Foods/Supplements-Vitamins: Fisetin

[1] In 1995, Edward Giovannucci created the lycopene industry via a Health Professionals Follow-up Study paper [1]:

"in 1986, we assessed dietary intake for a 1-year period for a cohort of 47,894 eligible subjects initially free of diagnosed cancer. Follow-up questionnaires were sent to the entire cohort in 1988, 1990, and 1992." "Between 1986 and 1992, 812 new cases of prostate cancer, including 773 non-stage A1 cases, were documented."

"Of 46 vegetables and fruits or related products, four were significantly associated with lower prostate cancer risk; of the four--tomato sauce .., tomatoes .., and pizza .., but not strawberries--were primary sources of lycopene."

Everyone seemed to ignore the reference to strawberries - the active ingredient was not even mentioned. & who could believe that the pathetic supermarket product, that was the only option for most of the year, had any nutritive value?

Those who became interested might have discovered that the putative agent was fisetin, & that there were no fisetin supplements.

Fisetin is a polyphenol in the flavonoid-flavonol subfamily [2].

Although chemically described in 1891, Klotz, et al, (Canada) described it as a "novel compound" in 2006 [3]. One of "five flavonoids" having "antiproliferative and cell cycle arresting properties in human PCa in vitro."

Even in 2008, Mukhtar was describing fisetin as a "a novel dietary flavonoid" [4]:

"Treatment of fisetin (10-60 microM, 48 h) was found to result in a decrease in the viability of LNCaP, CWR22Rupsilon1 and PC-3 cells but had only minimal effects on normal prostate epithelial cells ...", etc.

"These data provide the first evidence that fisetin could be developed as an agent against PCa."

&, also in 2008, "A novel dietary flavonoid fisetin inhibits androgen receptor signaling and tumor growth in athymic nude mice." [5]

[6] (2010 - Taiwan)

"Fisetin (3,3',4',7-tetrahydroxyflavone), a naturally occurring flavonoid, has been reported to possess some anti-cancer and anti-inflammation capabilities. In this study, fisetin has exhibited inhibitory effects on the adhesion, migration, and invasion ability of a highly metastatic PC-3 cells under non-cytotoxic concentrations."

"These results showed fisetin could inhibit the metastatic ability of PC-3 by reducing MMP-2 and MMP-9 expressions ..."

{Matrix metalloproteinases -2 & -9 break down the matrix that holds cells in place - thereby helping them to become mobile & metastatic.}

[7] (2010 - U.S. - Mukhtar again)

"The mammalian target of rapamycin (mTOR) kinase is an important component of PTEN/PI3K/Akt signaling pathway, which is frequently deregulated in prostate cancer (CaP). Recent studies suggest that targeting PTEN/PI3K/Akt and mTOR signaling pathway could be an effective strategy for the treatment of hormone refractory CaP. Here, we show that the treatment of androgen-independent and PTEN-negative human CaP PC3 cells with fisetin, a dietary flavonoid, resulted in inhibition of mTOR kinase signaling pathway. Treatment of cells with fisetin inhibited mTOR activity ..."

{This stuff does everything! LOL ... & yet there was still no product.}

[8] (2010 - Canada - Klotz again)

Strange study in that fisetin was studied along with a synthetic. Possibly a commercial interest. "In total, 100 cell cycle genes were altered by DHC and fisetin including 27 genes with key functions in G2/M phase that were downregulated by both compounds. Other functional categories altered included chromosome organization, apoptosis, and stress response."

[9] (2012 - U.S. - Mukhtar)

"Dietary flavonoid fisetin: A novel dual inhibitor of PI3K/Akt and mTOR for prostate cancer management"

[10] (2015 - U.S. - Mukhtar)

"Dietary flavonoid fisetin binds to β-tubulin and disrupts microtubule dynamics in prostate cancer cells."

"Microtubule targeting based therapies have revolutionized cancer treatment; however, resistance and side effects remain a major limitation. Therefore, novel strategies that can overcome these limitations are urgently needed. We made a novel discovery that fisetin, a hydroxyflavone, is a microtubule stabilizing agent. Fisetin binds to tubulin and stabilizes microtubules with binding characteristics far superior than paclitaxel."

[11] (2016 - U.S. - Mukhtar) Just published.

