title: New symmetrical quinazoline derivatives selectively induce apoptosis in human cancer cells.
abstract: In the search of new symmetrical derivatives with anticancer activity, we have looked for novel compounds able to induce a selective proapoptotic mechanism in cancer cells. The potential antitumoral activity of several quinazoline derivatives was evaluated in vitro examining their cytotoxic effects against human breast, colon and bladder cancer cell lines. The IC(50) value of the compounds that showed cytotoxic activity was calculated. These compounds were tested for their ability to induce caspase-3 activation and nuclear chromatin degradation. Non-tumoral human cell lines were used to test the selectivity of the cytotoxic compounds against cancer cells. Several compounds showed no cytotoxicity in these cell lines. Finally, JRF12 (2,4-dibenzylaminoquinazoline) was chosen as the best candidate and its mechanism of action was studied in more detail. A time dependent evaluation of apoptosis was performed in the three cancer cell lines, followed by an evaluation of the cell cycle regulation involvement that showed a decrease of cells in G(1) phase and increase of cells in G(2) phase before cell death. 2,4-dibenzylaminoquinazoline treatment produces few changes in the expression of genes as evaluated by using oligonucleotide microarrays and Q-RT-PCR assays. In conclusion, 2,4-dibenzylaminoquinazoline is a promising anticancer drug showing cytostatic and apoptotic effects mainly in a transcription independent manner.
authors.affiliation: Laboratorio de Farmacogenómica, Area de Oncología, Centro de Investigación Médica Aplicada, Pamplona, Spain. ecubgil@alumni.unav.es
authors.forename: Elena
authors.initials: E
authors.lastname: Cubedo
authors.forename: Lucia
authors.initials: L
authors.lastname: Cordeu
authors.forename: Eva
authors.initials: E
authors.lastname: Bandres
authors.forename: Amaia
authors.initials: A
authors.lastname: Rebollo
authors.forename: Raquel
authors.initials: R
authors.lastname: Malumbres
authors.forename: Carmen
authors.initials: C
authors.lastname: Sanmartin
authors.forename: Maria
authors.initials: M
authors.lastname: Font
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Palop
authors.forename: Jesús
authors.initials: J
authors.lastname: Gacía-Foncillas
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D052138:Genes, Neoplasm / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D012334:RNA, Neoplasm / Q000032:analysis
chemical_list: C515304:2,4-dibenzylaminoquinazoline; D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D011799:Quinazolines; D012334:RNA, Neoplasm; D053148:Caspase 3