Beyond T and DHT - Novel steroid derivatives capable of wild type androgen receptor activation

International Journal of Biological Sciences

Volumn 10, Issue 6, 2014, Pages 602-613

  Mostaghel, Elahe A ^a  

^a USA   (United States)

Author keywords

11beta hydroxyandrostenedione; 11ketodihydrotestosterone; Adrenal androgen; Androgen receptor; Castration resistant prostate cancer; Deoxycorticosterone; Intracrine steroidogenesis

Indexed keywords

ANDROGEN; ANDROGEN RECEPTOR; ANTINEOPLASTIC AGENT; AR PROTEIN, HUMAN; DEOXYCORTICOSTERONE;

CASTRATION RESISTANT PROSTATE CANCER; HUMAN; MALE; METABOLISM; PROSTATIC NEOPLASMS;

ANDROGENS; ANTINEOPLASTIC AGENTS; DESOXYCORTICOSTERONE; HUMANS; MALE; PROSTATIC NEOPLASMS; PROSTATIC NEOPLASMS, CASTRATION-RESISTANT; RECEPTORS, ANDROGEN;

EID: 84902159503     PISSN: 14492288     EISSN: None     Source Type: Journal    
DOI: 10.7150/ijbs.8844     Document Type: Review

References (81)

1. Ross RW, Xie W, Regan MM, Pomerantz M, Nakabayashi M, Daskivich TJ, et al. Efficacy of androgen deprivation therapy (ADT) in patients with advanced prostate cancer: association between Gleason score, prostate-specific antigen level, and prior ADT exposure with duration of ADT effect. Cancer. 2008; 112: 1247-53.
2. Mohler JL, Gregory CW, Ford OH, Kim D, Weaver CM, Petrusz P, et al. The androgen axis in recurrent prostate cancer. Clin Cancer Res. 2004; 10: 440-8.
3. Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008; 68: 4447-54.
4. Stanbrough M, Bubley GJ, Ross K, Golub TR, Rubin MA, Penning TM, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006; 66: 2815-25.
5. Holzbeierlein J, Lal P, LaTulippe E, Smith A, Satagopan J, Zhang L, et al. Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance. Am J Pathol. 2004; 164: 217-27.
6. Mostaghel EA, Plymate SR, Montgomery B. Molecular pathways: targeting resistance in the androgen receptor for therapeutic benefit. Clin Cancer Res. 2014; 20: 791-8.
7. Mostaghel EA. Abiraterone in the treatment of metastatic castration-resistant prostate cancer. Cancer Manag Res. 2014; 6: 39-51.
8. Uemura M, Honma S, Chung S, Takata R, Furihata M, Nishimura K, et al. 5alphaDH-DOC (5alpha-dihydro-deoxycorticosterone) activates androgen receptor in castration-resistant prostate cancer. Cancer Sci. 2010; 101: 1897-904.
9. Bloem LM, Storbeck KH, Schloms L, Swart AC. 11beta-hydroxyandrostenedione returns to the steroid arena: biosynthesis, metabolism and function. Molecules. 2013; 18: 13228-44.
10. Storbeck KH, Bloem LM, Africander D, Schloms L, Swart P, Swart AC. 11beta-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? Mol Cell Endocrinol. 2013; 377: 135-46.
11. Swart AC, Schloms L, Storbeck KH, Bloem LM, Toit T, Quanson JL, et al. 11beta-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5alpha-reductase yielding 11beta-hydroxy-5alpha-androstanedione. J Steroid Biochem Mol Biol. 2013; 138: 132-42.
12. Page ST, Plymate SR, Bremner WJ, Matsumoto AM, Hess DL, Lin DW, et al. Effect of medical castration on CD4+ CD25+ T cells, CD8+ T cell IFN-gamma expression, and NK cells: a physiological role for testosterone and/or its metabolites. Am J Physiol Endocrinol Metab. 2006; 290: E856-63.
13. Mizokami A, Koh E, Fujita H, Maeda Y, Egawa M, Koshida K, et al. The adrenal androgen androstenediol is present in prostate cancer tissue after androgen deprivation therapy and activates mutated androgen receptor. Cancer Res. 2004; 64: 765-71.
