Original Article | Published:

Basic Research

Celastrol, an active constituent of the TCM plant Tripterygium wilfordii Hook.f., inhibits prostate cancer bone metastasis

Prostate Cancer and Prostatic Diseases volume 20, pages 156164 (2017) | Download Citation

  • An Erratum to this article was published on 28 March 2017

Abstract

Background:

Treatment failure of prostate cancer (PCa) is often due to bone metastasis. Celastrol, an active constituent of Tripterygium wilfordii roots, has shown anti-tumor effects in previous studies in accordance with its indication in traditional Chinese medicine.

Methods:

Using a PC-3 cell model, in vitro assays were performed to evaluate the effects of celastrol on proliferation, migration (wound healing assay), tissues invasion (Transwell–Matrigel penetration assay) and vascular endothelial growth factor (VEGF) secretion (enzyme-linked immunosorbent assay). An intra-tibia injection mouse model was used to assess the effect of celastrol on PCa bone metastasis in vivo.

Results:

Pretreatment with celastrol significantly reduced proliferation of PC-3 cells in a dose-dependent manner and cell migration was much slower than in controls. Significantly fewer cells penetrated the gel-membrane after celastrol administration and their skeletal invasive ability was significantly reduced in a dose-dependent manner. Correspondingly, a significant, dose-dependent decrease in VEGF secretion was observed. In the in vivo mouse model, pretreatment with celastrol (8 μmol l−1) inhibited the tumorigenicity of PC-3 cells so that almost no bone invasion occurred as compared with control injections. Histological examinations using hematoxylin and eosin staining showed that tibiae injected with celastrol pretreated PC-3 cells retained their natural bone structure.

Conclusions:

Celastrol may have preventive potential against PCa bone metastasis.

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References

  1. 1.

    , , , , , et al. Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum Pathol 2000; 31: 578–583.

  2. 2.

    , , , , , et al. Androgen-independent prostate cancer is a heterogeneous group of diseases: lessons from a rapid autopsy program. Cancer Res 2004; 64: 9209–9216.

  3. 3.

    , . A perspective on cancer cell metastasis. Science 2011; 331: 1559–1564.

  4. 4.

    , . Cancer stemness and metastasis: therapeutic consequences and perspectives. Eur J Cancer 2010; 46: 1198–1203.

  5. 5.

    , , , , , et al. The white adipose tissue used in lipotransfer procedures is a rich reservoir of CD34+ progenitors able to promote cancer progression. Cancer Res 2012; 72: 325–334.

  6. 6.

    , , , , . Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol 1993; 143: 401–409.

  7. 7.

    , , , , , et al. Vascular endothelial growth factor (VEGF) expression in human prostate cancer: in situ and in vitro expression of VEGF by human prostate cancer cells. J Urol 1997; 157: 2329–2333.

  8. 8.

    , , , , , et al. Angiogenesis and prostate cancer: in vivo and in vitro expression of angiogenesis factors by prostate cancer cells. Urology 1998; 51: 161–167.

  9. 9.

    , , . The main anticancer bullets of the Chinese medicinal herb, thunder god vine. Molecules 2011; 16: 5283–5297.

  10. 10.

    , , , , . Celastrol, a triterpene extracted from the Chinese ‘Thunder of God Vine,’ is a potent proteasome inhibitor and suppresses human prostate cancer growth in nude mice. Cancer Res 2006; 66: 4758–4765.

  11. 11.

    , , , , , et al. The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations. Proc Natl Acad Sci USA 2009; 106: 268–273.

  12. 12.

    , , , , , et al. Hypoxia of PC-3 prostate cancer cells enhances migration and vasculogenesis in vitro of bone marrow-derived endothelial progenitor cells by secretion of cytokines. Oncol Rep 2013; 29: 2369–2377.

  13. 13.

    , , , , , et al. Celastrol inhibits vasculogenesis by suppressing the VEGF-induced functional activity of bone marrow-derived endothelial progenitor cells. Biochem Biophys Res Commun 2012; 423: 467–472.

  14. 14.

    , , , , , et al. Identification of miRs-143 and -145 that is associated with bone metastasis of prostate cancer and involved in the regulation of EMT. PLoS ONE 2011; 6: e20341.

  15. 15.

    , , , , , et al. Bone marrow-derived endothelial progenitor cells are a major determinant of nascent tumor neovascularization. Genes Dev 2007; 21: 1546–1558.

  16. 16.

    , , , , , et al. Bone marrow-derived endothelial progenitor cells contribute to the angiogenic switch in tumor growth and metastatic progression. Biochim Biophys Acta 2009; 1796: 33–40.

  17. 17.

    , , , , , . Patterns of bone metastasis and their prognostic significance in patients with carcinoma of the prostate. Br J Urol 1993; 72: 933–936.

  18. 18.

    , , , , , . Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis. Science 2008; 319: 195–198.

  19. 19.

    , , , , , et al. Bone marrow-derived cells contribute to tumor neovasculature and, when modified to express an angiogenesis inhibitor, can restrict tumor growth in mice. Clin Cancer Res 2001; 7: 2870–2879.

  20. 20.

    , , , , , et al. Celastrol suppresses angiogenesis-mediated tumor growth through inhibition of AKT/mammalian target of rapamycin pathway. Cancer Res 2010; 70: 1951–1959.

  21. 21.

    , , , , , et al. A randomized phase II study of pomegranate extract for men with rising PSA following initial therapy for localized prostate cancer. Prostate Cancer Prostatic Dis 2013; 16: 50–55.

  22. 22.

    , , , , , . Soy isoflavone genistein in prevention and treatment of prostate cancer. Prostate Cancer Prostatic Dis 2008; 11: 6–12.

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Acknowledgements

Dedicated to the memory of my friend and mentor Professor Dr Adolf Nahrstedt, Chair of Pharmacognosy at Münster University, Germany, who died on 7 January 2016 after a long battle with prostate cancer. This work was supported by the ‘Key Science and Technology Planning Project of Guangzhou’ Grant (2009A1-E031-3) and ‘Sino-Japanese scientific and technological cooperation program, MOST of China’ (No. 198-59).

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Affiliations

  1. Division of Pharmacognosy, Phytochemistry and Narcotics, National Institute of Health Sciences, Setagaya-ku, Tokyo, Japan

    • K Kuchta
  2. Department of Orthopaedic Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

    • Y Xiang
    • , S Huang
    • , Y Tang
    • , X Peng
    • , X Wang
    • , Y Zhu
    • , J Li
    • , J Xu
    • , Z Lin
    •  & T Pan

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Competing interests

The authors declare no conflict of interest.

Corresponding authors

Correspondence to K Kuchta or T Pan.

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DOI

https://doi.org/10.1038/pcan.2016.61

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