title: Novel quinuclidinone derivative 8a induced apoptosis in human MCF-7 breast cancer cell lines.
abstract: Novel quinuclidinone derivatives that cause cytotoxicity in human non-small lung carcinoma epithelial cells null for p53 (H1299) have been previously reported. The current study investigates the effect of these derivatives on cytotoxicity of human MCF-7 cells and normal breast epithelial cells (MCF-12a). This study shows that quinuclidinone derivatives 8a and 8b induce growth inhibition mainly through apoptosis of breast cancer cells (MCF-7) with less cytotoxic effect in normal breast epithelial cells (MCF-12a) for derivative 8a while 8b induced similar cytotoxicity for both breast cancer cells and normal breast epithelial cells. Derivative 8a was chosen for further investigation. 8a induced G(1) phase arrest, presumably sensitizing the breast cancer cells to apoptosis by increasing expression level of p21 and cyclin E. Moreover, 8a increased expression level of ERK1, p53 and BAX, and it reduced expression level of AKT and BCL-2. By investigating the sphingomyelinase apoptosis pathway, it was observed that 8a significantly increased sphingomyelinase activity and increased formation of ceramide as well as increased expression levels of JNK phoshorylation, caspase-8 and caspase-9. Based on previous results it is proposed that quinuclidinone derivative 8a provokes apoptosis in human breast cancer cells (MCF-7) via the sphingomyelinase pathway.
authors.affiliation: Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt. amalky@yahoo.com
authors.forename: Ahmed
authors.initials: A
authors.lastname: Malki
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Bergmeier
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002518:Ceramides / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects / Q000528:radiation effects; D005720:Gamma Rays; D006801:Humans; D011812:Quinuclidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism
chemical_list: D002518:Ceramides; D011812:Quinuclidines; D013108:Sphingomyelin Phosphodiesterase