14. Miyamoto H, Yeh S, Lardy H, Messing E, Chang C. Delta5-androstenediol is a natural hormone with androgenic activity in human prostate cancer cells. Proc Natl Acad Sci U S A. 1998; 95: 11083-8.
15. Mostaghel EA, Nelson PS, Lange P, Lin DW, Taplin ME, Balk S, et al. Targeted androgen pathway suppression in localized prostate cancer: a pilot study. J Clin Oncol. 2014; 32: 229-37.
16. Taplin M, Montgomery RB, Logothetis C, Bubley GJ, Richie JP, Dalkin BL, et al. Effect of neoadjuvant abiraterone acetate (AA) plus leuprolide acetate (LHRHa) on PSA, pathological complete response (pCR), and near pCR in localized high-risk prostate cancer (LHRPC): Results of a randomized phase II study. ASCO Annual Meeting. 2012; Chicago, Illinois: abstract 4521.
17. Culig Z, Hoffmann J, Erdel M, Eder IE, Hobisch A, Hittmair A, et al. 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.
18. Gregory CW, Johnson RT, Jr., Mohler JL, French FS, Wilson EM. Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen. Cancer Res. 2001; 61: 2892-8.
19. Gregory CW, Hamil KG, Kim D, Hall SH, Pretlow TG, Mohler JL, et al. Androgen receptor expression in androgen-independent prostate cancer is associated with increased expression of androgen-regulated genes. Cancer Res. 1998; 58: 5718-24.
20. Mohler JL, Morris TL, Ford OH, Alvey RF, Sakamoto C, Gregory CW. Identification of differentially expressed genes associated with androgen-independent growth of prostate cancer. Prostate. 2002; 51: 247-55.
21. de Bono JS. Abiraterone acetate improves survival in metastatic castration-resistant prostate cancer: Phase III results. 2010 European Society for Medical Oncology. Milan; 2010.
22. Scher HI, Beer TM, Higano CS, Anand A, Taplin ME, Efstathiou E, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet. 2010; 375: 1437-46.
23. Mostaghel EA, Marck B, Plymate S, Vessella RL, Balk SP, 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.
24. Cai C, Chen S, Ng P, Bubley GJ, Nelson PS, Mostaghel EA, et al. Intratumoral de novo steroid synthesis activates androgen receptor in castration-resistant prostate cancer and is upregulated by treatment with CYP17A1 inhibitors. Cancer Res. 2011; 71: 6503-13.
25. Efstathiou E, Titus M, Tsavachidou D, Tzelepi V, Wen S, Hoang A, et al. Effects of abiraterone acetate on androgen signaling in castrate-resistant prostate cancer in bone. J Clin Oncol. 2012; 30: 637-43.
26. Labrie F, Luu-The V, Lin S, Simard J, Labrie C, El-Alfy M, et al. Intracrinology: role of the family of 17 beta-hydroxysteroid dehydrogenases in human physiology and disease. J Mol Endocrinol. 2000; 25: 1-16.
27. Miller WL, Auchus RJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev. 2011; 32: 81-151.
28. Rainey WE, Carr BR, Sasano H, Suzuki T, Mason JI. Dissecting human adrenal androgen production. Trends in Endocrinology and Metabolism. 2002; 13: 234-9.
29. Auchus RJ. The backdoor pathway to dihydrotestosterone. Trends Endocrinol Metab. 2004; 15: 432-8.
30. Auchus RJ. Non-traditional metabolic pathways of adrenal steroids. Rev Endocr Metab Disord. 2009; 10: 27-32.
31. Endoh A, Kristiansen SB, Casson PR, Buster JE, Hornsby PJ. The zona reticularis is the site of biosynthesis of dehydroepiandrosterone and dehydroepiandrosterone sulfate in the adult human adrenal cortex resulting from its low expression of 3 beta-hydroxysteroid dehydrogenase. J Clin Endocrinol Metab. 1996; 81: 3558-65.
32. Nakamura Y, Hornsby PJ, Casson P, Morimoto R, Satoh F, Xing Y, et al. Type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3) contributes to testosterone production in the adrenal reticularis. J Clin Endocrinol Metab. 2009; 94: 2192-8.
