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Enhancing the effectiveness of androgen deprivation in prostate cancer by inducing Filamin A nuclear localization, "Beyond the Abstract," by Paramita M Ghosh, PhD, et al

BERKELEY, CA (UroToday.com) - Patients with metastatic prostate cancer (mCaP) on androgen deprivation therapy (ADT) eventually relapse – indicative of the development of castration resistant prostate cancer (CRPC). The goal of the present studies was to identify therapy to prolong the efficacy of ADT – and thereby delay CRPC. We had previously shown that nuclear localization of a structural protein, Filamin A (FlnA) sensitized CaP cells to ADT.[1, 2] We now demonstrate that a natural product, genistein combined polysaccharide (GCP), promotes FlnA nuclear localization and thereby enhances sensitivity to ADT in CaP cell lines and animal models.[3]

The current study revealed, in a mouse xenograft model, that administration of GCP for 2 weeks immediately prior to castration prevented recurrence of CWR22 tumors within 211 days following castration, whereas mice who got placebo experienced tumor recurrence after 179 days, a 17.9% increase in time-to-progression (life expectancy of a mouse is 24 months).[3] Immunohistochemistry (IHC) showed FlnA nuclear localization in GCP -- but not placebo-treated mice tumors 2-3 days following castration. However, prior to castration, GCP did not have an effect on tumor growth. These observations support the hypothesis that GCP is ineffective in the presence of an intact androgen axis, but promoted sensitivity to ADT. The results encourage use of GCP in a neo-adjuvant setting to prolong the efficacy of ADT. We did not have tumor samples, at the end of the study, to conduct molecular analyses; however, the data collected indicate that the presence of GCP prevented exodus of FlnA from the nucleus, following castration. Therefore, the AR remained androgen sensitive following castration; therefore ADT was able to prevent AR activation, and hence tumor regrowth.

It is worth noting that GCP, which is prepared from soy and mushroom products, contains 9% genistein, 6% daidzein, 2% glycetin, 3% equol, 15% lipid, 5% protein, and 60% carbohydrate.[4] While multiple reports noted that genistein inhibits metastasis in most cancers,[5, 6] including prostate cancer,[7] some reports found that genistein promoted metastasis.[8] Daidzein appears to prevent genistein-induced metastasis in some models,[9] but not in others.[10] Our data indicate that the effect of dietary isoflavones on tumor promotion and metastasis may be related to the ability of the isoflavones to induce FlnA proteolysis, which influences its ability to translocate to the nucleus.[3] FlnA is a structural protein, which in the cytoplasm promotes actin polymerization; however, upon proteolysis, such as that we propose is induced by GCP, FlnA migrates to the nucleus where it instead regulates AR function.

Indeed, clinical studies from our institute had previously shown that GCP is singularly safe when administered to patients with localized CaP at high doses.[4, 11] However, GCP failed to lower PSA significantly in men with an intact androgen axis – and in vitro studies showed that GCP was more effective in the absence of androgen receptor (AR) activity than in its presence.[12, 13, 14] The current study explains why that is so.[3] FlnA in the nucleus keeps the AR androgen sensitive by preventing ligand-independent AR activation. Castration caused FlnA to be excluded from the nucleus, thereby allowing ligand-independent activation of the AR by other stimuli, which resulted in CRPC development. On the other hand, GCP prevented this by keeping FlnA in the nucleus, and thereby prevented ligand-independent activation of the AR. Therefore, the AR could only be activated by androgen-binding; hence ADT+GCP were sufficient to prevent AR activation. GCP, however, did not prevent AR activity by androgens; hence in patients with localized disease, who are not undergoing ADT, GCP was not able to have an effect.

A 2006 study by Hussain, et al.[15] had shown that a post-treatment PSA nadir < 0.4 ng/ml within 6-7 months following ADT predicts increased survival. However only about 50% of men who undergo ADT experience PSA nadir < 0.4 ng/ml. Although our study did not measure PSA in the mice, the hope is that GCP will suppress PSA levels if administered at the time of or immediately before t < 0.4 ng/ml, and therefore prolong survival in patients with mCaP undergoing ADT.

