Genistein as a Potential Tool to Fight Metastasis & More

Author: Daniel S, PhD; Last update: January 31st, 2021

Dear Friends of Cancer Treatments Research Blog,

With this post I would like to share with you some consolidated research on Genistein. As discussed below, Genistein is an outstanding plant extract with promising pharmacological properties. According to a large amount of scientific literature, it has the ability to help address multiple health challenges including cancer. I see Genistein at the same level of importance as the well know plant extracts such as Curcumin, Quercetin, Berberine, EGCG. This is also the reason why RGCC included Genistein in the list of their chemo sensitivity analysis tests (Ref.).

What I find special about Genistein is not only the amount of science available and the numerous intracellular mechanisms that Genistein can modulate, but also the amount of clinical trials that have been performed and the positive result they have delivered in humans, in relation to a variety of health challenges. 

In oncology, Genistein stands out in relation to its capability to inhibit metastasis, and increase effectiveness of chemo- and radio-therapy. The scientific evidence indicates that it can be relevant in multiple types of cancers, with the most evidence clustering in the space of prostate cancer.

Please share if you find this post helpful!

Introduction

Genistein is a compound found in various plants including soybeans and Sophora Japonica. It is a flavonoids, part of the group called isoflavones.  Genistein has attracted major interests in the last few decades since several epidemiological studies indicated that intake of soy rich diets are contributing to a lower incidence of breast and prostate cancer in Asian countries (Ref.).

Genistein adds value to life by supporting the human body to fight various health challenges

Recent scientific and clinical studies suggest Genistein has numerous and various positive effects in the human body such as:

  • Protective effect on nonalcoholic fatty liver disease (Ref.) showing insulin resistance and inflammatory state in a clinical setting (Ref.)
  • Preventive effect against prostate cancer (Ref.1, Ref.2, Ref.3, Ref.4, Ref.5) and breast cancer (Ref.)
  • Presents benefits on menopause symptoms and menopause-related diseases like cardiovascular, osteoporosis, obesity, diabetes, anxiety, depression, and breast cancer. (Ref.)
    • For example, in a 24 month clinical study of 389 postmenopausal women with mild bone loss, use of genistein significantly improved bone density, as compared to placebo (Ref.).
    • When Genistein along with calcium and vitamin D3 were given for over two years to postmenopausal women suffering from osteoporosis, it was observed that the bone mineral density and the bone turnover increased significantly in a time-dependent manner. This also led to a decreased fracture risk in these women. (Ref.)
    • Another study on 247 women suffering from menopausal hot flashes compared the effects of placebo and genistein supplements over a period of one year. The conclusion was that genistein significantly reduced hot flashes as compared to placebo while no adverse effects were seen (Ref.).
  • Beneficial effects in lysosomal storage diseases (mucopolysaccharidoses – MPS) with impact on tissues and organs, including the heart, respiratory system, bones, joints, and central nervous system (Ref.)

Genistein helps fight tumors and metastasis

Next to all these potential health benefits, Genistein is an outstanding anti-cancer substance. Its anticancer activity it is often attributed to three different properties:

  • It has Metastasis inhibiting properties (Ref.1, Ref.2)
  • It has estrogenic-like properties (phytoestrogen) (Ref.)
  • It is a potent inhibitor of tyrosine kinase inhibitor (Ref.) and inhibits e.g., EGFR, PDGFR

Indeed, it has been also suggested that Genistein induces an increase in cell adhesion even in the low nanomolar concentrations. In this way, Genistein can act to inhibit cell detachment, which is an early step in the metastatic cascade (Ref.). Along the same line, other studies have shown that Genistein can inhibit metastasis (Ref.1, Ref.2, Ref.3). When given to animals, after surgery performed to remove implanted breast tumors, Genistein reduced by 10-fold the percent of metastatic burden in the lungs, from hormone-independent human breast cancer cells (Ref.).

