title: The selective cytotoxic activity in breast cancer cells by an anthranilic alcohol-derived acyclic 5-fluorouracil O,N-acetal is mediated by endoplasmic reticulum stress-induced apoptosis.
abstract: Advance in the knowledge of molecular biology has thrown light on many aspects of apoptosis regulation mechanisms. This has allowed a change in anti-cancer therapy trends, from classic cytotoxic strategies to the development of new non-harmful therapies which target the apoptosis response selectively only in tumour cells. We have selected an anthranilic alcohol-derived acyclic 5-fluorouracil O,N-acetal (5) to carry out the anti-cancer studies. This compound shows activity as a potent growth inhibitor of the tumour cell line MCF-7 at a very low concentration. Moreover, when this compound was administered to the non-neoplastic cell line, MCF-10A displayed less toxicity resulting in lower rates of apoptosis. Further studies by microarray hybridization, real-time PCR and western blot showed that when administered to human breast cancer cells, MCF-7, 5 had no activity against classic pro-apoptotic genes such as p53, and even induced the down-regulation of anti-apoptotic genes such as Bcl-2. In contrast, several pro-apoptotic genes related with the endoplasmic reticulum (ER)-stress-induced apoptosis, such as BBC3 and Noxa, appeared up-regulated. These results seem to show that the mechanism of action and selectivity of 5 was via the activation of the ER stress-induced apoptosis. The selective activity of this compound against tumour cells via the ER stress-induced apoptosis supposes a great advantage for future therapeutic use.
authors.affiliation: Departamento de Ciencias de la Salud, Facultad de Ciencias Experimentales y de la Salud, Paraje de las Lagunillas s/n, 23071 Jaén, Spain.
authors.forename: Octavio
authors.initials: O
authors.lastname: Caba
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodríguez-Serrano
authors.forename: Mónica
authors.initials: M
authors.lastname: Díaz-Gavilán
authors.forename: Ana
authors.initials: A
authors.lastname: Conejo-García
authors.forename: Raúl
authors.initials: R
authors.lastname: Ortiz
authors.forename: Antonio
authors.initials: A
authors.lastname: Martínez-Amat
authors.forename: Pablo
authors.initials: P
authors.lastname: Alvarez
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Gallo
authors.forename: Joaquín M
authors.initials: JM
authors.lastname: Campos
authors.forename: Juan A
authors.initials: JA
authors.lastname: Marchal
authors.forename: Antonia
authors.initials: A
authors.lastname: Aránega
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D001940:Breast / Q000166:cytology / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019295:Computational Biology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D005472:Fluorouracil / Q000737:chemistry* / Q000494:pharmacology*; D020869:Gene Expression Profiling; D006801:Humans; D015394:Molecular Structure; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D005472:Fluorouracil