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Androprostamine A: a unique antiprostate cancer agent

A Correction to this article was published on 18 August 2021

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Abstract

The androgen receptor (AR) is an important therapeutic target for all clinical states of prostate cancer. We screened cultured broths of microorganisms for their ability to suppress androgen-dependent growth of human prostate cancer LNCaP and VCaP cells without cytotoxicity. We have already identified androprostamine A (APA) from a Streptomyces culture broth as a functional inhibitor of AR. APA repressed R1881 (the synthetic androgen methyltrienolone)-induced androgen-regulated gene expression and dramatically inhibited R1881-induced prostate-specific antigen levels. However, APA did not act as an AR antagonist and did not inhibit AR transcriptional activity. Moreover, AS2405, an APA derivative, significantly inhibited the growth of VCaP cells in SCID mice upon oral administration.

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References

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

    Article  Google Scholar 

  2. American Cancer Society. Cancer facts & figures 2008. Atlanta, GA: American Cancer Society; 2008.

  3. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009;59:225–49.

    Article  Google Scholar 

  4. Koivisto P, Kononen J, Palmberg C, Tammela T, Hyytinen E, Isola J, et al. Androgen receptor gene amplification: a possible molecular mechanism for androgen deprivation therapy failure in prostate cancer. Cancer Res. 1997;57:314–9.

    CAS  PubMed  Google Scholar 

  5. Liu W, Xie CC, Zhu Y, Li T, Sun J, Cheng Y, et al. Homozygous deletions and recurrent amplifications implicate new genes involved in prostate cancer. Neoplasia. 2008;10:897–907.

    Article  CAS  Google Scholar 

  6. Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18:11–22.

    Article  CAS  Google Scholar 

  7. Ni L. FKBP51 promotes assembly of the Hsp90 chaperone complex and regulates androgen receptor signaling in prostate cancer cells. Mol Cell Biol. 2010;30:1243–53.

    Article  CAS  Google Scholar 

  8. Wang Q, Carroll JS, Brown M. Spatial and temporal recruitment of androgen receptor and its coactivators involves chromosomal looping and polymerase tracking. Mol Cell. 2005;19:631–42.

    Article  CAS  Google Scholar 

  9. Rennie PS, Nelson CC. Epigenetic mechanisms for progression of prostate cancer. Cancer Metastasis Rev. 1998;17:401–9.

    Article  CAS  Google Scholar 

  10. Dehm SM, Tindall DJ. Alternatively spliced androgen receptor variants. Endocr Relat Cancer. 2011;18:R183–96.

    Article  CAS  Google Scholar 

  11. Guo Z, Yang X, Sun F, Jiang R, Linn DE, Chen H, et al. A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Res. 2009;69:2305–13.

    Article  CAS  Google Scholar 

  12. Hu R, Dunn TA, Wei S, Isharwal S, Veltri RW, Humphreys E, et al. Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res. 2009;69:16–22.

    Article  CAS  Google Scholar 

  13. Sun S, Sprenger CC, Vessella RL, Haugk K, Soriano K, Mostaghel EA, et al. Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J Clin Investig. 2010;120:2715–30.

    Article  CAS  Google Scholar 

  14. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502–12.

    Article  CAS  Google Scholar 

  15. Rehman Y, Rosenberg JE. Abiraterone acetate: oral androgen biosynthesis inhibitor for treatment of castration-resistant prostate cancer. Drug Des Dev Ther. 2012;6:13–8.

    Article  CAS  Google Scholar 

  16. Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324:787–90.

    Article  CAS  Google Scholar 

  17. Scott LJ. Enzalutamide: a review in castration-resistant prostate cancer. Drugs. 2018;78:1913–24.

    Article  Google Scholar 

  18. Henshall SM, Quinn DI, Lee CS, Head DR, Golovsky D, Brenner PC, et al. Altered expression of androgen receptor in the malignant epithelium and adjacent stroma is associated with early relapse in prostate cancer. Cancer Res. 2001;61:423–7.

    CAS  PubMed  Google Scholar 

  19. Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004;10:33–9.

    Article  Google Scholar 

  20. Yamazaki Y, Someno T, Igarashi M, Kinoshita N, Hatano M, Kawada M, et al. Androprostamines A and B, the new anti-prostate cancer agents produced by Streptomyces sp. MK932-CF8. J Antibiot. 2015;68:279–85.

    Article  CAS  Google Scholar 

  21. Lonergan PE, Tindall DJ. Androgen receptor signaling in prostate cancer development and progression. J Carcinog. 2011;10:20.

    Article  CAS  Google Scholar 

  22. Li Y, Hwang TH, Oseth LA, Hauge A, Vessella RL, Schmechel SC, et al. AR intragenic deletions linked to androgen receptor splice variant expression and activity in models of prostate cancer progression. Oncogene. 2012;31:4759–67.