Besides these main activities listed above, other outstanding properties related to the anti-cancer activity of Genistein are:

  • Genistein targets topoisomerase II (Ref.1, Ref.2) essential for proliferating cells. This is a very rare property for a plant extract (similar action with several chemotherapies such as Etoposide)
  • Genistein stimulates Cl- secretion in endometrial epithelial cells (Ref.)
    • Due to this reason it is best not to combine Genistein with DCA (see here a discussion on the link between DCA effectiveness and Cl-)
  • Inhibits/reduces glucose absorption by the cancer cells, by binding to GLUT1 (binds the transporter on the external face whereas e.g. Quercetin interacts with the internal face) (Ref.). It is also a strong inhibitor of GLUT4 (Ref.) which is another highly relevant glucose transporter often over-expressed by cancer cells
  • Wnt signaling inhibition (Ref.)
  • Hedgehog Pathway inhibitor (Ref.)
  • Inhibition of vascular endothelial growth factor (VEGF) induction of COX-2 activity due to the tyrosine kinase inhibition (Ref.)
  • EGFR inhibition (Ref.)
  • Angiogenesis inhibitor (Ref.)
  • Down-regulates the expression of MMP-9, MMP-2 (Ref.)
  • Inhibits TGF-β signaling (Ref.)
    • patients with hereditary hemorrhagic telangiectasia (a genetic disorder involving mutations in proteins that regulate TGFbeta receptor complex formation and signaling) had dramatic attenuation of their symptoms after one weeg of ingesting soy-based beverages (Ref.)

Here is a diagram and here a table presenting more of the anticancer mechanisms related to Genistein.

In resonance with the highly relevant mechanisms listed above, Genistein has been found effective in killing cancer cells of various types such as:

  • Prostate Cancer (Ref.1, Ref.2)
  • Lung Cancer (Ref1., Ref.2)
  • Liver Cancer (Ref1, Ref.2.)
  • Renal Cancer (Ref.)
  • Pancreatic Cancer (Ref.)
  • Bladder cancer (Ref.)
  • Colon Cancer (Ref.)
  • Glioblastoma (Ref.)
  • Hormone-independent human Breast Cancer cells including triple negative breast cancer (Ref.)
  • Leukemia (Ref.)
  • Ovarian Cancer (Ref.)
  • and others

Indeed, as it will be discussed in the sections below, a wide range of clinical studies on Genistein have been performed, demonstrating both its good safety profile even at large doses, and encouraging anti cancer potential.

Genistein is also expected to reduce side effects of chemotherapy and increase its effectiveness (Ref.) due to mechanisms such as multi drug resistance (MDR) proteins inhibition (Ref.). As it will be see in some of the clinical studies presented below, it has been indeed found that Genistein can increase effectiveness of chemotherapy.

Pharmacokinetic & Increasing Absorption of Genistein

Pharmacokinetic and pharmacodynamic studies in humans have shown that doses such as 2, 4, or 8 mg/kg (8mg/kg would be 560mg for a person of 70kg) taken orally, are safe and can lead to plasma concentrations of genistein that have been associated with antimetastatic activity in vitro (Ref.).

Nevertheless, as it is the case for most of the natural extracts, the absorption of Genistein in the human body (Ref.) can be further improved using various techniques.

One such technique was the base for the creation of Genistein Combined Polysaccharide which is produced by culturing soybean with mycelia from the Ganoderma lucidum mushroom. This produces beta-glucosidase, an enzyme that can convert the glucoside forms of isoflavones into more easily absorbed aglycone forms (Ref.).

Another way to increase the absorption of Genistein is by combining its administration with Inulin. Inulins are a group of naturally occurring polysaccharides produced by many types of plants with prebiotic capabilities, meaning that it feeds the good bacteria in the gut. Indeed, a randomized, double-blind, crossover study including healthy postmenopausal women demonstrated that the intake of Genistein with Inulin for 21 d was followed by higher plasma concentrations. There was a 91% observed increase of Genistein plasma concentrations when combined with Inulin, compared with the formulation without inulin (Ref.).

