Skip to main content

Advertisement

SpringerLink
Log in

Tanshinones from Chinese Medicinal Herb Danshen (Salvia miltiorrhiza Bunge) Suppress Prostate Cancer Growth and Androgen Receptor Signaling

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

To test whether tanshinones inhibit prostate cancer (PCa) growth at least in part through inhibiting androgen receptor (AR) signaling.

Methods

We evaluated cell growth, survival and AR signaling parameters of PCa cells after exposure to tanshinones in in vitro models. We also tested the in vivo inhibitory efficacy of tanshinone IIA (TIIA) against LNCaP xenograft model in athymic nude mice.

Results

For androgen-dependent LNCaP cells, a colony growth assay showed strong inhibitory potency following the order of TIIA≈cryptotanshinone>tanshinone I, being 10–30 folds higher than Casodex (racemic). TIIA inhibited growth of LNCaP cells more than several androgen-independent PCa cell lines. All 3 tested tanshinones were devoid of AR agonist activity under castrate condition. Mechanistically, tanshinones inhibited AR nuclear translocation within 2 h, decreased protein and mRNA abundance of AR and its target prostate-specific antigen within 12 h, and stimulated proteosomal degradation of AR. Oral administration of TIIA (25 mg/kg, once daily) retarded LNCaP xenograft growth and down-regulated tumor AR abundance in athymic nude mice.

Conclusion

AR targeting action of tanshinones was distinct from Casodex and contributed to prostate cancer growth suppression in vitro and in vivo.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

AR:

androgen receptor

ATCC:

American type culture collection

Cas:

Casodex

cPARP:

cleaved poly (ADP)-ribose polymerase

CT:

cryptotanshinone

DMSO:

dimethylsulfoxide

Mib:

mibolerone

PCa:

prostate cancer

PSA:

prostate-specific antigen

TI:

tanshinone I

TIIA:

tanshinone IIA

REFERENCES

  1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277–300.

    Article  PubMed  Google Scholar 

  2. Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, Rosenfeld MG, Sawyers CL. Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004;10:33–9.

    Article  PubMed  Google Scholar 

  3. Kungand HJ, Evans CP. Oncogenic activation of androgen receptor. Urol Oncol. 2009;27:48–52.

    Article  Google Scholar 

  4. Li TH, Zhao H, Peng Y, Beliakoff J, Brooks JD, Sun Z. A promoting role of androgen receptor in androgen-sensitive and -insensitive prostate cancer cells. Nucleic Acids Res. 2007;35:2767–76.

    Article  PubMed  CAS  Google Scholar 

  5. Petrylak DP. The current role of chemotherapy in metastatic hormone-refractory prostate cancer. Urology. 2005;65:3–7. discussion 7–8 (2005).

    Article  PubMed  Google Scholar 

  6. Scherand HI, Sawyers CL. Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol. 2005;23:8253–61.

    Article  Google Scholar 

  7. Heinleinand CA, Chang C. Androgen receptor in prostate cancer. Endocr Rev. 2004;25:276–308.

    Article  Google Scholar 

  8. Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, Wongvipat J, Smith-Jones PM, Yoo D, Kwon A, Wasielewska T, Welsbie D, Chen CD, Higano CS, Beer TM, Hung DT, Scher HI, Jung ME, Sawyers CL. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science (New York, NY). 2009;324:787–90.

    Article  CAS  Google Scholar 

  9. Attard G, Reid AH, A’Hern R, Parker C, Oommen NB, Folkerd E, Messiou C, Molife LR, Maier G, Thompson E, Olmos D, Sinha R, Lee G, Dowsett M, Kaye SB, Dearnaley D, Kheoh T, Molina A, de Bono JS. Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin Oncol. 2009;27:3742–8.

    Article  PubMed  CAS  Google Scholar 

  10. Kawata H, Ishikura N, Watanabe M, Nishimoto A, Tsunenari T, Aoki Y. Prolonged treatment with bicalutamide induces androgen receptor overexpression and androgen hypersensitivity. Prostate. 2010;70:745–54.

    Article  PubMed  CAS  Google Scholar 

  11. Culig Z, Hoffmann J, Erdel M, Eder IE, Hobisch A, Hittmair A, Bartsch G, Utermann G, Schneider MR, Parczyk K, Klocker H. Switch from antagonist to agonist of the androgen receptor bicalutamide is associated with prostate tumour progression in a new model system. Br J Cancer. 1999;81:242–51.

