01/10/2009

A próstata possui dois tipos de receptores para os estrógenos : receptores alfa e beta.
A estimulação do receptor alfa provoca proliferação do epitélio glandular prostático e a estimulação do receptor beta suprime a proliferação tumoral.
No tratamento do câncer de próstata uma das possíveis abordagens é a  administração de antagonistas do receptor estrogênico alfa e dos agonistas do receptor beta.
            Estimulam o receptor estrogênico beta: quercetina com tamoxifeno, estradiol (E2), estriol (E3) , melatonina , etc....
            Lembrar que o cádmio provoca efeito estrogênico por ocupar os receptores alfa, proliferativos e produtores de tumor nos mais variados locais incluindo a próstata e que a melatonina inibe os efeitos estrogênicos do cádmio.

The Evolving Role of Oestrogens and Their Receptors in the Development and Progression of Prostate Cancer

Eur Urol. 2008 Nov 6
Bonkhoff H, Berges R.
Tietzenweg 129, 12203 Berlin, Germany.
CONTEXT: Oestrogens were proven effective in the hormonal treatment of advanced prostate cancer (PCa) >60 yr ago and are still used as second-line hormonal therapy. Paradoxically, oestrogens might also be involved in the development and progression of PCa. OBJECTIVE: To examine mechanisms of how oestrogens may affect prostate carcinogenesis and tumour progression. EVIDENCE ACQUISITION: Recent data obtained from animal, experimental, and clinical studies were reviewed. EVIDENCE SYNTHESIS: The human prostate is equipped with a dual system of oestrogen receptors (oestrogen receptor alpha [ERalpha], oestrogen receptor beta [ERbeta]) that undergoes profound remodelling during PCa development and tumour progression. In high-grade prostatic intraepithelial neoplasia (HGPIN), the ERalpha is upregulated and most likely mediates carcinogenic effects of estradiol as demonstrated in animal models. Preliminary clinical studies with the ERalpha antagonist toremifene have identified the ERalpha as a promising target for PCa prevention. The partial loss of the ERbeta in HGPIN indicates that the ERbeta acts as a tumour suppressor. The ERbeta is generally retained in hormone-naïve PCa but is partially lost in castration-resistant disease. The progressive emergence of the ERalpha and the oestrogen-regulated progesterone receptor (PR) during PCa progression and hormone-refractory disease suggests that these tumours can use oestrogens and progestins for their growth. The TMPRSS2-ERG gene fusion recently reported as a potentially aggressive molecular subtype of PCa is regulated by ER-dependent signalling. TMPRSS2-ERG expression has been found to be increased by ERalpha agonist (oestrogens) and decreased by ERbeta agonists. CONCLUSIONS: Oestrogens and their receptors are implicated in PCa development and tumour progression. There is significant potential for the use of ERalpha antagonists and ERbeta agonists to prevent PCa and delay disease progression. Tumours equipped with the pertinent receptors are potential candidates for this new therapeutic approach.
PMID: 19013008

Tamoxifen and gonadal steroids inhibit colon cancer growth in association with inhibition of thymidylate synthase, survivin and telomerase expression through estrogen receptor beta mediated system

Cancer Lett. 2000 Dec 8;161(1):63-71
Nakayama Y, Sakamoto H, Satoh K, Yamamoto T.
Department of Obstetrics and Gynecology, Nihon University School of Medicine, 30-1 Oyaguchi, Kamimachi, Itabashi, 178-0861, Tokyo, Japan.
Estrogen receptor beta (ERbeta) mediated system was tested in three colon cancer cell lines with different sensitivities. These cell lines express ERbeta and androgen receptor (AR) but not the classic estrogen receptor ERalpha. Combinations of ERbeta ligands such as estradiol (E(2)), 17 epiestriol (17E(3)), quercetin (Q) with tamoxifen (TMX) showed marked growth inhibition. The IC(50) were: 2. 0+/-0.3x10(-15), 3.0+/-1.3x10(-10) and 1.2+/-0.5x10(-14) M for DLD-1, DLD-1/5FU and DLD-1/FdUrd, respectively (TMX+E(2) treatment, mean+/-SD, n=3). The IC(50) of TMX+17E(3) were 3.5+/-1.8x10(-8), 2. 6+/-0.9x10(-8) and 1.4+/-1.1x10(-14) M and that of TMX+Q treatment were 3.4+/-2.1x10(-9), 3.6+/-0.2x10(-9) and 2.6+/-1.1x10(-9) M, respectively. This inhibition was significantly different from single agent treatment at the probability level of P<0.002. Thymidylate synthase expression and survivin expression were also markedly inhibited. The inhibition was highest with TMX+Q and lowest with TMX+dehydroepiandrosterone (DHEA). The expression of telomerase was also inhibited by TMX but combination with ERbeta agonists reversed the inhibition. The cellular sensitivity to 5FU was increased: TMX+E(2), TMX+17E(3) and TMX+Q were 1.7+/-0.5x10(-5), 8. 4+/-3.2x10(-8), 8.2+/-2.9x10(-8) and 6.3+/-3.3x10(-8) M for DLD-1 cells and 7.7+/-4.8x10(-5), 9.1+/-4.9x10(-7), 1.5+/-0.3x10(-9) and 5. 7+/-2.2x10(-8) M for DLD-1/5FU. DLD-1/FdUrd cells had IC(50) of 8. 5+/-6.1x10(-5), 1.8+/-0.8x10(-8), 37+/-1.1x10(-9) and 1.6+/-1. lx10(-9) M (mean+/-SD) for the control, TMX+E(2), TMX+17E(3) and TMX+Q. The present data indicate that ERbeta ligands in combination with TMX may have tumor static effects on colon cancer cells.
PMID: 11078914

Evaluation of estrogenicity of major heavy metals
 Sci Total Environ. 2003 Aug 1;312(1-3):15-21
Choe SY, Kim SJ, Kim HG, Lee JH, Choi Y, Lee H, Kim Y.
Department of Food and Nutrition, University of Ulsan, Ulsan, South Korea.
We have employed an estrogen receptor dependent transcriptional expression assay and E-Screen assay systems to evaluate the estrogenicity of various heavy metals and their species. Using the former, the following estrogenicity ranking was measured: bis(tri-n-butyltin)>cadmium chloride>antimony chloride>barium chloride=chromium chloride>lithium hydroxide>sodium selenate=lead acetate>stannous chloride. Using the latter, the following estrogenicity ranking was measured: bis(tri-n-butyltin)>cadmium chloride>antimony chloride>lithium hydroxide>barium chloride>sodium selenate>chromium chloride. Especially, bis(tri-n-butyltin), cadmium chloride, antimony chloride, lithium hydroxide, barium chloride, and chromium chloride showed estrogenicity in both assay systems. Recent studies suggesting that bis(tri-n-butyltin), cadmium chloride, and lithium hydroxide have estrogenicities are compatible with the present findings. Furthermore, our studies are the first to suggest that antimony, barium, chromium may be estrogenic. A range of estrogenicity was observed for different species of the same heavy metal. The results demonstrate that an estrogen receptor dependent transcriptional expression assay and the E-Screen assay systems could serve as a useful method to assess the estrogenicity of heavy metals.
PMID: 12873394