A Synthetic Small Molecule Carbazole SH-I-125 Degrades Androgen Receptor and Overcomes Castration-Resistance and Enzalutamide-Resistance in Prostate Cancer Cells

Main Article Content

Karishma S. Amin Shu-Jie Hou Joshua D. Brown-Clay Milton L. Brown Partha P. Banerjee

Abstract

Resistance to clinical anti-androgens is an ongoing problem in the treatment of castration-resistant prostate cancer (CRPC). Although second generation anti-androgens demonstrate initial clinical benefit, patients often develop resistance to these therapies, evidenced by rising serum PSA levels and disease progression. Several mechanisms including the expression of androgen receptor (AR) splice variants contribute to the reactivation of AR signaling in drug-resistant prostate cancer. Novel therapies that target AR signaling and suppress growth in castration-resistant and anti-androgen-resistant prostate cancer are essential for the effective management of advanced disease. We developed a synthetic small molecule analog of mahanine, SH-I-125, a compound with the ability to disrupt androgen receptor signaling and induce apoptosis in castration-resistant and drug-resistant prostate cancer cellular models. SH-I-125 disrupted AR signaling and induced apoptosis in CRPC cells and anti-androgen-resistant prostate cancer cells in a manner more effective than clinical anti-androgens, enzalutamide and ARN509. Furthermore, SH-I-125 decreased full-length AR and its splice variant AR-V7 levels in 22Rv1 prostate cancer cells by a proteasome-dependent mechanism. These findings indicate the therapeutic potential of SH-I-125 in prostate cancer patients that have progressed on currently approved therapies for CRPC.

Keywords: Androgen Receptor, Apoptosis, Enzalutamide, ARN509, Castration-Resistant Prostate Cancer, Enzalutamide-Resistant Prostate Cancer

Article Details

How to Cite
AMIN, Karishma S. et al. A Synthetic Small Molecule Carbazole SH-I-125 Degrades Androgen Receptor and Overcomes Castration-Resistance and Enzalutamide-Resistance in Prostate Cancer Cells. Medical Research Archives, [S.l.], v. 10, n. 6, june 2022. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/2876>. Date accessed: 20 apr. 2024. doi: https://doi.org/10.18103/mra.v10i6.2876.
Section
Research Articles

