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Beyond the Abstract - Does valproic acid induce neuroendocrine differentiation in prostate cancer? by Abhinav Sidana, MD

BERKELEY, CA (UroToday.com) - Histone acetylation and deacetylation by histone acetyl transferases and histone deacetylases (HDACs) is involved in the epigenetic regulation in human cells.1, 2

Recently, this post-translational modification has become a popular molecular target for cancer therapy. HDAC inhibitors (HDACIs) have demonstrated significant antitumor activity by hyperacetylation of nucleosomal histones resulting in re-expression of repressed genes that produce growth arrest, terminal differentiation, and/or apoptosis in carcinoma cells.3 More than 12 different HDACI are currently in clinical trials as cancer monotherapies, or in combination with chemotherapy or radiation therapy, in patients with hematologic and solid tumors. These preliminary studies show that HDACIs provide therapeutic effects and are well tolerated by patients.1 Valproic Acid (VPA), an HDACI causes marked decrease in proliferation of Prostate Cancer (PCa) cells in vitro and significant reduction in tumor volume in vivo.4 High expression of HDAC2 in prostate cancer was associated with poor prognosis.5 Thus VPA, which is capable of inhibiting HDACs classes I and IIa may be a good option for PCa therapy.

The concept of neuroendocrine differentiation in prostate cancer has attracted considerable attention as a new finding with potential diagnostic, prognostic and therapeutic role. Small cell PCa and prostatic carcinoid are relatively rare and are considered pure NE tumors with a poor prognosis. Neuroendocrine differentiation thus has been suggested as a poor prognostic sign by some authors. Studies evaluating the role of focal NE differentiation have produced varied results: some report it as a bad prognostic marker while other show little or no relationship to prognosis.6-10 Some studies have documented increased neuroendocrine markers (neuron-specific enolase) after in vitro treatment of prostate cancer cell lines with HDACI’s11, 12 indicating neuroendocrine transdifferentiation. This has raised some concerns about possible use of HDACI’s as antitumoral agent in PCa treatment.

We studied the expression of various NE markers through Immunohistochemistry after treatment by VPA of PCa cells both in vitro and in vivo. The findings in our study do not support any neuroendocrine differentiating role of VPA in in vivo setting. On the contrary, Chromogranin A which is reported to be better predictors of neuroendcocrine differentiation than neuron specific enolase13, 14 was reduced in all studied cell lines following chronic VPA treatment. Our results are in line with studies done on pure neuroendocrine tumors such as carcinoid, pheochromocytoma and small cell lung cancers where HDACIs have actually been shown to exert antitumor effects by promoting apoptosis, reducing NE phenotype and expression of NE markers.15-17 The current study allays the concerns about possibility of neuroendocrine differentiation of prostate cancer with VPA treatment. After our promising results with VPA treatment in vivo studies, we are now running a randomized clinical trial using VPA monotherapy in patients with advanced prostate cancer.

References: 

  1. Dokmanovic, M., Clarke, C., Marks, P. A.: Histone deacetylase inhibitors: overview and perspectives. Mol Cancer Res, 5: 981, 2007
  2. Konstantinopoulos, P. A., Karamouzis, M. V., Papavassiliou, A. G.: Focus on acetylation: the role of histone deacetylase inhibitors in cancer therapy and beyond. Expert Opin Investig Drugs, 16: 569, 2007
  3. Glaser, K. B.: HDAC inhibitors: Clinical update and mechanism-based potential. Biochem Pharmacol, 74: 659, 2007
  4. Xia, Q., Sung, J., Chowdhury, W. et al.: Chronic administration of valproic acid inhibits prostate cancer cell growth in vitro and in vivo. Cancer Res, 66: 7237, 2006
  5. Weichert, W., Roske, A., Gekeler, V. et al.: Histone deacetylases 1, 2 and 3 are highly expressed in prostate cancer and HDAC2 expression is associated with shorter PSA relapse time after radical prostatectomy. Br J Cancer, 2008
  6. Slovin, S. F.: Neuroendocrine differentiation in prostate cancer: a sheep in wolf's clothing? In: Nat Clin Pract Urol, vol. 3, pp. 138, 2006
  7. Bonkhoff, H.: Neuroendocrine differentiation in human prostate cancer. Morphogenesis, proliferation and androgen receptor status. Ann Oncol, 12 Suppl 2: S141, 2001
  8. Tamas, E. F., Epstein, J. I.: Prognostic significance of paneth cell-like neuroendocrine differentiation in adenocarcinoma of the prostate. Am J Surg Pathol, 30: 980, 2006
  9. Yamada, Y., Nakamura, K., Aoki, S. et al.: Is neuroendocrine cell differentiation detected using chromogranin A from patients with bone metastatic prostate cancer a prognostic factor for outcome? Oncol Rep, 15: 1309, 2006
  10. Ishida, E., Nakamura, M., Shimada, K. et al.: Immunohistochemical analysis of neuroendocrine differentiation in prostate cancer. Pathobiology, 76: 30, 2009
  11. Valentini, A., Biancolella, M., Amati, F. et al.: Valproic acid induces neuroendocrine differentiation and UGT2B7 up-regulation in human prostate carcinoma cell line. Drug Metab Dispos, 35: 968, 2007
  12. Frigo, D. E., McDonnell, D. P.: Differential effects of prostate cancer therapeutics on neuroendocrine transdifferentiation. Mol Cancer Ther, 7: 659, 2008
  13. Angelsen, A., Syversen, U., Haugen, O. A. et al.: Neuroendocrine differentiation in carcinomas of the prostate: do neuroendocrine serum markers reflect immunohistochemical findings? Prostate, 30: 1, 1997
  14. Kamiya, N., Suzuki, H., Kawamura, K. et al.: Neuroendocrine differentiation in stage D2 prostate cancers. Int J Urol, 15: 423, 2008
  15. Adler, J. T., Hottinger, D. G., Kunnimalaiyaan, M. et al.: Histone deacetylase inhibitors upregulate Notch-1 and inhibit growth in pheochromocytoma cells. Surgery, 144: 956, 2008
  16. Greenblatt, D. Y., Vaccaro, A. M., Jaskula-Sztul, R. et al.: Valproic acid activates notch-1 signaling and regulates the neuroendocrine phenotype in carcinoid cancer cells. Oncologist, 12: 942, 2007
  17. Platta, C. S., Greenblatt, D. Y., Kunnimalaiyaan, M. et al.: Valproic acid induces Notch1 signaling in small cell lung cancer cells. J Surg Res, 148: 31, 2008

 

Written by:
Abhinav Sidana, MD* 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.

 

*Division of Urology, University of Cincinnati College of Medicine, Cincinnati, OH
Previously- Post Doctoral Fellow at Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD

 

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