Summary
Selective estrogen receptor modulators (SERMs) are currently in use in the hormonal therapy of breast cancer. In that respect, a new hormone-related approach is the therapeutical inhibition of steroid sulfatase (STS), which converts inactive, sulfated steroids into active hormones. We investigated the potential of 6-EO-14, a non-steroidal STS inhibitor with SERM potential. The latter compound, which exhibits a sulfamate moiety, releases the phenol derivative 8-EO-14 after the irreversible inhibition of STS. STS was inhibited by 6-EO-14 (IC50 = 0.3 μM), but not 8-EO-14, in HEK-293 cells transfected with an STS expression vector. The SERM potential of 8-EO-14 was assessed in osteoblast-like Saos-2 cells by investigating its effect on cell proliferation and on the activity of alkaline phosphatase (ALP), a specific differentiation marker. Saos-2 cell proliferation was increased by 21 % following 8-EO-14 addition (1 μM), and 8-EO-14 induced ALP activity (31 % increase at 0.1 nM) via estrogen receptor alpha (ERα) similarly to the SERM raloxifene. As compared to estradiol (E2) (100 %), the relative binding affinity of 6-EO-14 and 8-EO-14) for ERα was found to be weak (0.09 and 0.01 %, respectively). When assessed in two estrogen-dependent human breast cancer cell lines (MCF-7 and T-47D), 8-EO-14 did not support MCF-7 cell proliferation, whereas both 8-EO-14 and 6-EO-14 exhibited estrogen-like growth stimulation in T-47D cells. These two compounds were also unable to block E2-induced cell proliferation, suggesting their lack of antiestrogenic activity. Despite the known potency of 6-EO-14 as an STS inhibitor, the observed trophic activity of this new scaffold towards ERα-positive cells needs to be carefully considered prior to its potential utilization as a therapeutic agent.
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References
American Cancer Society (2012) Cancer Facts and Figures 2012 [online], http://www.cancer.org/ Research/CancerFactsFigures/CancerFactsFigures/cancer-facts-figures
Canadian Cancer Society. Canadian Cancer Statistics 2011 [online], http://www.cancer.ca/Canada-wide/About%20cancer/Cancer%20statistics.aspx?sc_lang=en
Jonat W, Pritchard KI, Sainsbury R, Klijn JG (2006) Trends in endocrine therapy and chemotherapy for early breast cancer: a focus on the premenopausal patient. J Cancer Res Clin Oncol 132:275–286
Duggan C, Marriott K, Edwards R, Cuzick J (2003) Inherited and acquired risk factors for venous thromboembolic disease among women taking tamoxifen to prevent breast cancer. J Clin Oncol 21:3588–3593
Bergman L, Beelen ML, Gallee MP, Hollema H, Benraadt J, Van Leeuwen FE (2000) Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Comprehensive cancer Centres' ALERT group. Assessment of liver and endometrial cancer risk following tamoxifen. Lancet 356:881–887
Riggs BL, Khosla S, Melton LJ (2002) Third Sex steroids and the constructive and conservation of the adult skeleton. Endocr Rev 23:279–302
Obiorah I, Jordan VC (2011) Progress in endocrine approaches to the treatment and prevention of breast cancer. Maturas 70:315–321
Ghosh D (2007) Human sulfatases: a structural perspective to catalysis. Cell Mol Life Sci 64:2013–2022
Pasqualini JR, Gelly C, Nguyen BL, Vella C (1989) Importance of estrogen sulfates in breast cancer. J Steroid Biochem 34:155–163
Chetrite GS, Cortes-Prieto J, Philippe JC, Wright F, Pasqualini JR (2000) Comparison of estrogen concentrations, estrone sulfatase and aromatase activities in normal, and in cancerous, human breast tissues. J Steroid Biochem Mol Biol 72:23–27
Pasqualini JR, Chetrite G, Blacker C, Feinstein MC, Delalonde L, Talbi M, Maloche C (1996) Concentration of estrone, estradiol, and estrone sulfate and evaluation of sulfatase and aromatase activities in pre- and postmenopausal breast cancer patients. J Clin Endocrinol Metab 81:1460–1464
Santner SJ, Feil PD, Santen RJ (1984) In situ estrogen production via the estrone sulfatase pathway in breast tumors: relative importance versus the aromatase pathway. J Clin Endocrinol Metab 59:29–33
