title: Effects of Spiro-bisheterocycles on Proliferation and Apoptosis in Human Breast Cancer Cell Lines.
abstract: Breast cancer is the leading cause of cancer-related death in women worldwide and a critical public health concern. Here we investigated the anticancer potential and effects of low-molecular-weight bridgehead oxygen and nitrogen-containing spiro-bisheterocycles on proliferation and apoptosis of the human breast cancer cell lines MCF-7 and MDA-MB-231. The compounds feature a hydantoin moiety attached to either diazole, isoxazole, diazepine, oxazepine or benzodiazepine via the privileged tetrahedral spiro-linkage. Treatment with compounds spiro [hydantoin-isoxazole] and spiro [hydantoin-oxazepine] resulted in a dose-dependent decrease of cell proliferation and induction of apoptosis in both breast cancer cell lines, whereas spiro [hydantoin-diazepine] was only active against MDA-MB 231. Quantitative reverse transcription polymerase chain reaction analysis showed up-regulation of murine double minute 2 (MDM2), strictly p53-dependent, and detected an increase in expression of pro-apoptotic caspase 3 and BCL2-associated X (BAX) genes in both breast cancer cell lines expressing wild-type and mutant p53. In summary, the results suggest that our compounds promote apoptosis of breast cancer cell lines via p53-dependent and -independent pathways.
authors.affiliation: Scientific and Technical Research Center in Physico-Chemical Analysis (CRAPC), Tipaza, Algeria lamia_pharm@yahoo.fr.|Clermont University, University of Auvergne, UMR 1019, UNH CellulaR Micro-Environment, Immunomodulation and Nutrition ECREIN, Clermont-Ferrand, France.|Research Center in Human Nutrition CRNH Auvergne, Clermont-Ferrand, France.
authors.forename: Lamia Hamdan
authors.initials: LH
authors.lastname: Ramdani
authors.affiliation: Scientific and Technical Research Center in Physico-Chemical Analysis (CRAPC), Tipaza, Algeria.|Organic Chemistry, Natural Products and Agrifood (QOPNA), Department of Chemistry & QOPNA, University of Aveiro, Aveiro, Portugal.
authors.forename: Oualid
authors.initials: O
authors.lastname: Talhi
authors.affiliation: Scientific and Technical Research Center in Physico-Chemical Analysis (CRAPC), Tipaza, Algeria.
authors.forename: Nadia
authors.initials: N
authors.lastname: Taibi
authors.affiliation: Clermont University, University of Auvergne, UMR 1019, UNH CellulaR Micro-Environment, Immunomodulation and Nutrition ECREIN, Clermont-Ferrand, France.|Research Center in Human Nutrition CRNH Auvergne, Clermont-Ferrand, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Delort
authors.affiliation: Clermont University, University of Auvergne, UMR 1019, UNH CellulaR Micro-Environment, Immunomodulation and Nutrition ECREIN, Clermont-Ferrand, France.|Research Center in Human Nutrition CRNH Auvergne, Clermont-Ferrand, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Decombat
authors.affiliation: Organic Chemistry, Natural Products and Agrifood (QOPNA), Department of Chemistry & QOPNA, University of Aveiro, Aveiro, Portugal.
authors.forename: Artur
authors.initials: A
authors.lastname: Silva
authors.affiliation: Scientific and Technical Research Center in Physico-Chemical Analysis (CRAPC), Tipaza, Algeria.
authors.forename: Khaldoun
authors.initials: K
authors.lastname: Bachari
authors.affiliation: Clermont University, University of Auvergne, UMR 1019, UNH CellulaR Micro-Environment, Immunomodulation and Nutrition ECREIN, Clermont-Ferrand, France.|Research Center in Human Nutrition CRNH Auvergne, Clermont-Ferrand, France.|Anticancer Center Jean-Perrin, Clermont-Ferrand, France.
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Vasson
authors.affiliation: Clermont University, University of Auvergne, UMR 1019, UNH CellulaR Micro-Environment, Immunomodulation and Nutrition ECREIN, Clermont-Ferrand, France.|Research Center in Human Nutrition CRNH Auvergne, Clermont-Ferrand, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Caldefie-Chezet
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D013141:Spiro Compounds / Q000494:pharmacology*
chemical_list: D006571:Heterocyclic Compounds; D013141:Spiro Compounds
keywords: MDM2; Spiro-bisheterocycles; apoptosis; breast cancer; cell proliferation; oxygen and nitrogen heterocycles; p53