title: Activity of the antiestrogenic cajanin stilbene acid towards breast cancer.
abstract: Antiestrogenic therapy is a mainstay for estrogen receptor (ERα)-positive breast cancer. Due to the development of resistance to established antihormones such as tamoxifen, novel compounds are required. The low abundant cajanin stilbene acid (CSA) recently isolated by us from Pigeon Pea (Cajanus cajan) has structural similarities with estrogen. We analyzed the cytotoxic and anticancer activity of CSA in ERα-positive and -negative human breast cancer cells in vitro, in vivo and in silico. CSA exerts anticancer and antiestrogenic activities towards ERα-positive breast cancer, and it showed cytotoxicity towards tamoxifen-resistant MCF-7 cells, implying that CSA may be active against tamoxifen-resistant breast cancer cells. CSA showed low cytotoxicity in ERα-negative breast tumor cells as expected. Comparable cytotoxicity was observed towards p53 negative MCF-7 cells, implying that CSA is effective independent of the p53 status. Xenografted MCF-7 cells in nude mice were better inhibited by CSA than by cyclophosphamide. Testing of 8 primary cell cultures derived from human breast cancer biopsies showed that cell cultures from ER-positive tumors were more sensitive than from ER-negative ones. Dose-dependent decrease in ERα protein levels was observed upon CSA treatment. Synergistic effect with tamoxifen was observed in terms of increased p53 protein level. CSA affected pathways related to p53, cancer and cell proliferation. Gene promoter analyses supported the ERα regulation. CSA bound to the same site as 17β-estradiol and tamoxifen on ERα. In conclusion, CSA exerts its anticancer effects in ERα-positive breast cancer cells by binding and inhibiting ERα.
authors.affiliation: Key Laboratory of Forest Plant Ecology, Ministry of Education, Northeast Forestry University, Harbin 150040, China; Engineering Research Center of Forest Bio-Preparation, Ministry of Education, Northeast Forestry University, Harbin, China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
authors.forename: Onat
authors.initials: O
authors.lastname: Kadioglu
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wiench
authors.affiliation: Key Laboratory of Forest Plant Ecology, Ministry of Education, Northeast Forestry University, Harbin 150040, China; Engineering Research Center of Forest Bio-Preparation, Ministry of Education, Northeast Forestry University, Harbin, China.
authors.forename: Zuofu
authors.initials: Z
authors.lastname: Wei
authors.affiliation: Key Laboratory of Forest Plant Ecology, Ministry of Education, Northeast Forestry University, Harbin 150040, China; Engineering Research Center of Forest Bio-Preparation, Ministry of Education, Northeast Forestry University, Harbin, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Key Laboratory of Forest Plant Ecology, Ministry of Education, Northeast Forestry University, Harbin 150040, China; Engineering Research Center of Forest Bio-Preparation, Ministry of Education, Northeast Forestry University, Harbin, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Luo
authors.affiliation: Julius L. Chambers Biomedical/Biotechnology Research Institute North Carolina Central University North Carolina Research Campus Kannapolis, NC 28081, USA.
authors.forename: Xiaohe
authors.initials: X
authors.lastname: Yang
authors.affiliation: Key Laboratory of Forest Plant Ecology, Ministry of Education, Northeast Forestry University, Harbin 150040, China; Engineering Research Center of Forest Bio-Preparation, Ministry of Education, Northeast Forestry University, Harbin, China.
authors.forename: Chengbo
authors.initials: C
authors.lastname: Gu
authors.affiliation: Key Laboratory of Forest Plant Ecology, Ministry of Education, Northeast Forestry University, Harbin 150040, China; Engineering Research Center of Forest Bio-Preparation, Ministry of Education, Northeast Forestry University, Harbin, China.
authors.forename: Yuangang
authors.initials: Y
authors.lastname: Zu
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany. Electronic address: efferth@uni-mainz.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Efferth
mesh_terms: D000328:Adult; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004965:Estrogen Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D008819:Mice, Nude; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000378:metabolism; D012459:Salicylates / Q000008:administration & dosage / Q000494:pharmacology*; D013267:Stilbenes / Q000008:administration & dosage / Q000494:pharmacology*; D013629:Tamoxifen / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: C549543:3-hydroxy-4-prenyl-5-methoxystilbene-2-carboxylic acid; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen; D012459:Salicylates; D013267:Stilbenes; D013629:Tamoxifen
keywords: Breast cancer; Estrogen receptor; Microarray; Pharmacogenomics; Tamoxifen resistance; Xenograft tumor