Biphasic effects of genistein on PC-3 cells.

[pjoshea13]

New cell study below [1].

The biphasic effect of genistein has been discussed several times. It has been observed in PCa & BCa (breast) cell studies.

The take home message is that physiological levels (from diet) might stimulate proliferation, while pharmacological levels are required to inhibit proliferation. But this doesn't seem to discourage some men from using soy milk & other soy products.

"This study highlights for the first time that maximal physiologically achievable concentrations of genistein (0.5-10 μM) have proliferative effects evidenced by alterations in global gene expression patterns of PC-3 cells. Our results particularly represent a closer examination of dietary genistein consumption for the prevention and/or treatment of cancer that maximal physiologically achievable concentrations of genistein could have detrimental effects on individuals with prostate cancer."

"It was evidenced that maximal physiologically achievable concentrations of genistein (0.5-10 μM) lead to significant increase in cell viability ... and decrease in migration at 0.5 μM ... and 10 μM ... The highest percentage of apoptotic cells was obtained at 50 μM."

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/313...

J Food Biochem. 2019 Aug;43(8):e12951. doi: 10.1111/jfbc.12951. Epub 2019 Jun 24.

Achieving the balance: Biphasic effects of genistein on PC-3 cells.

Terzioglu-Usak S1, Yildiz MT2, Goncu B3, Ozten-Kandas N4.

Author information

Abstract

This study examined the response of PC-3 cells to physiological (0.5, 2.5, 5, 10 μM) and pharmacological (50 μM) concentrations of genistein which is a main bioactive compound in soy. Following 48 hr genistein treatment, cell-based assays and genome-wide microarray were performed. It was evidenced that maximal physiologically achievable concentrations of genistein (0.5-10 μM) lead to significant increase in cell viability (p < 0.05) and decrease in migration at 0.5 μM (p = 0.000) and 10 μM (p = 0.001). The highest percentage of apoptotic cells was obtained at 50 μM. Microarray analysis gave the most critical pathways such as cell cycle regulation and proliferation, tumorigenesis, DNA damage and repair, stress response, and apoptosis. Physiological concentrations (≤10 μM) induced activation of CDKs, MAPKs, and RPSKs, while high concentrations of genistein (>10 μM) appeared to have a novel mechanism of action, specifically down-regulating TGF-β by decreasing specifically SMAD 2/3,4 which are in the downstream TGF-β signaling cascade. PRACTICAL APPLICATIONS: This study highlights for the first time that maximal physiologically achievable concentrations of genistein (0.5-10 μM) have proliferative effects evidenced by alterations in global gene expression patterns of PC-3 cells. Our results particularly represent a closer examination of dietary genistein consumption for the prevention and/or treatment of cancer that maximal physiologically achievable concentrations of genistein could have detrimental effects on individuals with prostate cancer. Further studies as in vivo would be necessary to remove shadows on the effect of genistein on prostate cancer progression.

© 2019 Wiley Periodicals, Inc.

KEYWORDS:

PC-3 cells; genetic expression; genistein; microarray; nutrition; prostate cancer

PMID: 31368541 DOI: 10.1111/jfbc.12951

[FCoffey]

When they write "maximal physiologically achievable concentrations of genistein" it is not at all clear to me that they are talking only about diet. I downloaded the full paper and there is zero discussion of what levels of genistein are achievable with supplements.

FYI, a naturopath I consulted in 2011 knew about this effect, we discussed at length that soy in the diet was a very bad thing for prostate cancer, but he convinced me to try a few bottles of (expensive) genistein supplements. I don't recall any effects on PSA, but there is the ever-present n=1 problem plus the many limits of PSA as a proxy for prostate cancer activity.

In another paper I downloaded in 2012, there was this information about genistein plasma levels in actual humans who were given 300 mg per day for 28 days, followed by 600 mg/day for 56 days, for a total of 84 days treatment with a high quality genistein supplement.

