Intratumoral Estrogen Sulfotransferase Induction Contributes to the Anti-breast Cancer Effects of the Dithiocarbamate Derivative TM208

Overview

Journal Acta Pharmacol Sin

Specialty Pharmacology

Date 2015 May 5

PMID 25937633

Citations 10

Authors

Xi-Wei Ji

Guang-Ping Chen

Yan Song

Ming Hua

Li-Jie Wang

Liang Li

Yin Yuan

Si-Yuan Wang

Tian-Yan Zhou

Wei Lu

Affiliations

Soon will be listed here.

Abstract

Aim: Sulfotransferase-catalyzed sulfation is the most important pathway for inactivating estrogens. Thus, activation of estrogen sulfotransferase (EST) may be an alternative approach for the treatment of estrogen-dependent breast cancer. In this study we investigated the involvement of EST in anti-breast cancer effects of the dithiocarbamate derivative TM208 in vitro and in vivo.

Methods: The viability of human breast cancer MCF-7 cells was determined using a SBB assay. Nude mice bearing MCF-7 cells were orally administered TM208 (50 and 150 mg·kg(-1)·d(-1)) for 18 days. The xenograft tumors and uteri were collected. The mRNA expression of EST was examined with real-time PCR. EST protein was detected with Western blot, ELISA or immunohistochemical staining assays. A radioactive assay was used to measure the EST activity. Uterotropic bioassay was used to examine the uterine estrogen responses.

Results: Treatment with TM208 (10, 15 and 20 μmol/L) concentration-dependently increased EST expression in MCF-7 cells in vitro. Co-treatment with triclosan, an inhibitor of sulfonation, abolished TM208-induced cytotoxicity in MCF-7 cells. TM208 exhibited an apparent anti-estrogenic property: it exerted more potent cytotoxicity in E2-treated MCF-7 cells. In the nude mice bearing MCF-7 cells, TM208 administration time-dependently increased the expression and activity of EST, and blocked the gradual increase of E2 concentration in the xenograft tumors. Furthermore, TM208 administration blocked the estrogens-stimulated uterine enlargement. Tamoxifen, a positive control drug, produced similar effects on the expression and activity of EST in vitro and in vivo.

Conclusion: The induction of EST and reduction of estrogen concentration contribute to the anti-breast cancer action of TM208 and tamoxifen. TM208 may be developed as anticancer drug for the treatment of estrogen receptor-positive breast cancer.

Citing Articles

Developing liver-targeted naringenin nanoparticles for breast cancer endocrine therapy by promoting estrogen metabolism.

Zhao Y, Tan H, Zhang J, Zhan D, Yang B, Hong S J Nanobiotechnology. 2024; 22(1):122.

PMID: 38504208 PMC: 10953142. DOI: 10.1186/s12951-024-02356-0.

Estrogen sulfotransferase and sulfatase in steroid homeostasis, metabolic disease, and cancer.

Wang J, Feng Y, Liu B, Xie W Steroids. 2023; 201:109335.

PMID: 37951289 PMC: 10842091. DOI: 10.1016/j.steroids.2023.109335.

Breast Cancer MCF-7 Cell Spheroid Culture for Drug Discovery and Development.

Chen G, Liu W, Yan B J Cancer Ther. 2022; 13(3):117-130.

PMID: 36311820 PMC: 9611733. DOI: 10.4236/jct.2022.133009.

Naringenin in Si-Ni-San formula inhibits chronic psychological stress-induced breast cancer growth and metastasis by modulating estrogen metabolism through FXR/EST pathway.

Zhang J, Wang N, Zheng Y, Yang B, Wang S, Wang X J Adv Res. 2022; 47:189-207.

PMID: 35718080 PMC: 10173160. DOI: 10.1016/j.jare.2022.06.006.

Metabolomic studies in the inborn error of metabolism alkaptonuria reveal new biotransformations in tyrosine metabolism.

Norman B, Davison A, Hughes J, Sutherland H, Wilson P, Berry N Genes Dis. 2022; 9(4):1129-1142.

PMID: 35685462 PMC: 9170613. DOI: 10.1016/j.gendis.2021.02.007.