    Article  PubMed  CAS  Google Scholar 

  12. Hara T, Miyazaki J, Araki H, Yamaoka M, Kanzaki N, Kusaka M, Miyamoto M. Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome. Cancer Res. 2003;63:149–53.

    PubMed  CAS  Google Scholar 

  13. Zhou L, Zuo Z, Chow MS. Danshen: an overview of its chemistry, pharmacology, pharmacokinetics, and clinical use. J Clin Pharmacol. 2005;45:1345–59.

    Article  PubMed  CAS  Google Scholar 

  14. Won SH, Lee HJ, Jeong SJ, Lee EO, Jung DB, Shin JM, Kwon TR, Yun SM, Lee MH, Choi SH, Lu J, Kim SH. Tanshinone IIA induces mitochondria dependent apoptosis in prostate cancer cells in association with an inhibition of phosphoinositide 3-kinase/AKT pathway. Biol Pharm Bull. 2010;33:1828–34.

    Article  PubMed  CAS  Google Scholar 

  15. Lee CY, Sher HF, Chen HW, Liu CC, Chen CH, Lin CS, Yang PC, Tsay HS, Chen JJ. Anticancer effects of tanshinone I in human non-small cell lung cancer. Mol Cancer Ther. 2008;7:3527–38.

    Article  PubMed  CAS  Google Scholar 

  16. Sarker SD, Nahar L. Natural medicine: the genus Angelica. Curr Med Chem. 2004;11:1479–500.

    PubMed  CAS  Google Scholar 

  17. Mosaddik MA. In vitro cytotoxicity of tanshinones isolated from Salvia miltiorrhiza Bunge against P388 lymphocytic leukemia cells. Phytomedicine. 2003;10:682–5.

    Article  PubMed  CAS  Google Scholar 

  18. Nizamutdinova IT, Lee GW, Son KH, Jeon SJ, Kang SS, Kim YS, Lee JH, Seo HG, Chang KC, Kim HJ. Tanshinone I effectively induces apoptosis in estrogen receptor-positive (MCF-7) and estrogen receptor-negative (MDA-MB-231) breast cancer cells. Int J Oncol. 2008;33:485–91.

    PubMed  CAS  Google Scholar 

  19. Su CC, Lin YH. Tanshinone IIA inhibits human breast cancer cells through increased Bax to Bcl-xL ratios. Int J Mol Med. 2008;22:357–61.

    PubMed  CAS  Google Scholar 

  20. Wang J, Wang X, Jiang S, Yuan S, Lin P, Zhang J, Lu Y, Wang Q, Xiong Z, Wu Y, Ren J, Yang H. Growth inhibition and induction of apoptosis and differentiation of tanshinone IIA in human glioma cells. J Neurooncol. 2007;82:11–21.

    Article  PubMed  CAS  Google Scholar 

  21. Liu JJ, Zhang Y, Lin DJ, Xiao RZ. Tanshinone IIA inhibits leukemia THP-1 cell growth by induction of apoptosis. Oncol Rep. 2009;21:1075–81.

    Article  PubMed  CAS  Google Scholar 

  22. Sung HJ, Choi SM, Yoon Y, An KS. Tanshinone IIA, an ingredient of Salvia miltiorrhiza BUNGE, induces apoptosis in human leukemia cell lines through the activation of caspase-3. Exp Mol Med. 1999;31:174–8.

    PubMed  CAS  Google Scholar 

  23. Lee WY, Chiu LC, Yeung JH. Cytotoxicity of major tanshinones isolated from Danshen (Salvia miltiorrhiza) on HepG2 cells in relation to glutathione perturbation. Food Chem Toxicol. 2008;46:328–38.

    Article  PubMed  CAS  Google Scholar 

  24. Gong Y, Li Y, Lu Y, Li L, Abdolmaleky H, Blackburn GL, Zhou JR. Bioactive tanshinones in Salvia miltiorrhiza inhibit the growth of prostate cancer cells in vitro and in mice. Int J Cancer (2010 Sep 16. [Epub ahead of print]).