Lack of significant genotoxicity of purified soy isoflavones (genistein, daidzein, and glycitein) in 20 patients with prostate cancer

Mean (± SE) peak plasma total genistein concentrations during the plasma profile studies were 7.3 ± 0.8 umol/L on day 1 and 8.1 ± 1.2 umol/L on day 84 of treatment

booksc.xyz/book/73896419/29...

So even fairly intensive supplementation failed (by a factor of 6) to produce the "pharmacological level" of 50 umol.L that the lab study found was required.

The body is complex and it could well be that levels achieved by supplementation are cytotoxic or otherwise beneficial to prostate cancer patients. But I don't know any evidence to that effect. Given the well-documented association between soy consumption and prostate cancer, I will pass for now.

[HOPEFULSPOUSE]

Interesting Patrick - what do you think about Swanson's genistein from Sophora Japonica?

[pjoshea13 in reply to HOPEFULSPOUSE]

I use LEF's Ultra Soy [1]:

"std. to 40% isoflavones (1250 mg) providing 15% genistein (468.75 mg), 14% daidzein (437.5 mg)"

1 cap of the Swanson product [2] has 125 mg.

4 caps daily is almost equivalent. Personally, I wouldn't want to go lower. ... But I can't speak to the bioavailability questions regarding genistein in general. It might be best to divide the dose between meals.

-Patrick

[1] lifeextension.com/vitamins-...

[2] swansonvitamins.com/swanson...

[HOPEFULSPOUSE in reply to pjoshea13]

Thank you! He switched from LEF to Swanson last year due to the soy issue. Maybe time to revisit.

[Garp41]

I have been looking at this for years.....I dropped Genistein about 2 years ago....IMO, impossible to decipher, at this time.

Doug

[Canoehead]

I think this answers my long standing question about why some think soy is good and some think soy is bad.. Genistein May very well have anti cancer benefits, but at levels that are impossible to achieve with diet and supplementation.

[cashlessclay]

And yet, my diet contains soy, both for lunch and dinner, and the diet works well. My diet was already working well in 2013, when I removed soy from my diet for three months. The PSA increased 27% during those three months. I put the soy back into the diet, and PSA was unchanged over the next six months. So, why did I remove soy if the diet was already working pretty good? Because of all the conflicting data that I came across regarding soy, it seemed like a good idea to settle it. Looks this issue remains unsettled.

[pjoshea13 in reply to cashlessclay]

But soy wasn't the only variable. When you dropped soy, what did you replace it with? & when you reintroduced it, what did you drop.

Michael Milken seems to have eaten nothing but soy for a while (if one is to believe his cookbook) & he is still with us:

amazon.com/Taste-Living-Coo...

Seems that the junk bond king lived on junk food before diagnosis. He hired chef Beth Ginsberg to create fake versions from soy. I bought the book after I was diagnosed. 15 years ago, my wife was following the recipes daily until I said STOP. It was a relief to both of us.

("Upon his release from prison in 1993, Milken founded the Prostate Cancer Foundation for prostate cancer research, which by 2010 was "the largest philanthropic source of funds for research into prostate cancer." Milken himself was diagnosed with advanced prostate cancer in the same month he was released." (Wiki))

-Patrick

[monte1111 in reply to pjoshea13]

Your knowledge astounds me. I thought Michael Milken would be living in a rat hole. He is worth 3.6 Billion dollars!!! This is why companies ignore the laws. The fines are less than the profits. And rarely does anyone go to jail. Is it murder when non-disclosure kills thousands? According to wiki Prostate Cancer Foundation has helped fund almost every drug we are taking. If all of this is true, and Michael Milken isn't milking the Foundation, I want to see the movie.

[cashlessclay in reply to pjoshea13]

Patrick says . . . "But soy wasn't the only variable. When you dropped soy, what did you replace it with? & when you reintroduced it, what did you drop."

Patrick, this was 5-6 years ago . . . I can't possibly remember what I ate.