Here is a very good report on the Bioavailability and Pharmacokinetics of Genistein https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4010305/

Human Studies on Anti-Cancer Activity of Genistein by Cancer Type

Genistein & Prostate Cancer

Several phase I and II clinical trials using isoflavone supplementation have been conducted in the patients with prostate cancer. The studies performed so far and case reports expose the added value of Genistein for prostate cancer patients:

  • Regression of Prostate Cancer following administration of Genistein based nutritional supplement https://www.liebertpub.com/doi/10.1089/107555302760253694
    .
    Presented case, where the mass significantly decreased in size and PSA too significantly decreased following the administration of GCP, at a low dose of the supplement 1.5 g/d from 19.4 ng/mL to 4 ng/mL in 44 days. Moreover, no residual cancer was identified in the radical prostatectomy specimen
    .
  • Prostate Cancer Prior to Radical Prostatectomy: A Randomized, Placebo-Controlled, Double-Blind Phase 2 Clinical Trial (Ref.) concluding that “Genistein at a dose that can be easily obtained from a diet rich in soy reduced the level of serum PSA in patients with localized CaP, without any effects on hormones. It was well tolerated and had a beneficial effect on blood cholesterol.”
    .
  • A study published in 2020, performed in Belgium, investigating the efficacy of a 6-month fermented soy supplement to stabilize or decrease PSA  in men with an elevated risk of prostate cancer. Conclusion of the study: “we demonstrated a significant PSA modulatory effect of a 6-month intake of a fermented soy supplement in men with an elevated risk of PCa and a prior negative prostate biopsy. This modulatory effect was more strongly evident in the subgroup of patients with an elevated PSA (≥ 4 ng/ml) … Further evaluation of the role of fermented soy supplements is warranted in the preventive and therapeutic setting of men with an elevated risk of PCa.” (Ref.)
    .
  • Another human study also showed that a daily diet containing bread rich in soy favorably influences the PSA level and the free/total PSA ratio in patients with prostate cancer, suggesting the inhibitory effects of phytoestrogen on PSA level (Ref.)

Genistein & Breast Cancer

Genistein is a pythoestrogen that is structurally similar to Estradiol. Compared to the estrogens produced by the human body, Genistein is a weak estrogen. That means it has much lower binding affinity to the estrogen receptors compared to the normal estrogen. This makes Genistein a compound with potential to normalize hormones in the body. More specifically:

  • when the body has too much estrogen, the addition of Genistein could help as it competes with estrogen by binding to estrogen receptors, but in a weaker manner compared to the strong action of normal human estrogens – so it would act more like an estrogen-receptor blocker
  • on the other hand, when the body has too little estrogen, addition of Genistein could help to deliver some minimum estrogenic effects required for a normal function of the human body

Due to this reason, Genistein may have breast cancer prevention capabilities (as it has the tendency to normalize estrogen action in the body). Indeed, studies have shown that addition of soy food can reduce the risk of breast cancer and improve the prognosis of breast cancer patients (Ref.1, Ref.2, Ref.3).  A large nested case-control study including 140,420 subjects during 10.6 years of follow up showed 66% reduction in breast cancer risk with higher concentration of plasma genistein (>354ng/ml) in Japanese women (Ref.).

Nevertheless, it is best not to use phytoestrogens when the patient is on hormonal medication that needs to bind to estrogen receptors (such as Tamoxifen used to treat breast cancer). In such special condition, it is best to fully allow Tamoxifen to bind to estrogen receptors and do its job, and thus avoid the use of Genistein or other phytoestrogens (Ref.1, Ref.2) (even if this point is not totally clear since there is also literature suggesting that Genistein may actually help enhance Tamoxifen effectiveness (Ref.1, Ref.2)).

