Foods/Supplements-Vitamins: Crucifero... - Advanced Prostate...

Advanced Prostate Cancer

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Foods/Supplements-Vitamins: Cruciferous Phytochemicals - [5] Sulforaphane

pjoshea13•

8 years ago•5 Replies

This is the 5th & final installment on cruciferous vegetable phytochemicals.

The best source of sulforaphane is broccoli sprouts [1].

You may have seen BroccoSprouts in the local supermarket [2]:

"BroccoSprouts® Broccoli Sprouts are the only product that guarantees a consistent level of sulforaphane glucosinolate, a natural compound found in broccoli and other cruciferous plants that supports the body's own antioxidant function. Developed by scientists at Johns Hopkins University School of Medicine, the Broccoli Sprouts and Sprout Blends are now available in supermarkets around the country."

I was a little unhappy to note that our local sprout grower had stopped using BroccoSprout seed about 5 years ago. I sent him an email & told him so. He wrote back & explained how the price of the seed kept increasing for no apparent reason. There is only so much people will pay for the sprouts. The much cheaper generic seeds yield about 5% less sulforaphane, so it was no great loss.

He was a user himself, having recently discovered that he might have PCa (he refused a biopsy). He was taking many of the supplements I was using. Turned out that he was seeing my alternative doctor, who must have used my list as a guide. LOL

The glucosinolate of interest is glucoraphanin. As with the other glucosinolates in the earlier posts, the enzyme myrosinase is essential, to cleave the glucose structure & release the active agent - in this case, sulforaphane.

As mentioned in the previous post on PEITC from watercress, a blender is the most efficient way of doing this. The puree can be frozen in ice cube trays for daily doses.

PubMed currently has 100 hits for <prostate sulforaphane>. Nine for 2016 alone.

[3] Sulforaphane reverses Epigenetic silencing.

One method PCa uses to silence protective genes, is to produce histone deacetylase (HDAC). DNA is tightly wound around histones for efficient storage. Histone acetylase loosens strands so that they can be read. HDAC prevents that.

Another way in which tumor suppressor genes are silenced, is through methylation of the promoter regions. PCa tends to be hypermethylated. Restriction of dietary methyl donors such as folate (& folic acid) can help, but we need demethylation agents that can reverse epigenetic silencing.

[3a] (2006 - U.S.)

"... we show that addition of 15 μM SFN also inhibited HDAC activity by 40, 30 and 40% in BPH-1, LnCaP and PC-3 prostate epithelial cells, respectively. The inhibition of HDAC was accompanied by a 50–100% increase in acetylated histones in all three prostate cell lines ..."

"A corresponding 1.5- to 2-fold increase was seen for p21Cip1/Waf1 and Bax protein expression, consistent with previous studies using HDAC inhibitors, such as trichostatin A. The downstream events included cell cycle arrest and activation of apoptosis"

[3b] (2008 - U.S.)

"In human subjects, a single dose of 68 g BroccoSprouts inhibited HDAC activity significantly in peripheral blood mononuclear cells (PBMC) 3 and 6 hrs following consumption. These findings provide evidence that one mechanism through which SFN acts as a cancer chemopreventive agent in vivo is through the inhibition of HDAC activity."

[3c] (2009 - U.S.)

"Recent reports show that sulforaphane may impair prostate cancer growth through inhibition of histone deacetylases, which are up-regulated in cancer. Indeed, one of these enzymes, histone deacetylase 6 (HDAC6), influences the acetylation state of a key androgen receptor (AR) chaperone, HSP90."

"We hypothesized that sulforaphane treatment would lead to hyperacetylation of HSP90 and that this would destabilize AR and attenuate AR signaling. We confirmed this by demonstrating that sulforaphane enhances HSP90 acetylation, thereby inhibiting its association with AR. Moreover, AR is subsequently degraded in the proteasome, which leads to reduced AR target gene expression and reduced AR occupancy at its target genes."