That's why I write it down. When I dropped soy, the changes which could have had an effect on PSA was "beets", "oranges" and "grapefruit". So, there is some chance that the diet failure was due to these three, and not due to the "absence" of soy. But, there is no question that the best working diets that I had all contained "soy". Granted, it's possible that "soy" doesn't work for everyone.

Cashless

[Rexwaterbury]

I have been taking Genistein, but not associated with soy isoflavins, primarily due to PTEN loss. Do you think this inadvisable?

[pjoshea13 in reply to Rexwaterbury]

Presumably, the non-soy genistein is bio-identical.

Unless the dose is very high, you should stop.

If the dose is very high, you might want to stop anyway - until the bioavailability issue is settled.

-Patrick

[j-o-h-n]

Yo no soy... soy.

Good Luck, Good Health and Good Humor.

j-o-h-n Saturday 08/03/2019 12:40 PM DST

[cbgjr]

How do we reconcile that report vs this one:

ncbi.nlm.nih.gov/pmc/articl...

?

[pjoshea13 in reply to cbgjr]

The study I cited involved the PC-3 cell line. It was extracted from a bone met 40 years ago [1]. It might not be characteristic of the majority of bone mets in this group [2], although it has been used in countless studies.

However, one has to assume that genistein may have a biphasic effect on all of our bone mets.

It is possible that soy products protect against PCa incidence. Soy often replaces meat. Perhaps that helps. There is no suggestion that genistein might turn normal epithelia prostatic cells into cancer. The concern is in what happens once cancer occurs.

& so, the relevant part of the paper you cite appears to be:

"3.6. Soy and Advanced PCa Risk

"Seven [34,35,36,43,45,50,53] studies reported the risk of advanced PCa with soy intake and circulating isoflavone levels. Of these seven studies, four [34,43,45,53] studies were conducted in North America, two [35,36] studies were conducted in Asia, and one [50] study was conducted in Europe. Only one [34] was a case-control study, two [35,50] were NCC studies, and four [36,43,45,53] were cohort studies. Five [34,36,43,45,53] studies reported a risk of advanced PCa with dietary soy food intake and two [35,50] studies reported a risk of advanced PCa with circulating isoflavones."

From [36]: "positive associations were seen between isoflavones and advanced prostate cancer. These results were strengthened when analysis was confined to men ages >60 years, in whom isoflavones and soy food were associated with a dose-dependent decrease in the risk of localized cancer" [3]

Less cancer, but more advanced cases.

-Patrick

[1] ncbi.nlm.nih.gov/pubmed?cmd...

[2] en.wikipedia.org/wiki/PC3#c...

"The PC3 cell line was established in 1979 from bone metastasis of grade IV of prostate cancer in a 62-year-old Caucasian male.[2] These cells do not respond to androgens, glucocorticoids or fibroblast growth factors,[3] but results suggest that the cells are influenced by epidermal growth factors.[4] PC3 cells can be used to create subcutaneous tumor xenografts in mice to investigate the tumor environment and therapeutic drug functionality.

PC3 cells have high metastatic potential compared to DU145 cells, which have a moderate metastatic potential, and to LNCaP cells, which have low metastatic potential.[5] Comparisons of the protein expression of PC3, LNCaP, and other cells have shown that PC3 is characteristic of small cell neoendocrine carcinoma.[3]

PC3 cells have low testosterone-5-alpha reductase and acidic phosphatase activity, and do not express PSA (prostate-specific antigen). Furthermore, karyotypic analysis has shown that PC3 are near-triploid, having 62 chromosomes. Q-band analysis showed no Y chromosome. From a morphological point of view, electron microscopy revealed that PC3 cells show characteristics of a poorly-differentiated adenocarcinoma. They have features common to neoplastic cells of epithelial origins, such as numerous microvilli, junctional complexes, abnormal nuclei and nucleoli, abnormal mitochondria, annulate lamellae, and lipoidal bodies."

[3] cebp.aacrjournals.org/conte...