Intratumoral estrogen sulfotransferase induction contributes to the anti-breast cancer effects of the dithiocarbamate derivative TM208

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.

Breast cancer pathogenesis is linked to the intra-tumoral estrogen sulfotransferase (hSULT1E1) expressions regulated by cellular redox dependent Nrf-2/NFκβ interplay

“…Oxidative regulation of E2 function via SULT1E1 modification (at Cys83) is reported [23]. One recent article extensively analyze that not only SULT1E1 but also a large number of E2 metabolizing proteins including sulfatases (STs), formyl glycine forming enzymes are redox regulated.…”

“…This is important that the level of SULT1E1 expression is inversely correlated with malignancy in breast cancers [22]. Induction of intra-tumoral SULT1E1 and reduction of estrogen concentration by TM208 contributes to the anti-breast cancer action [23].…”

Dopamine D2 receptor antagonist sulpiride enhances dexamethasone responses in the treatment of drug-resistant and metastatic breast cancer

“…The cytosol of the harvested tumors in each group of the metastatic xenograft nude mice was prepared as previously described [21] . The concentrations of the metastasis-associated biomarkers MMP-2, MMP-9, E-cadherin, N-cadherin and clau-din1 were measured using commercial ELISA kits according to the manufacturer's instructions.…”

Intra-tumoural estrogen sulfotransferase (hSULT1E1) regulations in human breast cancer tissues are influenced by cellular redox-modifications through antioxidants and Nrf-2/NFκβ interplay.

“…This is important that the level of SULT1E1 expression is inversely correlated with malignancy in breast cancers [16]. Induction of intra-tumoural SULT1E1and reduction of estrogen concentration by TM208 contributes to the anti-breast cancer action [17]. Earlier studies suggested a potential oxidative inhibition mechanism for human SULT1E1 through Cys83 redox modification.…”