  25. Lu Q, Zhang P, Zhang X, Chen J. Experimental study of the anti-cancer mechanism of tanshinone IIA against human breast cancer. Int J Mol Med. 2009;24:773–80.

    Article  PubMed  CAS  Google Scholar 

  26. Wang X, Wei Y, Yuan S, Liu G, Lu Y, Zhang J, Wang W. Potential anticancer activity of tanshinone IIA against human breast cancer. Int J Cancer. 2005;116:799–807.

    Article  PubMed  CAS  Google Scholar 

  27. Wang DB, Liu AS. Tanshinone in the treatment of acne (a primary report of 20 cases (author’s transl). Zhongguo yi xue ke xue yuan xue bao Acta Academiae Medicinae Sinicae. 1980;2:187–8.

    PubMed  CAS  Google Scholar 

  28. Ju Q, Yin X, Shi J, Xin Y, Kang X, Chen Y, Cui P, Cao Y, Xia L. Effects of cryptotanshinone and tanshinone IIΑ on proliferation, lipid synthesis and expression of androgen receptor mRNA in human sebocytes in vitro. Chinese Journal of Dermatology. 2005;38(2).

  29. Gao Y, Wang L, Tang J. Sex hormone-like activity of tanshinone. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 1980;2:189–91.

    PubMed  CAS  Google Scholar 

  30. Cockshott ID. Bicalutamide: clinical pharmacokinetics and metabolism. Clin Pharmacokinet. 2004;43:855–78.

    Article  PubMed  CAS  Google Scholar 

  31. Zhang Y, Kim KH, Zhang W, Guo Y, Kim SH, Lu J. Galbanic acid decreases androgen receptor abundance and signaling and induces G(1) arrest in prostate cancer cells. Int J Cancer (2011 Feb 15. [Epub ahead of print]).

  32. Zhang Y, Shaik AA, Xing C, Chai Y, Li L, Zhang J, Zhang W, Kim SH, Lu J, Jiang C. A synthetic decursin analog with increased in vivo stability suppresses androgen receptor signaling in vitro and in vivo. Investigational new drugs (2011).

  33. Wang Z, Lee HJ, Chai Y, Hu H, Wang L, Zhang Y, Jiang C, Lu J. Persistent P21Cip1 induction mediates G(1) cell cycle arrest by methylseleninic acid in DU145 prostate cancer cells. Curr Cancer Drug Targets. 2010;10:307–18.

    Article  PubMed  CAS  Google Scholar 

  34. Wang F, Ezell SJ, Zhang Y, Wang W, Rayburn ER, Nadkarni DH, Murugesan S, Velu SE, Zhang R. FBA-TPQ, a novel marine-derived compound as experimental therapy for prostate cancer. Invest New Drugs. 2010;28:234–41.

    Article  PubMed  CAS  Google Scholar 

  35. Cho SD, Jiang C, Malewicz B, Dong Y, Young CY, Kang KS, Lee YS, Ip C, Lu J. Methyl selenium metabolites decrease prostate-specific antigen expression by inducing protein degradation and suppressing androgen-stimulated transcription. Mol Cancer Ther. 2004;3:605–11.

    PubMed  CAS  Google Scholar 

  36. Zhang Y, Zhang J, Wang L, Quealy E, Gary BD, Reynolds RC, Piazza GA, Lu J. A novel sulindac derivative lacking cyclooxygenase-inhibitory activities suppresses carcinogenesis in the transgenic adenocarcinoma of mouse prostate model. Cancer Prev Res (Phila). 2010;3:885–95.

    Article  CAS  Google Scholar 

  37. Jiang C, Lee HJ, Li GX, Guo J, Malewicz B, Zhao Y, Lee EO, Lee JH, Kim MS, Kim SH, Lu J. Potent antiandrogen and androgen receptor activities of an Angelica gigas-containing herbal formulation: identification of decursin as a novel and active compound with implications for prevention and treatment of prostate cancer. Cancer Res. 2006;66:453–63.

    Article  PubMed  CAS  Google Scholar 

  38. Guo J, Jiang C, Wang Z, Lee HJ, Hu H, Malewicz B, Lee HJ, Lee JH, Baek NI, Jeong JH, Kim DK, Kang KS, Kim SH, Lu J. A novel class of pyranocoumarin anti-androgen receptor signaling compounds. Mol Cancer Ther. 2007;6:907–17.