"Fisetin enhances chemotherapeutic effect of cabazitaxel against human prostate cancer cells."

"Although treatment of prostate cancer (PCa) has improved over the past several years, taxanes such as cabazitaxel remain the only form of effective chemotherapy that improves survival in patients with metastatic castration-resistant PCa. However, the effectiveness of this class of drugs has been associated with various side effects and drug resistance. We previously reported that fisetin, a hydroxyflavone, is a microtubule stabilizing agent and inhibits PCa cell proliferation, migration, and invasion and suggested its use as an adjuvant for treatment of prostate and other cancer types. In this study, we investigated the effect of fisetin in combination with cabazitaxel with the objective to achieve maximum therapeutic benefit, reduce dose and toxicity and minimize or delay the induction of drug resistance and metastasis. Our data show for the first time that a combination of fisetin (20 μM) enhances cabazitaxel (5nM) and synergistically reduces 22Rν1, PC-3M-luc-6, and C4-2 cell viability and metastatic properties with minimal adverse effects on normal prostate epithelial cells. In addition, the combination of fisetin with cabazitaxel was associated with inhibition of proliferation and enhancement of apoptosis. Furthermore, combination treatment resulted in inhibition of tumor growth, invasion and metastasis when assessed in two in-vivo xenograft mouse models. These results provide evidence that fisetin may have therapeutic benefit for patients with advanced PCa through enhancing the efficacy of cabazitaxel under both androgen-dependent and androgen-independent conditions. This study underscores the benefit of the combination of fisetin with cabazitaxel for the treatment of advanced and resistant PCa and possibly other cancer types."

...

Cabazitaxel belongs to the same family (taxanes) as Docetaxel (Taxotere). Fisetin might act synergistically.

...

Eventually, two products came to market. Oddly, with very similar names. That was resolved & Cognisetin was renamed as Novusetin™, which Swanson sells as "Fisetin" - so much for names:

swansonvitamins.com/swanson...

"When researchers discovered a positive correlation between strawberry consumption and mental functioning, they set out on a fast path to discover why. It turns out strawberries are high in a flavonoid called Fisetin, which preliminary research suggests may be responsible for the berries' apparent brain-health benefits. Now Swanson Ultra® Fisetin lets you harness these mind-nourishing powers with Novusetin™, an advanced Fisetin extract from the "wax tree" (an Asian species of sumac). Novusetin is produced under license from the Salk Institute for Biological Studies, where much of the exciting research on Fisetin is taking place. In the field of brain nutrition, Novusetin Fisetin is truly on the cutting edge, and you can get it today in Swanson Ultra Fisetin—the clear choice for cognitive support."

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/747...

[2] en.wikipedia.org/wiki/Fisetin

[3] ncbi.nlm.nih.gov/pubmed/163...

[4] carcin.oxfordjournals.org/c...

[5] cancerres.aacrjournals.org/...

[6] ncbi.nlm.nih.gov/pubmed/196...

[7] carcin.oxfordjournals.org/c...

[8] ncbi.nlm.nih.gov/pubmed/205...

[9] ncbi.nlm.nih.gov/pmc/articl...

[10] ncbi.nlm.nih.gov/pubmed/262...

[11] ncbi.nlm.nih.gov/pubmed/277...

2 Replies

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  • Thanks, Patrick. Great research, as always. When are you going to publish a compilation of all of this material in book form? It goes way beyond Moyad's Supplement Handbook.

    I was particularly interested in what you learned about fisetin because my FoundationOne results a couple of months ago found one DNA mutation, a variant of PI3K. Metformin has been shown to inhibit PI3K signaling; now I know that fisetin may also help. This pathway plays an important PCa progression role for many with the disease, as discussed here: ncbi.nlm.nih.gov/pmc/articl...

  • Thanks Dave,

    We know a lot more about the cell signaling pathways that are in play in PCa, than we did a dozen years ago when I started reading PubMed papers. I guess that for most it is TMI, but I have been tempted to rework the supplement material in a series of pathway posts.

    The most obvious benefit concerns treatment resistance. PCa cells respond very quickly to the stress of treatment. Natural substances may inhibit escape pathways. One would think that BigPharma would be tackling the problem, but ...

    -Patrick