33. Sanford EJ, Paulson DF, Rohner TJ, Jr., Santen RJ, Bardin CW. The effects of castration on adrenal testosterone secretion in men with prostatic carcinoma. J Urol. 1977; 118: 1019-21.
34. Mostaghel EA, Nelson PS. Intracrine androgen metabolism in prostate cancer progression: mechanisms of castration resistance and therapeutic implications. Best Pract Res Clin Endocrinol Metab. 2008; 22: 243-58.
35. Penning TM, Bauman DR, Jin Y, Rizner TL. Identification of the molecular switch that regulates access of 5[alpha]-DHT to the androgen receptor. Molecular and Cellular Endocrinology. 2007; 265-266: 77-82.
36. Guillemette C, Levesque E, Beaulieu M, Turgeon D, Hum DW, Belanger A. Differential regulation of two uridine diphospho-glucuronosyltransferases, UGT2B15 and UGT2B17, in human prostate LNCaP cells. Endocrinology. 1997; 138: 2998-3005.
37. Chouinard S, Barbier O, Belanger A. UDP-glucuronosyltransferase 2B15 (UGT2B15) and UGT2B17 enzymes are major determinants of the androgen response in prostate cancer LNCaP cells. J Biol Chem. 2007; 282: 33466-74.
38. Chouinard S, Pelletier G, Belanger A, Barbier O. Cellular specific expression of the androgen-conjugating enzymes UGT2B15 and UGT2B17 in the human prostate epithelium. Endocr Res. 2004; 30: 717-25.
39. Gupta MK, Guryev OL, Auchus RJ. 5alpha-reduced C21 steroids are substrates for human cytochrome P450c17. Arch Biochem Biophys. 2003; 418: 151-60.
40. Bauman DR, Steckelbroeck S, Williams MV, Peehl DM, Penning TM. Identification of the Major Oxidative 3{alpha}-Hydroxysteroid Dehydrogenase in Human Prostate That Converts 5{alpha}-Androstane-3{alpha},17{beta}-diol to 5{alpha}-Dihydrotestosterone: A Potential Therapeutic Target for Androgen-Dependent Disease. Mol Endocrinol. 2006; 20: 444-58.
41. Mohler JL, Titus MA, Bai S, Kennerley BJ, Lih FB, Tomer KB, et al. Activation of the androgen receptor by intratumoral bioconversion of androstanediol to dihydrotestosterone in prostate cancer. Cancer Res. 2011; 71: 1486-96.
42. Huang XF, Luu-The V. Molecular characterization of a first human 3(alpha-->beta)-hydroxysteroid epimerase. J Biol Chem. 2000; 275: 29452-7.
43. Muthusamy S, Andersson S, Kim HJ, Butler R, Waage L, Bergerheim U, et al. Estrogen receptor beta and 17beta-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer. Proc Natl Acad Sci U S A. 2011; 108: 20090-4.
44. Negri-Cesi P, Motta M. Androgen metabolism in the human prostatic cancer cell line LNCaP. J Steroid Biochem Mol Biol. 1994; 51: 89-96.
45. Thigpen AE, Cala KM, Russell DW. Characterization of Chinese hamster ovary cell lines expressing human steroid 5 alpha-reductase isozymes. J Biol Chem. 1993; 268: 17404-12.
46. Samson M, Labrie F, Zouboulis CC, Luu-The V. Biosynthesis of dihydrotestosterone by a pathway that does not require testosterone as an intermediate in the SZ95 sebaceous gland cell line. J Invest Dermatol. 2010; 130: 602-4.
47. Chang KH, Li R, Papari-Zareei M, Watumull L, Zhao YD, Auchus RJ, et al. Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer. Proc Natl Acad Sci U S A. 2011; 108: 13728-33.
48. Klein H, Bressel M, Kastendieck H, Voigt KD. Androgens, adrenal androgen precursors, and their metabolism in untreated primary tumors and lymph node metastases of human prostatic cancer. Am J Clin Oncol. 1988; 11 Suppl 2: S30-6.
49. Luo J, Dunn TA, Ewing CM, Walsh PC, Isaacs WB. Decreased gene expression of steroid 5 alpha-reductase 2 in human prostate cancer: implications for finasteride therapy of prostate carcinoma. Prostate. 2003; 57: 134-9.
