title: Cytotoxic effects of fascaplysin against small cell lung cancer cell lines.
abstract: Fascaplysin, the natural product of a marine sponge, exhibits anticancer activity against a broad range of tumor cells, presumably through interaction with DNA, and/or as a highly selective cyclin-dependent kinase 4 (CDK4) inhibitor. In this study, cytotoxic activity of fascaplysin against a panel of small cell lung cancer (SCLC) cell lines and putative synergism with chemotherapeutics was investigated. SCLC responds to first-line chemotherapy with platinum-based drugs/etoposide, but relapses early with topotecan remaining as the single approved therapeutic agent. Fascaplysin was found to show high cytotoxicity against SCLC cells and to induce cell cycle arrest in G1/0 at lower and S-phase at higher concentrations, respectively. The compound generated reactive oxygen species (ROS) and induced apoptotic cell death in the chemoresistant NCI-H417 SCLC cell line. Furthermore, fascaplysin revealed marked synergism with the topoisomerase I-directed camptothecin and 10-hydroxy-camptothecin. The Poly(ADP-ribose)-Polymerase 1 (PARP1) inhibitor BYK 204165 antagonized the cytotoxic activity of fascaplysin, pointing to the involvement of DNA repair in response to the anticancer activity of the drug. In conclusion, fascaplysin seems to be suitable for treatment of SCLC, based on high cytotoxic activity through multiple routes of action, affecting topoisomerase I, integrity of DNA and generation of ROS.
authors.affiliation: Ludwig Boltzmann Cluster of Translational Oncology, A-1090, Vienna, Austria. gerhard.hamilton@toc.lbg.ac.at.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Hamilton
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents; D002166:Camptothecin / Q000494:pharmacology; D018288:Carcinoma, Small Cell / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects; D059447:Cell Cycle Checkpoints; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011161:Porifera / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism; D019772:Topotecan / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds; D002243:Carbolines; D007212:Indolizines
chemical_list: D000970:Antineoplastic Agents; D002166:Camptothecin; D051358:Cyclin-Dependent Kinase 4; D007211:Indoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017382:Reactive Oxygen Species; D019772:Topotecan; C069346:fascaplysine; D000644:Quaternary Ammonium Compounds; D002243:Carbolines; D007212:Indolizines