title: Novel quinuclidinone derivatives induce apoptosis in lung cancer via sphingomyelinase pathways.
abstract: We previously reported novel quinuclidinone analogs which induced apoptosis in lung and breast cancer cells. In this study, we designed and synthesized novel quinuclidinone analogs that showed cytotoxicity in lung cancer cells. The effects of these analogs were studied in H1299 human large cell lung carcinoma cells that are null for p53 and normal lung epithelial cell lines (NL-20). The effects of the analogs were investigated by MTT assay, ELISA based apoptotic assay, TUNEL assay, sphingomylinase activity, flow cytometry and western blot analysis. Our data indicated that derivatives 4 and 6 decreased cell proliferation and induced apoptosis in H1299 cells more than NL-20 cells. Derivatives 4 and 6 reduced percent of cells in G2/M phase in H1299 cells more than NL-20 cells and these results were confirmed by increased expression levels of cyclin E. Furthermore, derivatives 4 and 6 increased sphingomyelinase activity, caspase-8, and caspase-9 and JNK-1 expression level in H1299. Additionally, derivatives 4 and 6 induced Procaspase-3, PARP-1 cleavage, and increased caspase-3 activity. All these results confirm that our quinuclidinone derivatives provoke cytotoxicity in lung cancer cells through the interplay of key apoptosis molecules in different compartments of the cell beginning with an increase in sphingomyelinase activity.
authors.affiliation: Biochemistry department, Faculty of Science, Alexandria University, Alexandria, Egypt. ahmed.malki@gmail.com
authors.forename: A
authors.initials: A
authors.lastname: Malki
authors.forename: L
authors.initials: L
authors.lastname: Fathy
authors.forename: E S H
authors.initials: ES
authors.lastname: El Ashry
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D018287:Carcinoma, Large Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020287:In Situ Nick-End Labeling; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011812:Quinuclidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D011812:Quinuclidines; D013108:Sphingomyelin Phosphodiesterase