50. Titus MA, Gregory CW, Ford OH, Schell MJ, Maygarden SJ, Mohler JL. Steroid 5{alpha}-Reductase Isozymes I and II in Recurrent Prostate Cancer. Clin Cancer Res. 2005; 11: 4365-71.
51. Xing Y, Edwards MA, Ahlem C, Kennedy M, Cohen A, Gomez-Sanchez CE, et al. The effects of ACTH on steroid metabolomic profiles in human adrenal cells. J Endocrinol. 2011; 209: 327-35.
52. Nakamura Y, Rege J, Satoh F, Morimoto R, Kennedy MR, Ahlem CN, et al. Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein corticosteroids before and after adrenocorticotropic hormone stimulation. Clin Endocrinol (Oxf). 2012; 76: 778-84.
53. Godoy A, Kawinski E, Li Y, Oka D, Alexiev B, Azzouni F, et al. 5alpha-reductase type 3 expression in human benign and malignant tissues: a comparative analysis during prostate cancer progression. Prostate. 2011; 71: 1033-46.
54. Azzouni F, Godoy A, Li Y, Mohler J. The 5 alpha-reductase isozyme family: a review of basic biology and their role in human diseases. Adv Urol. 2012; 2012: 530121.
55. Belanger B, Fiet J, Belanger A. Effects of adrenocorticotropin on adrenal and plasma 11 beta-hydroxyandrostenedione in the guinea pig and determination of its relative androgen potency. Steroids. 1993; 58: 29-34.
56. Goldzieher JW, de la Pena A, Aivaliotis MM. Radioimmunoassay of plasma androstenedione, testosterone and 11beta-hydroxyandrostenedione after chromatography on Lipidex-5000 (hydroxyalkoxypropyl Sephadex). J Steroid Biochem. 1978; 9: 169-73.
57. Yokokawa A, Yamamoto K, Omori Y, Shibasaki H, Shinohara Y, Kasuya Y, et al. Simultaneous determination of androstenedione, 11beta-hydroxyandrostenedione, and testosterone in human plasma by stable isotope dilution mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2009; 877: 621-6.
58. Rege J, Nakamura Y, Satoh F, Morimoto R, Kennedy MR, Layman LC, et al. Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation. J Clin Endocrinol Metab. 2013; 98: 1182-8.
59. Dovio A, Sartori ML, De Francia S, Mussino S, Perotti P, Saba L, et al. Differential expression of determinants of glucocorticoid sensitivity in androgen-dependent and androgen-independent human prostate cancer cell lines. J Steroid Biochem Mol Biol. 2009; 116: 29-36.
60. Page N, Warriar N, Govindan MV. 11 beta-Hydroxysteroid dehydrogenase and tissue specificity of androgen action in human prostate cancer cell LNCaP. J Steroid Biochem Mol Biol. 1994; 49: 173-81.
61. Pelletier G, Luu-The V, Li S, Ouellet J, Labrie F. Cellular Localization of mRNA Expression of Enzymes Involved in the Formation and Inactivation of Hormonal Steroids in the Mouse Prostate. 10.1369/jhc.4A6311. J Histochem Cytochem. 2004; 52: 1351-6.
62. Albiston AL, Obeyesekere VR, Smith RE, Krozowski ZS. Cloning and tissue distribution of the human 11 beta-hydroxysteroid dehydrogenase type 2 enzyme. Mol Cell Endocrinol. 1994; 105: R11-7.
63. Dufort I, Rheault P, Huang XF, Soucy P, Luu-The V. Characteristics of a highly labile human type 5 17beta-hydroxysteroid dehydrogenase. Endocrinology. 1999; 140: 568-74.
64. Yazawa T, Uesaka M, Inaoka Y, Mizutani T, Sekiguchi T, Kajitani T, et al. Cyp11b1 is induced in the murine gonad by luteinizing hormone/human chorionic gonadotropin and involved in the production of 11-ketotestosterone, a major fish androgen: conservation and evolution of the androgen metabolic pathway. Endocrinology. 2008; 149: 1786-92.
65. Grigoryev DN, Long BJ, Njar VC, Brodie AH. Pregnenolone stimulates LNCaP prostate cancer cell growth via the mutated androgen receptor. J Steroid Biochem Mol Biol. 2000; 75: 1-10.