Note that HSP90 is a 'heat shock protein'. When PCa are subjected to heat treatment, radiation & a number of other insults, HSP90's role is to protect AR as it moves to the nucleus. Hence the term 'chaperone protein'.

[3d] (2009 - U.S.)

"The reversible acetylation of histones is an important mechanism of gene regulation. During prostate cancer progression, specific modifications in acetylation patterns on histones are apparent. Targeting the epigenome, including the use of histone deacetylase (HDAC) inhibitors, is a novel strategy for cancer chemoprevention. Recently, drugs classified as HDAC inhibitors have shown promise in cancer clinical trials. We have previously found that sulforaphane (SFN), a compound found in cruciferous vegetables, inhibits HDAC activity in human colorectal and prostate cancer cells. Based on the similarity of SFN metabolites and other phytochemicals to known HDAC inhibitors, we previously demonstrated that sulforaphane acted as an HDAC inhibitor in the prostate, causing enhanced histone acetylation, derepression of P21 and Bax, and induction of cell cycle arrest/apoptosis, leading to cancer prevention. The ability of SFN to target aberrant acetylation patterns, in addition to effects on phase 2 enzymes, may make it an effective chemoprevention agent."

[3e] (2011 - U.S.)

"One mechanism that may contribute to the anti-proliferative effects of SFN is the modulation of epigenetic marks, such as inhibition of histone deacetylase (HDAC) enzymes. However, the effects of SFN on other common epigenetic marks such as DNA methylation are understudied. Promoter hyper-methylation of cyclin D2, a major regulator of cell cycle, is correlated with prostate cancer progression, and restoration of cyclin D2 expression exerts anti-proliferative effects on LnCap prostate cancer cells."

"We found that SFN significantly decreased the expression of DNA methyltransferases (DNMTs), especially DNMT1 and DNMT3b. Furthermore, SFN significantly decreased methylation in cyclin D2 promoter regions containing c-Myc and multiple Sp1 binding sites. Reduced methlyation of cyclin D2 promoter corresponded to an increase in cyclin D2 transcript levels, suggesting that SFN may de-repress methylation-silenced cyclin D2 by impacting epigenetic pathways."

[3f] (2013 - U.S.)

"Growing evidence suggests epigenetic alteration is involved during the development and progression of prostate cancer. Previously, we found Nrf2, a key regulator of cellular antioxidant defense systems, was silenced through epigenetic mechanism during tumorigenesis in vivo TRAMP mice and in vitro TRAMP C1 cells."

"SFN increased mRNA and protein expressions of Nrf2 and Nrf2 downstream target gene NQO-1."

[4] Sulforaphane & Glutathione S-transferase (GST)

GST is a 'phase 2 enzyme' important in the defense against cancer.

[4a] (2001 - U.S.)

"Sulforaphane induces phase 2 enzyme expression and activity significantly in human prostatic cells. This induction is accompanied by, but not because of, increased intracellular glutathione synthesis."

[4b] (2006 - U.S.)

"Modest induction of phase 2 enzyme activity in the F-344 rat prostate."

"In prostatic tissues, sulforaphane produced modest but significant increases in the enzymatic activities of NQO1, total GST and GST-mu compared to control animals."

[5] Sulforaphane & the effect on cell line proliferation.

[5a] (2003 - Australia)

"PC-3 prostate cancer cells were cultured ... {with} sulforaphane concentrations ranging from 0.01 mmol/L to 0.06 mmol/L"

"Cell proliferation in PC-3 prostate cancer cells was significantly inhibited by ...sulforaphane at media concentrations of ... 0.02 mmol/L"

[5b] (2004 - U.S.)

"This study showed that exposure of human androgen-independent DU-145 prostate cancer cells to SFN resulted in the inhibition of growth and tumorigenesis, as revealed by a reduction in cell density, DNA synthesis, and clonogenesis."

[5c] (2006 - U.S.)

"Sulforaphane causes autophagy to inhibit release of cytochrome C and apoptosis in human prostate cancer cells."

[6] Sulforaphane & mice / rats.

