title: Inhibition of estrogen signaling through depletion of estrogen receptor alpha by ursolic acid and betulinic acid from Prunella vulgaris var. lilacina.
abstract: Extracts of Prunella vulgaris have been shown to exert antiestrogenic effects. To identify the compounds responsible for these actions, we isolated the constituents of P. vulgaris and tested their individual antiestrogenic effects. Rosmarinic acid, caffeic acid, ursolic acid (UA), oleanolic acid, hyperoside, rutin and betulinic acid (BA) were isolated from the flower stalks of P. vulgaris var. lilacina Nakai (Labiatae). Among these constituents, UA and BA showed significant antiestrogenic effects, measured as a decrease in the mRNA level of GREB1, an estrogen-responsive protein; the effects of BA were stronger than those of UA. UA and BA were capable of suppressing estrogen response element (ERE)-dependent luciferase activity and expression of estrogen-responsive genes in response to exposure to estradiol, further supporting the suppressive role of these compounds in estrogen-induced signaling. However, neither UA nor BA was capable of suppressing estrogen signaling in cells ectopically overexpressing estrogen receptor α (ERα). Furthermore, both mRNA and protein levels of ERα were reduced by treatment with UA or BA, suggesting that UA and BA inhibit estrogen signaling by suppressing the expression of ERα. Interestingly, both compounds enhanced prostate-specific antigen promoter activity. Collectively, these findings demonstrate that UA and BA are responsible for the antiestrogenic effects of P. vulgaris and suggest their potential use as therapeutic agents against estrogen-dependent tumors.
authors.affiliation: Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyung-Heedaero, Seoul 130-701, Republic of Korea.
authors.forename: Hye-In
authors.initials: HI
authors.lastname: Kim
authors.affiliation: Department of Medical Zoology, Kyung Hee University School of Medicine, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors.forename: Fu-Shi
authors.initials: FS
authors.lastname: Quan
authors.affiliation: Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyung-Heedaero, Seoul 130-701, Republic of Korea.
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Kim
authors.affiliation: Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyung-Heedaero, Seoul 130-701, Republic of Korea.
authors.forename: Na-Rae
authors.initials: NR
authors.lastname: Lee
authors.affiliation: Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyung-Heedaero, Seoul 130-701, Republic of Korea.
authors.forename: Hyun Ji
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyung-Heedaero, Seoul 130-701, Republic of Korea.
authors.forename: Su Ji
authors.initials: SJ
authors.lastname: Jo
authors.affiliation: Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyung-Heedaero, Seoul 130-701, Republic of Korea.
authors.forename: Chae-Min
authors.initials: CM
authors.lastname: Lee
authors.affiliation: Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyung-Heedaero, Seoul 130-701, Republic of Korea; Department of Life and Nanopharmaceutical Science, Kyung Hee University, Seoul 130-701, Republic of Korea. Electronic address: dsjang@khu.ac.kr.
authors.forename: Dae Sik
authors.initials: DS
authors.lastname: Jang
authors.affiliation: Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyung-Heedaero, Seoul 130-701, Republic of Korea. Electronic address: innks@khu.ac.kr.
authors.forename: Kyung-Soo
authors.initials: KS
authors.lastname: Inn
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D020847:Estrogen Receptor Modulators / Q000302:isolation & purification / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics; D053978:Pentacyclic Triterpenes; D008517:Phytotherapy; D010946:Plants, Medicinal / Q000737:chemistry; D011401:Promoter Regions, Genetic; D017430:Prostate-Specific Antigen / Q000235:genetics; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D031347:Prunella / Q000737:chemistry; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014315:Triterpenes / Q000302:isolation & purification / Q000494:pharmacology*; D000094062:Betulinic Acid; D000097245:Ursolic Acid
chemical_list: D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D004967:Estrogens; D009363:Neoplasm Proteins; D053978:Pentacyclic Triterpenes; D017430:Prostate-Specific Antigen; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D014315:Triterpenes; D000094062:Betulinic Acid; D000097245:Ursolic Acid; C506487:ESR1 protein, human; C416830:GREB1 protein, human
keywords: Antiestrogenic effect; Betulinic acid; Estrogen; Estrogen receptor; Prunella vulgaris var. lilacina; Ursolic acid