title: Excentric cleavage products of beta-carotene inhibit estrogen receptor positive and negative breast tumor cell growth in vitro and inhibit activator protein-1-mediated transcriptional activation.
abstract: Both retinoids and carotenoids are potentially useful chemopreventive agents. In this study we tested the effect of synthetic excentric cleavage products of beta-carotene on the growth of the MCF-7, Hs578T and MDA-MB-231 human breast cancer cells. The apo-beta-carotenoic acids (beta-apo-CA) beta-apo-14'-, beta-apo-12'-, beta-apo-10'- and beta-apo-8'-CA are structurally similar to all-trans-retinoic acid (atRA) but have different side chain lengths. Nine days of treatment with atRA inhibited MCF-7 and Hs578T cell proliferation in a dose-dependent manner. beta-apo-14'-CA and beta-apo-12'-CA significantly inhibited MCF-7 growth, whereas only beta-apo-14'-CA inhibited Hs578T growth. None of these treatments inhibited the growth of MDA-MB-231 cells. Potential mechanisms of growth inhibition, i.e., regulation of the cell cycle control proteins E2F1 and retinoblastoma protein (RB), and effect on activator protein-1 (AP-1)-mediated gene regulation were examined. beta-apo-14'-CA and atRA inhibited the expression of E2F1 protein in MCF-7 and Hs578T cells. beta-apo-14'-CA, beta-apo-12'-CA and atRA down-regulated RB protein expression in MCF-7 but not in Hs578T cells. The effect of phorbol ester-induced transcriptional activation of a collagenase promoter-reporter gene construct was strongly inhibited by 1 micromol/L beta-apo-14'-CA, atRA (MCF-7, Hs578T) or beta-apo-12'-CA (MCF-7). These effects were due neither to cellular conversion of beta-apo-CA to atRA nor to high affinity binding to the retinoid acid receptors. Thus, beta-apo-CAs were effective inhibitors of breast tumor cell proliferation, possibly mediated through down-regulation of cell cycle regulatory proteins and/or inhibition of AP-1 transcriptional activity. The ability of beta-apo-CA to regulate breast tumor cell growth independently of conversion to atRA suggests that these compounds may have fewer side effects than retinoids and, therefore, have a potential chemotherapeutic value that deserves further examination.
authors.affiliation: Molecular Pharmacology Research Center, New England Medical Center, Boston, MA 02111, USA.
authors.forename: Elmi C
authors.initials: EC
authors.lastname: Tibaduiza
authors.forename: James C
authors.initials: JC
authors.lastname: Fleet
authors.forename: Robert M
authors.initials: RM
authors.lastname: Russell
authors.forename: Norman I
authors.initials: NI
authors.lastname: Krinsky
mesh_terms: D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000517:prevention & control; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000473:pathology*; D012176:Retinoids / Q000737:chemistry / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D019207:beta Carotene / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D012176:Retinoids; D018808:Transcription Factor AP-1; D019207:beta Carotene