), enterolactone (P<0.0001) and enterodiol (P<0.0001 ). Total urinary enterolignans and enterolactone were inversely correlated with tumor tissue levels of Ki-67 (P=0.011 and P=0.007, respectively). Although not statistically significant, an inverse association was also observed with enterolactone and VEGF (P=0.141). There was no association with urinary lignan levels and NF-κB expression in the tumor tissue.
Lignans are a type of phytoestrogen found in a variety of foods, including brassica vegetables, legumes, seeds, and whole grains. Flaxseed has exceptionally high content, with the lignan secoisolariciresinol-diglucoside comprising approximately 0.05% to 0.2% by weight.1 Epidemiological studies suggest diets high in lignans have a protective effect against many cancers, including breast, colon, and prostate.2-4 The current study demonstrates this “protection” may go one step further—reducing the aggressiveness of an already existing tumor.
What is striking is that a disease process that takes many years to develop is affected at all by a dietary change lasting only 30 days.
This publication is a follow-up to the authors’ previous publication, “Flaxseed supplementation (not dietary fat restriction) reduces prostate cancer proliferation rates.”5 Using the same group of participants, the authors established that both groups consuming flaxseed supplement had a lower proliferative index (Ki-67) compared to the control and low-fat groups. In the current abstract the authors analyzed the same prostatic tissues to assess the molecular changes in VEGF and NF-κB. For statistical analysis, the 4 groups were divided into just 2—flaxseed and no flaxseed. VEGF and NF-κB were assessed in addition to Ki-67. Once again, Ki-67 was significantly lower in the flaxseed group. While the VEGF expression trended lower in the flaxseed group, the NF-κB had no associated changes. This implies the lower proliferation of cells may be due to factors other than VEGF and NF-κB.
Precisely how enterolignans such as enterolactone may lessen prostate cancer development and growth is not well known. One in vitro study suggests enterolactone can increase apoptosis in prostate cancer through mitochondrial effects.6 Another in vitro study suggests it is able to block 5 alpha reductase enzyme.7 Yet another possible mechanism is downregulation of insulin-like growth receptors, an antiproliferative effect demonstrated in androgen-sensitive and androgen-independent prostate cell lines.8 While the mechanism will continue to be elucidated in time, the reduction of proliferation through the downregulation of the cell cycle appears to be one net effect of enterolactone on prostate cancer.9
Of course, flaxseed was given as a whole food in this study (just under ¼ c daily), and reducing it down to merely a source of enterolignans is an oversimplification. Another component, alpha linolenic acid (ALA), is also high in flaxseeds. Epidemiological data on the effects of linolenic acid on prostate cancer risk and aggressiveness are conflicting, so it is not clear whether dietary ALA gives some protection or whether the trend toward an increased risk of prostate cancer risk is real.10-12
The authors of the current study have shed some light on this inconsistency. Using the same study participants and flaxseed intervention as the current abstract, they assessed levels of ALA, Ki-67 and prostate specific antigen (PSA) in prostate cancer tissue.13 In addition, they tracked 6 different single nucleotide polymorphisms (SNPs) of the enzyme used to metabolize ALA, delta6desaturase. They found 2 surprising results. First, levels of ALA in prostatic tissue were not higher in those consuming flaxseed, despite the fact that they were ingesting 7 times the levels of ALA compared with the no flaxseed group. Second, the higher the ALA level in the prostate itself, the more aggressive the cancer as measured by Ki-67 (P=0.058) and the higher the PSA (P=0.004). Variants of SNPs in the delta6desaturase gene were correlated with higher or lower levels of Ki-67, suggesting there is genetic influence on ALA’s role in prostatic tissue. Such variability may explain the disparate results in epidemiological studies of ALA consumption and prostate cancer.
Prostate cancer takes years, even decades to develop. What is striking is that a disease process that takes many years to develop is affected at all by a dietary change lasting only 30 days. It is a reminder that cancerous growth, no matter what the stage, is dynamic and may be influenced by lifestyle choices.
While this study is small and further prospective studies are needed to guide clinical decision-making, flaxseed is also a food and there is little to no down side risk in encouraging our patients with prostate cancer to indulge in a liberal amount of flaxseed in their diets.
- Setchell KD, Brown NM, Zimmer-Nechemias L, Wolfe B, Jha P, Heubi JE. Metabolism of secoisolariciresinol-diglycoside the dietary precursor to the intestinally derived lignan enterolactone in humans. Food Funct. 2014 Jan 16. Epub ahead of print.
- Hedelin M, Klint A, Chang ET, et al. Dietary phytoestrogen, serum enterolactone and risk of prostate cancer: the cancer prostate Sweden study (Sweden). Cancer Causes Control. 2006;17(2):169-180.
- Zamora-Ros R, Not C, Guinó E, et al. Association between habitual dietary flavonoid and lignan intake and colorectal cancer in a Spanish case-control study (the Bellvitge Colorectal Cancer Study). Cancer Causes Control. 2013;24(3):549-557.
- Suzuki R, Rylander-Rudqvist T, Saji S, Bergkvist L, Adlercreutz H, Wolk A. Dietary lignans and postmenopausal breast cancer risk by oestrogen receptor status: a prospective cohort study of Swedish women. Br J Cancer. 2008;98(3):636-640.
- Demark-Wahnefried W, Polascik TJ, George SL, et al. Flaxseed supplementation (not dietary fat restriction) reduces prostate cancer proliferation rates in men presurgery. Cancer Epidemiol Biomarkers Prev. 2008;17(12):3577-3587.
- Chen LH, Fang J, Li H, Demark-Wahnefried W, Lin X. Enterolactone induces apoptosis in human prostate carcinoma LNCaP cells via a mitochondrial-mediated, caspase-dependent pathway. Mol Cancer Ther. 2007;6(9):2581-2590.
- Evans BA, Griffiths K, Morton MS. Inhibition of 5 alpha-reductase in genital skin fibroblasts and prostate tissue by dietary lignans and isoflavonoids. J Endocrinol. 1995;147(2):295-302.
- Chen LH, Fang J, Sun Z, et al. Enterolactone inhibits insulin-like growth factor-1 receptor signaling in human prostatic carcinoma PC-3 cells. J Nutr. 2009;139(4):653-659.
- McCann MJ, Gill CI, Linton T, Berrar D, McGlynn H, Rowland IR. Enterolactone restricts the proliferation of the LNCaP human prostate cancer cell line in vitro. Mol Nutr Food Res. 2008;52(5):567-580.
- Brouwer IA, Katan MB, Zock PL. Dietary alpha-linolenic acid is associated with reduced risk of fatal coronary heart disease, but increased prostate cancer risk: a meta-analysis. J Nutr. 2004;134(4):919-922.
- Simon JA, Chen YH, Bent S. The relation of alpha-linolenic acid to the risk of prostate cancer: a systematic review and meta-analysis. Am J Clin Nutr. 2009;89(5):1558S-1564S.
- Carleton AJ, Sievenpiper JL, de Souza R, McKeown-Eyssen G, Jenkins DJ. Case-control and prospective studies of dietary α-linolenic acid intake and prostate cancer risk: a meta-analysis. BMJ Open. 2013;3(5).
- Azrad M, Zhang K, Vollmer RT, et al. Prostatic alpha-linolenic acid (ALA) is positively associated with aggressive prostate cancer: a relationship which may depend on genetic variation in ALA metabolism. PLoS One. 2012;7(12):e53104.