title: 4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol}, 1 a novel resveratrol analog, differentially regulates estrogen receptors α and β in breast cancer cells.
abstract: Breast cancer is a public health concern worldwide. Prolonged exposure to estrogens has been implicated in the development of breast neoplasms. Epidemiologic and experimental evidence suggest a chemopreventive role of phytoestrogens in breast cancers. Resveratrol, a naturally occurring phytoestrogen, has been shown to have potent anti-cancer properties. However, poor efficacy and bioavailability have prevented the use of resveratrol in clinics. In order to address these problems, we have synthesized a combinatorial library of azaresveratrol analogs and tested them for their ability to inhibit the proliferation of breast cancer cells. We have recently shown that 4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol} (TIMBD), has better anti-cancer properties than resveratrol and any other resveratrol analog we have synthesized so far. The objective of this study was to investigate the regulation of estrogen receptors (ERs) α and β by TIMBD in breast cancer cell lines. We demonstrate that TIMBD significantly induces the mRNA and protein expression levels of ERβ and inhibits that of ERα. TIMBD inhibits mRNA and protein expression levels of oncogene c-Myc, and cell cycle protein cyclin D1, which are important regulators of cellular proliferation. TIMBD significantly induces protein expression levels of tumor suppressor genes p53 and p21 in MCF-7 cells. TIMBD inhibits c-Myc in an ERβ-dependent fashion in MCF-10A and ERβ1-transfected MDA-MB-231 cells, suggesting regulation of ERs as an important upstream mechanism of this analog. ERβ plays a partial role in inhibition of proliferation by TIMBD while ERα overexpression does not significantly affect TIMBD's inhibition.
authors.affiliation: Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Amruta
authors.initials: A
authors.lastname: Ronghe
authors.affiliation: Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Anwesha
authors.initials: A
authors.lastname: Chatterjee
authors.affiliation: Department of Genetics, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Bhupendra
authors.initials: B
authors.lastname: Singh
authors.affiliation: ISTRA, Department of Chemistry, Abeda Inamdar Senior College, University of Pune, India.
authors.forename: Prasad
authors.initials: P
authors.lastname: Dandawate
authors.affiliation: Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Fatma
authors.initials: F
authors.lastname: Abdalla
authors.affiliation: Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Nimee K
authors.initials: NK
authors.lastname: Bhat
authors.affiliation: ISTRA, Department of Chemistry, Abeda Inamdar Senior College, University of Pune, India.
authors.forename: Subhash
authors.initials: S
authors.lastname: Padhye
authors.affiliation: Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA. Electronic address: bhath@umkc.edu.
authors.forename: Hari K
authors.initials: HK
authors.lastname: Bhat
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: C000619336:4-(E)-((p-tolylimino)-methylbenzene-1,2-diol); D000970:Antineoplastic Agents; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013267:Stilbenes; D000077185:Resveratrol
keywords: Breast cancer inhibition; Estrogen receptors; Resveratrol analogs; TIMBD