[6a] (2004 - U.S.)

"Oral administration of SFN (5.6 micro mol, 3 times/week) significantly inhibited growth of PC-3 xenografts in nude mice. For instance, 10 days after starting therapy, the average tumor volumes in control and SFN-treated mice were 170 +/- 13 and 80 +/- 14 mm3, respectively, reflecting a >50% reduction in tumor volume due to SFN administration."

[6b] (2009 - U.S.)

"TRAMP mice fed with 240 mg broccoli sprouts/mouse/day exhibited a significant retardation of prostate tumor growth.l"

[7] Sulforaphane & reactive oxygen species [ROS].

Phytochemicals that are generally considered to be antioxidants, usually become effective at doses that induce ROS. The standard test is to use N-acetylcysteine, a reliable antioxidant. If the protection ceases, ROS is assumed to be present & essential for cell death.

[7a] (2005 - U.S.)

"Exposure of PC-3 cells to growth-suppressive concentrations of SFN resulted in ROS generation, which was accompanied by disruption of mitochondrial membrane potential, cytosolic release of cytochrome c, and apoptosis."

[8] Sulforaphane & nuclear factor kappa B (NF-kB)

Chronic activation of NF-kB is common in PCa. It results in generation of a myriad of proteins associated with cell survival.

[8a] (2005 - U.S.)

"The nuclear factor kappa B (NF-kappaB) is believed to play an important role in cancer chemoprevention due to its involvement in tumor cell growth, proliferation, angiogenesis, invasion, apoptosis, and survival. In this study, we investigated the effects and the molecular mechanisms of SFN and PEITC on NF-kappaB transcriptional activation and NF-kappaB-regulated gene expression in human prostate cancer PC-3 C4 cells. Treatment with SFN (20 and 30 microM) and PEITC (5 and 7.5 microM) significantly inhibited NF-kappaB transcriptional activity, nuclear transloction of p65, and gene expression of NF-kappaB-regulated VEGF, cylcin D1, and Bcl-X(L) in PC-3 C4 cells."

[9] Sulforaphane & hypoxia-inducible factor-1alpha [HIF-1alpha]

HIF-1alpha is nominally induced when a tumor outgrows its blood supply.

"Hypoxia-inducible factor 1 (HIF-1) expression is associated with tumorigenesis and angiogenesis. It regulates the expression of many genes including vascular endothelial growth factor (VEGF), inducible nitric oxide synthase, and lactate dehydrogenase A." [9a]

[9a] (2008 - U.S.)

"In our study, we investigated the effects of sulforaphane on expression of hypoxia-inducible factor-1alpha (HIF-1alpha), which was overexpressed in ... prostate cancer DU145 cells. Sulforaphane inhibited hypoxia induced expression of HIF-1alpha via inhibiting synthesis of HIF-1alpha. Sulforaphane was also found to inhibit hypoxia induced HIF-1alpha expression through activating JNK and ERK signaling pathways, but not AKT pathway. Inhibition of HIF-1alpha by sulforaphane resulted in decreasing expression of VEGF. Taken together, these results suggest that sulforaphane is an effective chemopreventive compound against ... prostate cell angiogenesis in vitro"

[10] Sulforaphane & STAT3

STAT3 (signal transducer and activator of transcription 3) is an important PCa target.

[10a] (2010 - U.S)

"We ... show that SFN inhibits constitutive and interleukin-6 (IL-6)-inducible activation of signal transducer and activator of transcription 3 (STAT3), which is an oncogenic transcription factor activated in many human malignancies, including prostate cancer."

[11] Sulforaphane & Stem-like Cells.

[11a] (2011 - Germany)

"Considerable attention has focused on broccoli compound sulforaphane (SF), which is suggested as combination therapy for targeting of ... cancer stem cells (CSCs). However, there are concerns that antioxidative properties of SF may interfere with cytotoxic drugs-as suggested, e.g., for vitamins."