References

Pasqualini J, Chetrite G . Correlation of estrogen sulfotransferase activity and proliferation in normal and carcinomatous human breast. A hypothesis. Anticancer Res. 2007; 27(5A):3219-25. View

Spink B, Katz B, Hussain M, Pang S, Connor S, Aldous K . SULT1A1 catalyzes 2-methoxyestradiol sulfonation in MCF-7 breast cancer cells. Carcinogenesis. 2000; 21(11):1947-57. DOI: 10.1093/carcin/21.11.1947. View

Aranda A, Pascual A . Nuclear hormone receptors and gene expression. Physiol Rev. 2001; 81(3):1269-304. DOI: 10.1152/physrev.2001.81.3.1269. View

Zhou T, Huang C, Chen Y, Xu J, Shanbhag P, Chen G . Methamphetamine regulation of sulfotransferase 1A1 and 2A1 expression in rat brain sections. Neurotoxicology. 2012; 34:212-8. PMC: 3557703. DOI: 10.1016/j.neuro.2012.09.010. View

Wang L, Falany C, James M . Triclosan as a substrate and inhibitor of 3'-phosphoadenosine 5'-phosphosulfate-sulfotransferase and UDP-glucuronosyl transferase in human liver fractions. Drug Metab Dispos. 2004; 32(10):1162-9. DOI: 10.1124/dmd.104.000273. View

Guo B, Ge Z, Cheng T, Li R . [Synthesis and anti-tumor activities of 1,4-bis[3-(amino-dithiocarboxy)propionyl] piperazine derivatives]. Yao Xue Xue Bao. 2003; 36(3):185-7. View

Fu J, Weise A, Falany J, Falany C, Thibodeau B, Miller F . Expression of estrogenicity genes in a lineage cell culture model of human breast cancer progression. Breast Cancer Res Treat. 2009; 120(1):35-45. PMC: 3772670. DOI: 10.1007/s10549-009-0363-8. View

Alnouti Y, Klaassen C . Regulation of sulfotransferase enzymes by prototypical microsomal enzyme inducers in mice. J Pharmacol Exp Ther. 2007; 324(2):612-21. DOI: 10.1124/jpet.107.129650. View

Gamage N, Barnett A, Hempel N, Duggleby R, Windmill K, Martin J . Human sulfotransferases and their role in chemical metabolism. Toxicol Sci. 2005; 90(1):5-22. DOI: 10.1093/toxsci/kfj061. View

10.

Vichai V, Kirtikara K . Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc. 2007; 1(3):1112-6. DOI: 10.1038/nprot.2006.179. View

11.

Yarden R, Wilson M, Chrysogelos S . Estrogen suppression of EGFR expression in breast cancer cells: a possible mechanism to modulate growth. J Cell Biochem Suppl. 2001; Suppl 36:232-46. DOI: 10.1002/jcb.1142. View

12.

Chen Y, Huang C, Zhou T, Zhang S, Chen G . Biochanin A induction of sulfotransferases in rats. J Biochem Mol Toxicol. 2010; 24(2):102-14. DOI: 10.1002/jbt.20318. View

13.

Shibuya R, Suzuki T, Miki Y, Yoshida K, Moriya T, Ono K . Intratumoral concentration of sex steroids and expression of sex steroid-producing enzymes in ductal carcinoma in situ of human breast. Endocr Relat Cancer. 2008; 15(1):113-24. DOI: 10.1677/ERC-07-0092. View

14.

Suzuki T, Miki Y, Nakamura Y, Moriya T, Ito K, Ohuchi N . Sex steroid-producing enzymes in human breast cancer. Endocr Relat Cancer. 2005; 12(4):701-20. DOI: 10.1677/erc.1.00834. View

15.

Ahn K, Yi K, Park H, Shin J, Hur J, Kim S . Anti-proliferative effect of Klimaktoplan® on human breast cancer cells. Arch Gynecol Obstet. 2013; 288(4):833-8. DOI: 10.1007/s00404-013-2849-1. View

16.

Johnson M, Zuo H, Lee K, Trebley J, Rae J, Weatherman R . Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res Treat. 2004; 85(2):151-9. DOI: 10.1023/B:BREA.0000025406.31193.e8. View

17.

Maiti S, Chen G . Tamoxifen induction of aryl sulfotransferase and hydroxysteroid sulfotransferase in male and female rat liver and intestine. Drug Metab Dispos. 2003; 31(5):637-44. DOI: 10.1124/dmd.31.5.637. View

18.

Falany C, Krasnykh V, Falany J . Bacterial expression and characterization of a cDNA for human liver estrogen sulfotransferase. J Steroid Biochem Mol Biol. 1995; 52(6):529-39. DOI: 10.1016/0960-0760(95)00015-r. View

19.

Jiang X, Ling X, Han F, Li R, Cui J . Studies on the metabolism of 4-methyl-piperazine-1-carbodithioc acid 3-cyano-3,3-diphenylpropyl ester hydrochloride in rats by high-performance liquid chromatography/electrospray ionization tandem mass spectrometry. J Pharm Biomed Anal. 2007; 44(5):1127-32. DOI: 10.1016/j.jpba.2007.05.026. View

20.

Pasqualini J, Chetrite G . Recent insight on the control of enzymes involved in estrogen formation and transformation in human breast cancer. J Steroid Biochem Mol Biol. 2005; 93(2-5):221-36. DOI: 10.1016/j.jsbmb.2005.02.007. View