References:

  1. Bedolla RG, Wang Y, Asuncion A, Chamie K, Siddiqui S, Mudryj MM, Prihoda TJ, Siddiqui J, Chinnaiyan AM, Mehra R et al.: Nuclear versus cytoplasmic localization of filamin A in prostate cancer: immunohistochemical correlation with metastases. Clin Cancer Res. 15: 788-96, 2009.
  2. Wang Y, Kreisberg JI, Bedolla RG, Mikhailova M, deVere White RW and Ghosh PM: A 90 kDa fragment of filamin A promotes Casodex-induced growth inhibition in Casodex-resistant androgen receptor positive C4-2 prostate cancer cells. Oncogene. 26: 6061-70, 2007.
  3. Mooso BA, Vinall RL, Tepper CG, Savoy RM, Cheung JP, Singh S, Siddiqui S, Wang Y, Bedolla RG, Martinez A et al.: Enhancing the effectiveness of androgen deprivation in prostate cancer by inducing Filamin A nuclear localization. Endocr Relat Cancer, 2012.
  4. deVere White RW, Tsodikov A, Stapp EC, Soares SE, Fujii H and Hackman RM: Effects of a high dose, aglycone-rich soy extract on prostate-specific antigen and serum isoflavone concentrations in men with localized prostate cancer. Nutr Cancer. 62: 1036-43, 2010.
  5. Pavese JM, Farmer RL and Bergan RC: Inhibition of cancer cell invasion and metastasis by genistein. Cancer Metastasis Rev. 29: 465-82, 2010.
  6. Zhang Y, Zhu G, Gu S, Chen X, Hu H and Weng S: Genistein inhibits osteolytic bone metastasis and enhances bone mineral in nude mice. Environ Toxicol Pharmacol. 30: 37-44, 2010.
  7. Lakshman M, Xu L, Ananthanarayanan V, Cooper J, Takimoto CH, Helenowski I, Pelling JC and Bergan RC: Dietary genistein inhibits metastasis of human prostate cancer in mice. Cancer Res. 68: 2024-32, 2008.
  8. Nakamura H, Wang Y, Kurita T, Adomat H and Cunha GR: Genistein increases epidermal growth factor receptor signaling and promotes tumor progression in advanced human prostate cancer. PLoS One. 6: e20034, 2011.
  9. Singh-Gupta V, Zhang H, Yunker CK, Ahmad Z, Zwier D, Sarkar FH and Hillman GG: Daidzein effect on hormone refractory prostate cancer in vitro and in vivo compared to genistein and soy extract: potentiation of radiotherapy. Pharm Res. 27: 1115-27, 2010.
  10. Martinez-Montemayor MM, Otero-Franqui E, Martinez J, De La Mota-Peynado A, Cubano LA and Dharmawardhane S: Individual and combined soy isoflavones exert differential effects on metastatic cancer progression. Clin Exp Metastasis. 27: 465-80, 2010.
  11. deVere White RW, Hackman RM, Soares SE, Beckett LA, Li Y and Sun B: Effects of a genistein-rich extract on PSA levels in men with a history of prostate cancer. Urology. 63: 259-63, 2004.
  12. Burich RA, Holland WS, Vinall RL, Tepper C, White RW and Mack PC: Genistein combined polysaccharide enhances activity of docetaxel, bicalutamide and Src kinase inhibition in androgen-dependent and independent prostate cancer cell lines. BJU Int. 102: 1458-66, 2008.
  13. Tepper CG, Vinall RL, Wee CB, Xue L, Shi XB, Burich R, Mack PC and de Vere White RW: GCP-mediated growth inhibition and apoptosis of prostate cancer cells via androgen receptor-dependent and -independent mechanisms. Prostate. 67: 521-35, 2007.
  14. Vinall RL, Hwa K, Ghosh P, Pan CX, Lara PN, Jr. and de Vere White RW: Combination treatment of prostate cancer cell lines with bioactive soy isoflavones and perifosine causes increased growth arrest and/or apoptosis. Clin Cancer Res. 13: 6204-16, 2007.
  15. Hussain M, Tangen CM, Higano C, Schelhammer PF, Faulkner J, Crawford ED, Wilding G, Akdas A, Small EJ, Donnelly B et al.: Absolute prostate-specific antigen value after androgen deprivation is a strong independent predictor of survival in new metastatic prostate cancer: data from Southwest Oncology Group Trial 9346 (INT-0162). J Clin Oncol. 24: 3984-90, 2006.

 

Written by:
Benjamin A. Mooso, Ruth L. Vinall, Ralph W. deVere White and Paramita M. Ghosh as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

Department of Urology, University of California Davis, Sacramento, CA 95817 USA

Enhancing the effectiveness of androgen deprivation in prostate cancer by inducing Filamin A nuclear localization - Abstract

 

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