    Article  PubMed  CAS  Google Scholar 

  39. Wang L, Bonorden MJ, Li GX, Lee HJ, Hu H, Zhang Y, Liao JD, Cleary MP, Lu J. Methyl-selenium compounds inhibit prostate carcinogenesis in the transgenic adenocarcinoma of mouse prostate model with survival benefit. Cancer Prev Res (Phila Pa). 2009;2:484–95.

    Article  CAS  Google Scholar 

  40. Kim KH, Lee HJ, Jeong SJ, Lee EO, Kim HS, Zhang Y, Ryu SY, Lee MH, Lu J, Kim SH. Galbanic acid isolated from ferula assafoetida exerts in vivo anti-tumor activity in association with anti-angiogenesis and anti-proliferation. Pharm Res. 2011;28:597–609.

    Article  PubMed  CAS  Google Scholar 

  41. Joly-Pharaboz MO, Ruffion A, Roch A, Michel-Calemard L, Andre J, Chantepie J, Nicolas B, Panaye G. Inhibition of growth and induction of apoptosis by androgens of a variant of LNCaP cell line. J Steroid Biochem Mol Biol. 2000;73:237–49.

    Article  PubMed  CAS  Google Scholar 

  42. Masiello D, Cheng S, Bubley GJ, Lu ML, Balk SP. Bicalutamide functions as an androgen receptor antagonist by assembly of a transcriptionally inactive receptor. J Biol Chem. 2002;277:26321–6.

    Article  PubMed  CAS  Google Scholar 

  43. Xu D, Lin TH, Zhang C, Tsai YC, Li S, Zhang J, Yin M, Yeh S, Chang C. The selective inhibitory effect of a synthetic tanshinone derivative on prostate cancer cells. The Prostate (2011).

  44. Shin DS, Kim HN, Shin KD, Yoon YJ, Kim SJ, Han DC, Kwon BM. Cryptotanshinone inhibits constitutive signal transducer and activator of transcription 3 function through blocking the dimerization in DU145 prostate cancer cells. Cancer Res. 2009;69:193–202.

    Article  PubMed  CAS  Google Scholar 

  45. Park IJ, Kim MJ, Park OJ, Park MG, Choe W, Kang I, Kim SS, Ha J. Cryptotanshinone sensitizes DU145 prostate cancer cells to Fas(APO1/CD95)-mediated apoptosis through Bcl-2 and MAPK regulation. Cancer Lett. 2010;298:88–98.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments & Disclosures

This work was supported, in part, by Hormel Foundation, NIH grant CA136953, Korean Medical Research Center (MRC) grant (No. 2009-0063466) and TTUHSC School of Pharmacy startup fund. We thank Mr. Todd Schuster at Hormel Institute for help with flow cytometric analyses.

Author information

Authors and Affiliations

  1. Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, Minnesota, 55912, USA

    Yong Zhang, Cheng Jiang, Jinhui Zhang & Junxuan Lü

  2. Cancer Preventive Material Development Research Center College of Oriental Medicine, Kyunghee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul, 131-701, Republic of Korea

    Suk-Hyun Won, Hyo-Jeong Lee, Soo-Jin Jeong, Eun-Ok Lee & Sung-Hoon Kim

  3. State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China

    Min Ye

  4. Department of Biomedical Sciences, Texas Tech University Health Sciences Center School of Pharmacy, 1300 S. Coulter, Amarillo, Texas, 79106, USA

    Yong Zhang, Cheng Jiang, Jinhui Zhang & Junxuan Lü

Authors
  1. Yong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Suk-Hyun Won
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cheng Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hyo-Jeong Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Soo-Jin Jeong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eun-Ok Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jinhui Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Min Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sung-Hoon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Junxuan Lü
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Sung-Hoon Kim or Junxuan Lü.

Additional information

Yong Zhang, Suk-Hyun Won and Cheng Jiang contributed equally to this paper as co-first authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, Y., Won, SH., Jiang, C. et al. Tanshinones from Chinese Medicinal Herb Danshen (Salvia miltiorrhiza Bunge) Suppress Prostate Cancer Growth and Androgen Receptor Signaling. Pharm Res 29, 1595–1608 (2012). https://doi.org/10.1007/s11095-012-0670-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-012-0670-3

KEY WORDS

Search

Navigation