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Genistein, a phytoestrogen in soy, may accelerate castrate resistant prostate cancer


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JimJimJimJim

Jim Marshall (not a doctor) said ...


Genistein, a component of soy, is sometimes added to alternative medicines for prostate cancer. It is a type of chemical called a phytoestrogen. It may protect against getting prostate cancer in the first place.


 


But this paper reports the bad news that once your prostate cancer gets more advanced, genistein may help it to grow faster.


 


An unusual feature of the drug's activity is that it made cancers grow faster in the lab at concentrations our bodies can take (physiological doses), but slowed the cancers in the lab at higher doses than our bodies can take.


... end Jim


 


PLoS One. 2013 Oct 22;8(10):e78479. doi: 10.1371/journal.pone.0078479. eCollection 2013.


Differential effects of genistein on prostate cancer cells depend on mutational status of the androgen receptor.


Mahmoud AM1, Zhu T, Parray A, Siddique HR, Yang W, Saleem M, Bosland MC.


Author information


 


 


Abstract


Blocking the androgen receptor (AR) activity is the main goal of therapies for advanced prostate cancer (PCa). However, relapse with a more aggressive, hormone refractory PCa arises, which harbors restored AR activity. One mechanism of such reactivation occurs through acquisition of AR mutations that enable its activation by various steroidal and non-steroidal structures. Thus, natural and chemical compounds that contribute to inappropriate (androgen-independent) activation of the AR become an area of intensive research. Here, we demonstrate that genistein, a soy phytoestrogen binds to both the wild and the Thr877Ala (T877A) mutant types of AR competitively with androgen, nevertheless, it exerts a pleiotropic effect on PCa cell proliferation and AR activity depending on the mutational status of the AR. Genistein inhibited, in a dose-dependent way, cell proliferation and AR nuclear localization and expression in LAPC-4 cells that have wild AR. However, in LNCaP cells that express the T877A mutant AR, genistein induced a biphasic effect where physiological doses (0.5-5 µmol/L) stimulated cell growth and increased AR expression and transcriptional activity, and higher doses induced inhibitory effects. Similar biphasic results were achieved in PC-3 cells transfected with AR mutants; T877A, W741C and H874Y. These findings suggest that genistein, at physiological concentrations, potentially act as an agonist and activate the mutant AR that can be present in advanced PCa after androgen ablation therapy.


PMID: 24167630


 


This extract can be found on http://PubMed.com, and is in the public domain.


On PubMed.com there will be a link to the full paper (often $30, sometimes free).


 


Any highlighting (except the title) is not by the author, but by Jim Marshall.


Jim is not a doctor.


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alanbarlee

Hi Jim (and All),

 

I want to clarify a bit further this excellent but quite complex research paper about how a soy (genistein)-containing diet affects prostate cancer at its different stages.

 

The key finding is that whether soy inhibits or stimulates cell proliferation depends very much on the mutation (molecular) profile of one's individual cancer. Since the presence of adverse mutations increases with advanced (and castrate-resistant prostate, the possibility of a crossover effect - where soy changes from an inhibitor to a promoter - is higher in such cases. However, in the absence of an individual androgen receptor (AR) profile, the benefit or otherwise of continued use of soy for an individual is hard to judge. Like much in life, it's tricky balancing benefits and costs in an uncertain world!       

 

A relevant extract toward the end of the full paper referred to above (that omits most of the technical stuff) provides some material that may help. 

 

 

Collectively, our data provides strong evidence that the differential response of LNCaP and LAPC-4 cells to genistein is AR mediated and T877A mutation dependent.

 

Results from other in vitro studies examining the effects of genistein on PCa cells have yielded conflicting results: some studies demonstrated that genistein downregulates AR expression and inhibits cell proliferation, whereas others reported stimulatory effects of genistein on PCa cell proliferation and AR activity. Our findings indicate that these discrepancies are conceivably attributable to - 

(a) the utilization of the LNCaP PCa cell line because it contains the T877A AR mutation and

(B) the limited range of mostly pharmacological genistein concentrations used in most of these studies.

 

Although in vitro studies with purified soy compounds in cancer cells may not reflect effects of dietary soy on prostate cancer in vivo, epidemiological observations suggest a protective role of soy in PCa, implicating genistein because it is the most abundant and biologically active soy isoflavone. We observed maximal stimulation of cell proliferation and inhibition of apoptosis in response to genistein in LNCaP cells at a dose of 1µmol/L, indicating that apparently modest exposure to the phytoestrogen genistein can have significant adverse biological consequences for prostate cancers that carry promiscuously mutant AR. The concentrations we used are well within the range of physiological levels that can be achieved by humans through daily soy consumption. The upper limit of genistein serum levels in Japanese people consuming soy-rich diets is in the order of 2 µmol/L. Levels of soy isoflavones in prostate tissue may exceed that in serum by 4 to 6-fold, indicating that genistein levels in prostate tissue do not exceed 8 to 12 µmol/L, emphasizing the importance of the physiological concentrations used in our study.

 

Cumulatively, our data add a new insight to the understanding of the bioactivities of genistein in PCa, which are affected by several factors including the dose of genistein and the mutational status of the AR. This study indicated that genistein at low, physiologically relevant exposure levels can be an endocrine disruptor and can result in altered activity of multiple tumor-derived mutant AR alleles. Therefore, genistein, especially at lower doses, can function as a potential ‘‘hormone sensitizer’’ of the mutant ARs present in advanced PCa following androgen ablation therapy, thereby possibly contributing toward therapeutic relapse in soy consuming PCa patients who have cancers carrying the T877A or similar mutations such as W741C and H874Y. The T877A AR variant is of obvious biological relevance as it has been reported in up to 12.5% of hormone-refractory PCa, and is considered an example of a range of AR variants in PCa that have promiscuous ligand specificity, such as the K580R and the V715M variants that are induced by estradiol at 0.1 nmol/L.

 

Cheers,

Alan 

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