If Tamoxifen or similar hormonal drugs (estrogen reducing or estrogen binding modulators) are not used due to various reasons, the use of Genistein may make very much sense in order to try and reduce the action of normal estrogen on the estrogen receptors. However, considering the agonist activity of genistein against estrogn receptors (ER), its use in women with established ER-positive breast cancers must be carefully considered and best avoided.

Recent studies have also proposed that Genistein may be effective for the prevention and reversal of AHR-dependent BRCA1 hypermethylation, and the restoration of ERα-mediated response, thus imparting the sensitivity of Triple Negative Breast Cancer (TNBC) to antiestrogen therapy (Ref.).  These effects were linked to acquired sensitivity of TNBC cells to the growth inhibitory effects of tamoxifen. Based on these results, it may make sense to add Genistein to a treatment strategy focused on regaining sensitivity of breast tumors to Tamoxifen, when that sensitivity is lost.

Therefore, here is my interpretation based on the availble literature: 

  • for prevention it seems to be good, specifically after menopause, but I would use moderate doses
  • for active cancer – If ER-negative breast cancer including TNBC, Genistein is expected to add value as discussed above
  • for active cancer – if ER-positive and patient on Tamoxifen, there is conflicting science so I would probably stay away
  • for active cancer – if ER-positive and patient lost sensitivity (effectivness) to Tamoxifen, Genistein may help recover that sensitivity
  • active cancer – if ER-positive and patient does not want or have acess to Tamoxifen and no other hormonal treatment, it is expected to help lower the effect of estrogen as Genistein will compete with estrogen on ER

Genistein effectiveness against breast cancer cell lines has been increased when Genistein was combined with Sulforaphane (an extract from cruciferous vegetables such as broccoli sprouts and kale) (Ref.).

Finally, due to this weak estrogenic action, Genistein may be an outstanding supplement for women at menopause. Indeed, age-related lower levels of produced estrogen during the menopause can lead to osteoporosis and atherosclerosis. Genistein, has been shown to have the abilities to at least partially compensate for the need of estrogen in such cases. Furthermore, it has been suggested that phytoestrogens can potentially be used as chemopreventive agents in older postmenopausal women (Ref.).

Genistein and Colorectal Cancer

Genistein has been found to kill colorectal cancer cells via various mechanisms such as PI3K/Akt pathway attenuation (Ref.) and Wnt signaling inhibition (Ref.). It has also been suggested that Genistein reduces chemotherapy resistance in cancer cell lines when combined with either 5FU or platinum-based chemotherapeutic agents (Ref.).

In line with the above, a phase I/II pilot clinical trials has been recently performed. In this study, Genistein has been given to cancer patients in combination with FOLFOX to treat metastatic colorectal cancer (Ref.). It has been administered orally for 7 days every 2 weeks, at a dose of 30–600 mg/day without any significant adverse effects. According to the published results, the addition of Genistein lead to an improved efficacy of treatment in comparison to published response rates and PFS with chemotherapy alone.

Genistein and Pancreatic Cancer

A phase 1b clinical trial using up to 1600 mg/day Genistein in combination with Gemcitabine, to treat pancreatic cancer patients in Sweden has demonstrated positive results (Ref.): “9/16 demonstrated response (SD, PR) according to the RECIST criteria and in some the survival time was remarkably long. In seven out of these nine patients, the clinical response was accompanied by a significant drop in CA 19-9.”

Genistein and Bladder Cancer

Epidemiologic data indicate that populations with high dietary soy intake have lower incidences of bladder cancer than those following more Western diets (Ref.). In addition, it has been suggested that Genistein has the ability to sensitizes bladder cancer cells to HCPT treatment (Ref.). Hydroxycamptothecin (HCPT) is a DNA topoisomerase I inhibitor, which has been utilized in chemotherapy for bladder cancer for nearly 40 years. 