References

1. Siegel RL, Miller KD, Jemal A: Cancer statistics, 2022. CA Cancer J Clin 2022, 72:7-33.
2. Feldman BJ, Feldman D: The development of androgen-independent prostate cancer. Nat Rev Cancer 2001, 1:34-45.
3. Linja MJ, Savinainen KJ, Saramaki OR, Tammela TL, Vessella RL, Visakorpi T: Amplification and overexpression of androgen receptor gene in hormone-refractory prostate cancer. Cancer Res 2001, 61:3550-3555.
4. Yeh S, Lin HK, Kang HY, Thin TH, Lin MF, Chang C: From HER2/Neu signal cascade to androgen receptor and its coactivators: a novel pathway by induction of androgen target genes through MAP kinase in prostate cancer cells. Proc Natl Acad Sci U S A 1999, 96:5458-5463.
5. Wen Y, Hu MC, Makino K, Spohn B, Bartholomeusz G, Yan DH, Hung MC: HER-2/neu promotes androgen-independent survival and growth of prostate cancer cells through the Akt pathway. Cancer Res 2000, 60:6841-6845.
6. Tilley WD, Buchanan G, Hickey TE, Bentel JM: Mutations in the androgen receptor gene are associated with progression of human prostate cancer to androgen independence. Clin Cancer Res 1996, 2:277-285.
7. Ferraldeschi R, Sharifi N, Auchus RJ, Attard G: Molecular pathways: Inhibiting steroid biosynthesis in prostate cancer. Clin Cancer Res 2013, 19:3353-3359.
8. Sun S, Sprenger CC, Vessella RL, Haugk K, Soriano K, Mostaghel EA, Page ST, Coleman IM, Nguyen HM, Sun H, et al: Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J Clin Invest 2010, 120:2715-2730.
9. Guo Z, Yang X, Sun F, Jiang R, Linn DE, Chen H, Chen H, Kong X, Melamed J, Tepper CG, et al: A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Res 2009, 69:2305-2313.
10. Clegg NJ, Wongvipat J, Joseph JD, Tran C, Ouk S, Dilhas A, Chen Y, Grillot K, Bischoff ED, Cai L, et al: ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res 2012, 72:1494-1503.
11. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, de Wit R, Mulders P, Chi KN, Shore ND, et al: Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012, 367:1187-1197.
12. Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, Iversen P, Bhattacharya S, Carles J, Chowdhury S, et al: Enzalutamide in Metastatic Prostate Cancer before Chemotherapy. N Engl J Med 2014.
13. Li Y, Chan SC, Brand LJ, Hwang TH, Silverstein KA, Dehm SM: Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. Cancer Res 2012, 73:483-489.
14. Joseph JD, Lu N, Qian J, Sensintaffar J, Shao G, Brigham D, Moon M, Maneval EC, Chen I, Darimont B, Hager JH: A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509. Cancer Discov 2013, 3:1020-1029.
15. Korpal M, Korn JM, Gao X, Rakiec DP, Ruddy DA, Doshi S, Yuan J, Kovats SG, Kim S, Cooke VG, et al: An F876L mutation in androgen receptor confers genetic and phenotypic resistance to MDV3100 (enzalutamide). Cancer Discov 2013, 3:1030-1043.
16. Arora VK, Schenkein E, Murali R, Subudhi SK, Wongvipat J, Balbas MD, Shah N, Cai L, Efstathiou E, Logothetis C, et al: Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell 2013, 155:1309-1322.
17. Amin KS, Jagadeesh S, Baishya G, Rao PG, Barua NC, Bhattacharya S, Banerjee PP: A naturally derived small molecule disrupts ligand-dependent and ligand-independent androgen receptor signaling in human prostate cancer cells. Mol Cancer Ther 2014, 13:341-352.
18. Nazareth LV, Weigel NL: Activation of the human androgen receptor through a protein kinase A signaling pathway. J Biol Chem 1996, 271:19900-19907.
19. Chen T, Wang LH, Farrar WL: Interleukin 6 activates androgen receptor-mediated gene expression through a signal transducer and activator of transcription 3-dependent pathway in LNCaP prostate cancer cells. Cancer Res 2000, 60:2132-2135.
20. Huggins C, Stephens, R. C. & Hodges, C. V: The effects of castration on
advanced carcinoma of the prostate gland. Arch Surg 1941, 43:209.
21. Labrie F, Belanger A, Luu-The V, Labrie C, Simard J, Cusan L, Gomez J, Candas B: Gonadotropin-releasing hormone agonists in the treatment of prostate cancer. Endocr Rev 2005, 26:361-379.
22. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB, Jr., Saad F, et al: Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011, 364:1995-2005.
23. Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, Wongvipat J, Smith-Jones PM, Yoo D, Kwon A, et al: Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 2009, 324:787-790.
24. Salami J, Alabi S, Willard RR, Vitale NJ, Wang J, et al: Androgen receptor degradation by the proteolysis-targeting chimera ARCC-4 outperforms enzalutamide in cellular models of prostate cancer drug resistance. Commun Biol. 2018;1:100.
25. Han X, Wang C, Qin C, Xiang W, Fernandez-Salas E, Yang CY, et al: Discovery of ARD-69 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Androgen
Receptor (AR) for the Treatment of Prostate Cancer. J Med Chem. 2019 Jan
24;62(2):941-964.
26. Chen L, Han L, Mao S, Xu P, Xu X, Zhao R, et al: Discovery of A031 as effective proteolysis targeting chimera (PROTAC) androgen receptor (AR) degrader for the treatment of prostate cancer. Eur J Med Chem. 2021, 216: 113370.
27. Xiang W, Zhao L, Han X, Qin C, Miao B, et al: Discovery of ARD-2585 as an Exceptionally Potent and Orally Active PROTAC Degrader of Androgen Receptor for the Treatment of Advanced Prostate Cancer. J Med Chem. 2021 Sep 23;64(18):13487-13509.