Ouellet E, Maltais R, Ouellet C, Poirier D (2013) Investigation of a tetrahydroisoquinoline scaffold as dual-action steroid sulfatase inhibitors generated by parallel solid-phase synthesis. Med Chem Commun 4:681–692
Ciobanu LC, Luu-The V, Martel C, Labrie F, Poirier D (2003) Inhibition of estrone sulfate-induced uterine growth by potent nonestrogenic steroidal inhibitors of steroid sulfatase. Cancer Res 63:6442–6446
Wakeling AE, Bowler J (1988) Novel antioestrogens without partial agonist activity. J Steroid Biochem 31:645–653
Ciobanu LC, Luu-The V, Poirier D (2002) Nonsteroidal compounds designed to mimic potent steroid sulfatase inhibitors. J Steroid Biochem Mol Biol 80:339–353
Arcaro KF, Yi L, Seegal RF, Vakharia DD, Yang Y, Spink DC, Brosch K, Gierthy GF (1999) 2,2′,6,6′-Tetrachlorobiphenyl is estrogenic in vitro and in vivo. J Cell Biochem 72:94–102
Davis DD, Diaz-Cruz ES, Landini S, Kim YW, Brueggemeier RW (2008) Evaluation of synthetic isoflavones on cell proliferation, estrogen receptor binding affinity, and apoptosis in human breast cancer cells. J Steroid Biochem Mol Biol 108:23–31
Qu Q, Perälä-Heape M, Kapanen A, Dahllund J, Salo J, Väänänen HK, Härkönen P (1998) Estrogen enhances differentiation of osteoblasts in mouse bone marrow culture. Bone 22:201–209
Qu Q, Härkönen PL, Väänänen HK (1999) Comparative effects of estrogen and antiestrogens on differentiation of osteoblasts in mouse bone marrow culture. J Cell Biochem 73:500–507
Sun J, Huang YR, Harrington WR, Sheng S, Katzenellenbogen JA, Katzenellenbogen BS (2002) Antagonists selective for estrogen receptor alpha. Endocrinology 143:941–947
Compton DR, Sheng S, Carlson KE, Rebacz NA, Lee IY, Katzenellenbogen BS, Katzenellenbogen JA (2004) Pyrazolo[1,5-a]pyrimidines: estrogen receptor ligands possessing estrogen receptor β antagonist activity. J Med Chem 47:5872–5893
Fujikawa H, Okura F, Kuwano Y, Sekizawa A, Chiba H, Shimodaira K, Saito H, Yanaihara T (1997) Steroid sulfatase activity in osteoblast cells. Biochem Biophys Res Commun 231:42–47
Nussbaumer P, Winiski AP, Billich A (2003) Estrogenic potential of 2-alkyl-4-(thio)chromenone 6-O-sulfamates: potent inhibitors of human steroid sulfatase. J Med Chem 46:5091–5094
Kumar R, Zakharov MN, Khan SH, Miki R, Jang H, Toraldo G, Singh R, Bhasin S, Jasuja R (2011) The dynamic structure of the estrogen receptor, J Amino Acids, Article ID 81254 0
Dahlman-Wright K, Cavailles V, Fuqua SA, Jordan VC, Katzenellenbogen JA, Korach KS, Maggi A, Muramatsu M, Parker MG, Gustafsson JA (2006) International union of pharmacology. LXIV. Estrogen receptors. Pharmacol Rev 58:773–781
Brzozowski AM, Pike ACW, Dauter Z, Hubbard RE, Bonn T, Engstrom O, Öhman L, Greene GL, Gustafsson JA, Carlquist M (1997) Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389:753–758
Acknowledgments
This study was made possible through a grant from the Fondation du Cancer du Sein du Québec. We are grateful to Jenny Roy and Diana Ayan for their help with the in vitro assays. Careful revisions of the manuscript by Micheline Harvey and Richard Poulin are also greatly appreciated.
Conflict of interest
D. Poirier has ownership interests on a patent application related to STS inhibitors.
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1) Experimental procedure for the STS inhibition assay. 2) Experimental procedure for ERα binding assay. 3) Effect of E2 and raloxifene on Saos-2 cell proliferation after a 3-, 5- and 7-day treatment (Figure A). 4) Effect of tamoxifen and E2 on ALP activity in Saos-2 cells after a 3-day incubation (Figure B). (DOC 232 kb)
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Ouellet, C., Ouellet, É. & Poirier, D. In vitro evaluation of a tetrahydroisoquinoline derivative as a steroid sulfatase inhibitor and a selective estrogen receptor modulator. Invest New Drugs 33, 95–103 (2015). https://doi.org/10.1007/s10637-014-0187-1
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DOI: https://doi.org/10.1007/s10637-014-0187-1