"SF potentiated the drug effect in established prostate CSCs revealing that SF enhances drug cytotoxicity"

[11b] (2016 - U.S.)

"Here, we show that the prostate cancer stem cell (pCSC)-like traits, such as accelerated activity of aldehyde dehydrogenase 1 (ALDH1), enrichment of CD49f+ fraction, and sphere forming efficiency, are attenuated by SFN treatment."

[12] Sulforaphane & protein synthesis.

[12a] (2012 - Poland)

"In the present study we show that SFN inhibits protein synthesis in PC-3 cells in a dose- and time-dependent manner ..."

"Although SFN affects mitochondria and slightly decreases glycolysis, the ATP level is maintained on the level characteristic for control cells. Inhibition of protein synthesis might be a protective response of prostate cancer cells to save energy. However, translation inhibition contributes to the death of PC-3 cells due to decreased level of a short-lived protein, survivin. Overexpression of this anti-apoptotic factor protects PC-3 cells against SFN cytotoxicity."

[13] Sulforaphane & anti-androgens.

[13a] (2016 - U.S.)

"Sulforaphane increases the efficacy of anti-androgens by rapidly decreasing androgen receptor levels in prostate cancer cells."

[14] Sulforaphane & Clinical Trials.

I would never use sulforaphane or any other phytochemical as monotherapy. My own otc combination is designed to cover a number of areas: coagulation, inflamation, etc., etc. I have had 13 fairly good years, but I never expected a complete remission. I had a metastatic lesion at L5 radiated two years ago, but so far, there have been no others. Impossible to give credit to a single supplement.

So, while the trial in [14a] is a disappointment, 40% of the 20 men did have a PSA response. All I ask of an additional supplement is the possibility of some incremental benefit, & [14b] showed almost a doubling of PSADT.

[14a] (2016 - U.S.)

"We treated 20 patients who had recurrent prostate cancer with 200μmoles/day of sulforaphane-rich (broccoli sprout) extracts for a maximum period of 20 weeks"

"Only one subject (5%) achieved a ≥50% PSA decline while on study ... Seven subjects achieved lesser PSA declines ranging from 3% to 20%. Overall, a total of eight subjects (40%) experienced any degree of PSA decline while on study"

[14b] (2015 - France)

"... we performed a double-blinded, randomized, placebo-controlled multicenter trial with sulforaphane in 78 patients (mean age, 69 ± 6 years) with increasing PSA levels after radical prostatectomy. Treatment comprised daily oral administration of 60 mg of a stabilized free sulforaphane for 6 months (M0–M6) followed by 2 months without treatment (M6–M8)."

"PSA doubling time was 86% longer in the sulforaphane than in the placebo group (28.9 and 15.5 months, respectively)."

"Sulforaphane effects were prominent after 3 months of intervention (M3–M6)."

"After treatment, PSA slopes from M6 to M8 remained the same in the 2 arms."

"Daily administration of free sulforaphane shows promise in managing biochemical recurrences in prostate cancer after radical prostatectomy."

...

I used BroccoMax [15], from broccoli seeds, for about 5 years before I realized that the glucosinolate form was probably ineffective. I went back to it after a couple of years, when I heard that they had added the enzyme myrosinase. Jarrow seemed reluctant to mention the change on the label for a while, but it now states: "MYROSINASE ACTIVATED".

In pulling up the link, I noticed that Swanson & iHerb are both out of stock.

Anyway, when shopping for a product, make sure there is mention of myrosinase.

-Patrick

[1] en.wikipedia.org/wiki/Sulfo...

[2] broccosprouts.com

[3a] ncbi.nlm.nih.gov/pmc/articl...

[3b] ncbi.nlm.nih.gov/pmc/articl...

[3c] ncbi.nlm.nih.gov/pubmed/198...

[3d] ncbi.nlm.nih.gov/pubmed/198...

[3e] ncbi.nlm.nih.gov/pubmed/223...

[3f] ncbi.nlm.nih.gov/pubmed/234...

[4a] cebp.aacrjournals.org/conte...