    Article  CAS  Google Scholar 

  23. Joseph JD, Lu N, Qian J, Sensintaffar J, Shao G, Brigham D, et al. A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509. Cancer Discov. 2013;3:1020–9.

    Article  CAS  Google Scholar 

  24. Li Y. Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. Cancer Res. 2013;73:483–9.

    Article  CAS  Google Scholar 

  25. Nadiminty N, Tummala R, Liu C, Yang J, Lou W, Evans CP, et al. NF-kappaB2/p52 induces resistance to enzalutamide in prostate cancer: role of androgen receptor and its variants. Mol Cancer Ther. 2013;12:1629–37.

    Article  CAS  Google Scholar 

  26. Mostaghel EA, Marck BT, Plymate SR, Vessella RL, Balk S, Matsumoto AM, et al. Resistance to CYP17A1 inhibition with abiraterone in castration-resistant prostate cancer: induction of steroidogenesis and androgen receptor splice variants. Clin Cancer Res. 2011;17:5913–25.

    Article  CAS  Google Scholar 

  27. Korenchuk S, Lehr JE, MClean L, Lee YG, Whitney S, Vessella R, et al. VCaP, a cell-based model system of human prostate cancer. In Vivo. 2001;15:163–8.

    CAS  PubMed  Google Scholar 

  28. Falkenstein E, Tillmann HC, Christ M, Feuring M, Wehling M. Multiple actions of steroid hormones—a focus on rapid, nongenomic effects. Pharm Rev. 2000;52:513–56.

    CAS  PubMed  Google Scholar 

  29. Peterziel H, Mink S, Schonert A, Becker M, Klocker H, Cato AC. Rapid signalling by androgen receptor in prostate cancer cells. Oncogene. 1999;18:6322–9.

    Article  CAS  Google Scholar 

  30. Migliaccio A, Castoria G, Di Domenico M, de Falco A, Bilancio A, Lombardi M, et al. Steroid-induced androgen receptor–oestradiol receptor β–Src complex triggers prostate cancer cell proliferation. EMBO J. 2000;19:5406–17.

    Article  CAS  Google Scholar 

  31. Zarif CJ, Lamb LE, Schulz VV, Nollet EA, Miranti CK. Androgen receptor non-nuclear regulation of prostate cancer cell invasion mediated by Src and matriptase. Oncotarget. 2015;6:6862–76.

    Article  Google Scholar 

  32. Leung JK, Sadar MD. Non-genomic actions of the androgen receptor in prostate cancer. Front Endocrinol. 2017;8:1–8.

    Article  Google Scholar 

  33. Zamagni A, Cortesi M, Zanoni M, Tesei A, Non-nuclear AR. Signaling in prostate cancer. Front Chem. 2019;7:1–11.

    Article  Google Scholar 

  34. Zarif JC, Miranti CK. The importance of non-nuclear ar signaling in prostate cancer progression and therapeutic resistance. Cell Signal. 2016;28:348–56.

    Article  CAS  Google Scholar 

  35. Yamori T, Matsunaga A, Sato S, Yamazaki K, Komi A, Ishizu K, et al. Potent antitumor activity of MS-247, a novel DNA minor groove binder, evaluated by an in vitro and in vivo human cancer cell line panel. Cancer Res. 1999;59:4042–9.

    CAS  PubMed  Google Scholar 

  36. Minamiguchi K, Kawada M, Someno T, Ishizuka M. Androgen-independent prostate cancer DU145 cells suppress androgen-dependent growth of prostate stromal cells through production of inhibitory factors for androgen responsiveness. Biochem Biophys Res Commun. 2003;306:629–36.

    Article  CAS  Google Scholar 

  37. Abe H, Yamazaki Y, Sakashita C, Momose I, Watanabe T, Shibasaki M. Synthesis of androprostamine A and resormycin. Chem Pharm Bull. 2016;64:982–7.

    Article  CAS  Google Scholar 

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Acknowledgements

The authors are grateful to Screening Committee of Anticancer Drugs supported by the Grant-in-Aid for Scientific Research on Innovative Areas and to the Scientific Support Programs for Cancer Research, from the Ministry of Education, Culture, Sports, Science and Technology of Japan for supplying the measurements of growth inhibitory activities of 39 human cancer cell lines. This work was supported by Grant-in-Aid for Scientific Research (C) (15K10615).

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YY designed the study, performed the experiments, analyzed data, and wrote the manuscript; HA, CS, and SO performed the experiments; TW, IM, and MK provided discussions and helped write the paper. All the authors discussed the results and approved the manuscript.

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Correspondence to Yohko Yamazaki.

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The original online version of this article was revised: plus the same explanatory text of the problem as in the erratum/correction article.

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Yamazaki, Y., Abe, H., Sakashita, C. et al. Androprostamine A: a unique antiprostate cancer agent. J Antibiot 74, 717–725 (2021). https://doi.org/10.1038/s41429-021-00449-8

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