66. Tan J, Sharief Y, Hamil KG, Gregory CW, Zang DY, Sar M, et al. Dehydroepiandrosterone activates mutant androgen receptors expressed in the androgen-dependent human prostate cancer xenograft CWR22 and LNCaP cells. Mol Endocrinol. 1997; 11: 450-9.
67. Veldscholte J, Ris-Stalpers C, Kuiper GG, Jenster G, Berrevoets C, Claassen E, et al. A mutation in the ligand binding domain of the androgen receptor of human LNCaP cells affects steroid binding characteristics and response to anti-androgens. Biochem Biophys Res Commun. 1990; 173: 534-40.
68. Zhao XY, Malloy PJ, Krishnan AV, Swami S, Navone NM, Peehl DM, et al. Glucocorticoids can promote androgen-independent growth of prostate cancer cells through a mutated androgen receptor. Nat Med. 2000; 6: 703-6.
69. Taplin ME, Bubley GJ, Ko YJ, Small EJ, Upton M, Rajeshkumar B, et al. Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist. Cancer Res. 1999; 59: 2511-5.
70. Taplin ME, Rajeshkumar B, Halabi S, Werner CP, Woda BA, Picus J, et al. Androgen receptor mutations in androgen-independent prostate cancer. J Clin Oncol. 2003; 21: 2673-8.
71. Mitsiades N, Sung CC, Schultz N, Danila DC, He B, Eedunuri VK, et al. Distinct patterns of dysregulated expression of enzymes involved in androgen synthesis and metabolism in metastatic prostate cancer tumors. Cancer Res. 2012; 72: 6142-52.
72. Biancolella M, Valentini A, Minella D, Vecchione L, D'Amico F, Chillemi G, et al. Effects of dutasteride on the expression of genes related to androgen metabolism and related pathway in human prostate cancer cell lines. Invest New Drugs. 2007; 25: 491-7.
73. Shah SK, Trump DL, Sartor O, Tan W, Wilding GE, Mohler JL. Phase II study of Dutasteride for recurrent prostate cancer during androgen deprivation therapy. J Urol. 2009; 181: 621-6.
74. Sartor O, Nakabayashi M, Taplin ME, Ross RW, Kantoff PW, Balk SP, et al. Activity of dutasteride plus ketoconazole in castration-refractory prostate cancer after progression on ketoconazole alone. Clin Genitourin Cancer. 2009; 7: E90-2.
75. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012; 367: 1187-97.
76. Attard G, Reid AH, Yap TA, Raynaud F, Dowsett M, Settatree S, et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol. 2008; 26: 4563-71.
77. Ge RS, Dong Q, Niu EM, Sottas CM, Hardy DO, Catterall JF, et al. 11{beta}-Hydroxysteroid dehydrogenase 2 in rat leydig cells: its role in blunting glucocorticoid action at physiological levels of substrate. Endocrinology. 2005; 146: 2657-64.
78. Latif SA, Pardo HA, Hardy MP, Morris DJ. Endogenous selective inhibitors of 11beta-hydroxysteroid dehydrogenase isoforms 1 and 2 of adrenal origin. Mol Cell Endocrinol. 2005; 243: 43-50.
79. Coeli FB, Ferraz LF, Lemos-Marini SH, Rigatto SZ, Belangero VM, de-Mello MP. Apparent mineralocorticoid excess syndrome in a Brazilian boy caused by the homozygous missense mutation p. R186C in the HSD11B2 gene. Arq Bras Endocrinol Metabol. 2008; 52: 1277-81.
80. Hu Q, Jagusch C, Hille UE, Haupenthal J, Hartmann RW. Replacement of imidazolyl by pyridyl in biphenylmethylenes results in selective CYP17 and dual CYP17/CYP11B1 inhibitors for the treatment of prostate cancer. J Med Chem. 2010; 53: 5749-58.
81. Pinto-Bazurco Mendieta MA, Hu Q, Engel M, Hartmann RW. Highly potent and selective nonsteroidal dual inhibitors of CYP17/CYP11B2 for the treatment of prostate cancer to reduce risks of cardiovascular diseases. J Med Chem. 2013; 56: 6101-7.