A Phase 2 cancer chemopreventionbBiomarker trial of Isoflavone G-2535 (Genistein) in presurgical Bladder Cancer patients has been performed https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324663/  In this study, a significant reduction of EGFR phosphorylation was seen in the genistein-treated subjects as compared with placebo. This anti-cancer activity is inline with previous studies indicating that genistein can induce inhibition of EGFR activity and EGF-mediated responses such as proliferation and cell motility (Ref.).

Case Reports in Human

  • A series of successfull case reports presented in a patent published during 2016, where Genistein may be one of the major contributor to the results given the high dose used (Ref.). Very intresting read!
  • An ancdotal report on Inspire: “Genistein – my wife was told she was chemo resistant and when we added genistein, her CA125 dropped from 79 to 18 in 1 chemo treatment. Genistein is claimed to 1. block estrogen, 2. kill OVC, 3. Overcome chemo resistance, 4. Restore P53 function
    NOTE: I recently had a discussion with Our Oncologist at Jefferson in Phila and he was quite interested in Genistein – even to the point as possible maintenance therapy” (Ref.)

Dose & Source

The typical dose in the studies discussed above were in the range of 300 to 600 mg/day. This dose range was found safe. However, the case reports addressed in the patent (Ref) seem to suggest higher doses as well.

Genistein can be found as a food supplements in capsules at online shops. The maximum dose available in the market per capsule is at 250 mg. 

Others

Scientists have demonstrated an increase in intracellular levels of EGCG of 2- to 5-fold in the presence of genistein, in HT-29 human colon cancer cells. (Ref.) Therfore, Genistein increases the potential of the Green Tea Extract EGCG.

Recommended Food Supplements Shop: MCS Formulas

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References

CANCER THERAPY, United States Patent Application 20160030454 https://www.freepatentsonline.com/y2016/0030454.html

The present invention is directed to compositions and methods for the treatment of cancers, particularly cancers of epithelial origin. Therapy with a plurality of nutraceutical, non-chemotherapeutic and chemotherapeutic agents, that together target a plurality of cancer-supportive processes in a patient are disclosed. Among other things, the present invention encompasses the insight that redundant targeting of multiple such pathways provides effective treatment of various cancer, including late-stage cancers, metastasized cancers, and/or cancers that have failed treatment with traditional chemotherapy and/or other therapeutic modalities.

Genistein as Potential Therapeutic Candidate for Menopausal Symptoms and Other Related Diseases https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864469/

Plant-derived compounds have recently attracted greater interest in the field of new therapeutic agent development. These compounds have been widely screened for their pharmacological effects. Polyphenols, such as soy-derived isoflavones, also called phytoestrogens, have been extensively studied due to their ability to inhibit carcinogenesis. These compounds are chemically similar to 17β-estradiol, and mimic the binding of estrogens to its receptors, exerting estrogenic effects in target organs. Genistein is an isoflavone derived from soy-rich products and accounts for about 60% of total isoflavones found in soybeans. Genistein has been reported to exhibit several biological effects, such as anti-tumor activity (inhibition of cell proliferation, regulation of the cell cycle, induction of apoptosis), improvement of glucose metabolism, impairment of angiogenesis in both hormone-related and hormone-unrelated cancer cells, reduction of peri-menopausal and postmenopausal hot flashes, and modulation of antioxidant effects. Additionally, epidemiological and clinical studies have reported health benefits of genistein in many chronic diseases, such as cardiovascular disease, diabetes, and osteoporosis, and aid in the amelioration of typical menopausal symptoms, such as anxiety and depression. Although the biological effects are promising, certain limitations, such as low bioavailability, biological estrogenic activity, and effects on target organs, have limited the clinical applications of genistein to some extent. Moreover, studies report that modification of its molecular structure may eliminate the biological estrogenic activity and its effects on target organs. In this review, we summarize the potential benefits of genistein on menopause symptoms and menopause-related diseases like cardiovascular, osteoporosis, obesity, diabetes, anxiety, depression, and breast cancer.

