Piper cubeba Targets Multiple Aspects of the Androgen-Signalling Pathway. A Potential Phytotherapy against Prostate Cancer Growth?

Abstract

Despite the high prevalence of prostate cancer (PC) in the Western world, there is a dearth of effective medication. Since the androgen-signalling pathway is very much involved in PC growth and development, we investigated the potential of Piper cubeba L. extract, P9605, in targeting multiple events simultaneously within this pathway. This may be more effective compared to an antiandrogen monotherapy. Our results indicated that P9605 inhibited proliferation in androgen-dependent LNCaP human prostate cancer cells by reducing DNA synthesis and inducing apoptosis. This antigrowth effect was less pronounced in androgen-independent PC-3 prostate cancer cell lines. P9605 potently inhibited 5α-reductase II activity, which is responsible for converting testosterone to its active form, dihydrotestosterone (DHT), in the prostate. It also acted as an antagonist at recombinant wild-type androgen receptors (AR). P9605 suppressed cell growth and prostate-specific antigen (PSA) secretion stimulated by physiological concentrations of DHT in LNCaP cells. Interestingly, it down-regulated AR levels. In conclusion, our findings suggest that P9605 may potentially retard the growth of androgen-dependent PC via several mechanisms.

Key words

Piper cubeba (L.) - Piperaceae - LNCaP cells - apoptosis - 5α-reductase II - androgen receptor - PSA

References

• 1 Coffey D S, Isaacs J T. Control of prostate growth.  Urology. 1981;  17 17-24
• 2 Michael K Brawer M. Hormonal therapy for prostate cancer.  Rev Urol. 2006;  8 (Suppl 2) 35-47
• 3 Feldman B J. The developement of androgen-independent prostate cancer.  Nat Rev Cancer. 2001;  1 34-5
• 4 Hsu J C, Zhang J, Dev A, Wing A, Bjeldanes L F, Firestone G L. Indole-3-carbinol inhibition of androgen receptor expression and downregulation of androgen responsiveness in human prostate cancer cells.  Carcinogenesis. 2005;  26 1896-904
• 5 Bemis D L, Capodice J L, Desai M, Buttyan R, Katz A E. A concentrated aglycone isoflavone preparation (GCP) that demonstrates potent anti-prostate cancer activity in vitro and in vivo.  Clin Cancer Res. 2004;  10 5282-92
• 6 Medicinal Herb Index Indonesia, 2nd edition. Jakarta; PT Eisai Indonesia 1995: 21
• 7 Usia T, Watabe T, Kadota S, Tezuka Y. Potent CYP3A4 inhibitory constituents of Piper cubeba.  J Nat Prod. 2005;  68 64-8
• 8 Gormley G J, Stoner E, Bruskewitz R C, Imperato-McGinley J, Walsh P C, McConnell J D. et al . The effect of finasteride in men with benign prostatic hyperplasia. The Finasteride study group.  N Engl J Med. 1992;  327 1185-91
• 9 Balk S P, Ko Y J, Bubley G J. Biology of prostate-specific antigen.  J Clin Oncol. 2003;  21 383-91
• 10 Le H T, Schaldach C M, Firestone G L, Bjeldanes L F. Plant derived 3,3′-diindolylmethane is a strong androgen antagonist in human prostate cancer cells.  J Biol Chem. 2003;  278 21 136-45
• 11 Sciarra A, Cardi A, Di Silverio F. Antiandrogen monotherapy: recommendations for the treatment of prostate cancer.  Urol Int. 2004;  72 91-8
• 12 Suzuki H, Ueda T, Ichikawa T, Ito H. Androgen receptor involvement in the progression of prostate cancer.  Endocr Rel Cancer. 2003;  10 209-16
• 13 Buchanan G, Greenberg N M, Scher H I, Harris J M, Marshall V R, Tilley W D. Collocation of androgen receptor gene mutations in prostate cancer.  Mol Oncol. 2001;  7 1273-81
• 14 Edwards J, Bartlett J MS. The androgen receptor and signal-transduction pathways in hormone-refractory prostate cancer. Part 1: modifications to the androgen receptor.  BJU Int. 2005;  95 1320-6
• 15 Edwards J, Bartlett J MS. The androgen receptor and signal-transduction pathways in hormone-refractory prostate cancer. Part 2: androgen-receptor cofactors and bypass pathways.  BJU Int. 2005;  95 1327-35
• 16 Johnstone R, Ruefli A, Lowe S. Apoptosis a link between cancer genetics and chemotherapy.  Cell. 2002;  108 153-64
• 17 Horoszewicz J S, Leong S S, Kawinski E, Karr J P, Rosenthal H, Chu T M. et al . LNCaP model of human prostatic carcinoma.  Cancer Res. 1983;  43 1809-18
• 18 Kaighn M E, Narayan K S, Ohnuki Y, Lechner J F, Jones L W. Establishment and characterization of a human prostatic carcinoma cell line (PC-3).  Invest Urol. 1979;  17 16-23
• 19 Lee C, Sutkowski D M, Sensibar J A, Zelner D, Kim I, Amsel I. et al . Regulation of proliferation and production of prostate-specific antigen in androgen-sensitive prostatic cancer cells, LNCaP, by dihydrotestosterone.  Endocrinology. 1995;  136 796-803
• 20 Cleutjens K BJM, van Eekelen C CEM, van der Korput H AGM, Brinkmann A O, Trapman J. Two androgen response regions cooperate in steroid hormone regulated activity of the prostate-specific antigen promoter.  J Biol Chem. 1996;  271 6379-88
• 21 Cohen P, Peehl D M, Graves H C, Rosenfeld R G. Biological effects of prostate specific antigen as an insulin-like growth factor binding protein-3 protease.  J Endocrinol. 1994;  142 407-15
• 22 Webber M M, Waghray A, Bello D. Prostate-specific antigen, a serine protease, facilitates human prostate cancer cell invasion.  Clin Cancer Res. 1995;  1 1089-94