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

• Published in: European journal of medicinal chemistry 2012-04, Vol.50, p.376-382
• Main Authors: Caba, Octavio, Rodríguez-Serrano, Fernando, Díaz-Gavilán, Mónica, Conejo-García, Ana, Ortiz, Raúl, Martínez-Amat, Antonio, Álvarez, Pablo, Gallo, Miguel A., Campos, Joaquín M., Marchal, Juan A., Aránega, Antonia
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; Anthranilic alcohol; Antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Biological and medical sciences; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Blotting, Western; Breast - cytology; Breast - drug effects; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell Proliferation - drug effects; Cells, Cultured; Computational Biology; Endoplasmic Reticulum Stress - drug effects; Endoplasmic reticulum stress-induced apoptosis; Female; Fluorouracil - chemistry; Fluorouracil - pharmacology; Gene Expression Profiling; General aspects; Humans; In vitro therapeutic index; MCF-10A; MCF-7; Medical sciences; Microarray hybridization; Molecular Structure; Oligonucleotide Array Sequence Analysis; Pharmacology. Drug treatments; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2012.02.017

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. [Display omitted] ► An alcohol-derived acyclic 5-FU O,N-acetal has been studied for anti-cancer activity. ► It shows potent growth inhibition of the cell line MCF-7 at a very low concentration. ► ER stress-induced apoptosis is the mechanism of action against MCF-7. ► When it is administered to the non-neoplastic cell line MCF-10A displayed less toxicity. ► It has no activity against p53 and induces down-regulation of Bcl-2.