A phase I dose escalation trial of AXP107-11, a novel multi-component crystalline form of genistein, in combination with gemcitabine in chemotherapy-naive patients with unresectable pancreatic cancer https://pubmed.ncbi.nlm.nih.gov/27234064/

Phytoestrogens for Cancer Prevention and Treatment https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759898/

Efficacy and Safety of Short-Term Genistein Intervention in Patients with Localized Prostate Cancer Prior to Radical Prostatectomy: A Randomized, Placebo-Controlled, Double-Blind Phase 2 Clinical Trial https://www.tandfonline.com/doi/abs/10.1080/01635581.2011.582221

Prostate-Specific Antigen Modulatory Effect of a Fermented Soy Supplement for Patients with an Elevated Risk of Prostate Cancer: a Non-Randomized, Retrospective Observational Registration https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659407/

Genistein supplementation improves insulin resistance and inflammatory state in non-alcoholic fatty liver patients: A randomized, controlled trial https://www.clinicalnutritionjournal.com/article/S0261-5614(17)30202-9/fulltext

Effects of the phytoestrogen genistein on bone metabolism in osteopenic postmenopausal women: a randomized trial https://pubmed.ncbi.nlm.nih.gov/17577003/

Effects of the phytoestrogen genistein on hot flushes, endometrium, and vaginal epithelium in postmenopausal women: a 1-year randomized, double-blind, placebo-controlled study https://pubmed.ncbi.nlm.nih.gov/17251874/

Inhibition of cancer cell invasion and metastasis by genistein https://link.springer.com/article/10.1007/s10555-010-9238-z

Understanding genistein in cancer: The “good” and the “bad” effects: A review 

Phase I and II studies of the decitabine–genistein drug combination in advanced solid tumors. https://ascopubs.org/doi/abs/10.1200/jco.2015.33.15_suppl.e13556

It’s Time for Clinicians to Reconsider Their Proscription Against the Use of Soyfoods by Breast Cancer Patients

Antiosteoporotic Activity of Genistein Aglycone in Postmenopausal Women: Evidence from a Post-Hoc Analysis of a Multicenter Randomized Controlled Trial https://pubmed.ncbi.nlm.nih.gov/28241420/

Natural Bioactive Compounds: Alternative Approach to the Treatment of Glioblastoma Multiforme (Ref.)

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7 thoughts on “Genistein as a Potential Tool to Fight Metastasis & More

  1. Hi Daniel~

    Thank you very much for creating this post to share the research information on Genistein.

    I’ve started to drink Soy Milk quite often after I learnt this isoflavone, Genistein, from foods introduced in the following website:

    https://www.eattobeat.org/

    Food: Soy Milk

    Scientific Name: From Glycine max
    Type: Beverages & Soups

    Natural Antiangiogenic Molecules:
    Genistein,
    Daidzein, Pyridoxine (Vitamin B6), Bowman-Birk inhibitor, Kaempferol, Phytic acid

    Isoflavones in soy products are:
    anti-proliferative, anti-oxidant, anti-inflammatory, and demonstrate activity against cancer in multiple studies.

    Soy Milk, made by boiling soy beans, has 60% more active (aglycone form of) Genistein than raw soy beans.

    Thanks.
    Kimster

    1. Thank you, Manuel! Inulin would only indirectly help for that just because the Genistein blood level is going to be higher, there will be more going through BBB. But it will not enhance the penetration of BBB. Based on the info I came across while going through the literature, Genistein is not that bad at going through BBB.

      Very nice to hear your mom is well! 🙂

      Kind regards,
      Daniel

  2. Thank you Daniel,

    My RGCC some years ago showed genistein good sensibility to my lymphoma no avoid angiogenesis so i think still is a good supplement in my NED status.

    My question is if you see any problem to take it the four days ,during the week, that i take mcs artemisin supplement or is better to take the rest of the 3 days

    Excelent info and supplement of genistein

    Warm regards

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