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


CONCLUSIONS
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.
Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.|Institute of Clinical Pharmacology, Peking University First Hospital, Beijing 100191, China.
Xi-wei
XW
Ji
Department of Physiological Sciences, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK 74078, USA.
Guang-ping
GP
Chen
Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Yan
Y
Song
Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Ming
M
Hua
Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Li-jie
LJ
Wang
Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Liang
L
Li
Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Yin
Y
Yuan
Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Si-yuan
SY
Wang
Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.|State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.
Tian-yan
TY
Zhou
Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.|State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.
Wei
W
Lu
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001940:Breast / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics; D015238:Sulfotransferases / Q000032:analysis / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects*
C522133:4-methylpiperazine-1-carbodithioc acid 3-cyano-3,3-diphenylpropyl ester hydrochloride; D000970:Antineoplastic Agents; D010879:Piperazines; D012333:RNA, Messenger; D015238:Sulfotransferases; C020122:estrone sulfotransferase