title: Efficacy of substituted 9-aminoacridine derivatives in small cell lung cancer.
abstract: Topoisomerase II (TopoII) plays a critical role in the processes of replication, transcription, and decantenation in the cell and is an important chemotherapeutic target in the treatment of small cell lung cancer (SCLC). Current treatment strategies for SCLC employ the use of topoII poisons which stabilize the topoII-DNA transient covalent complex, inducing double stranded DNA damage and cellular death via apoptosis in cancer cells. Despite their effectiveness the topoII poisons are known to induce secondary malignancies in a small population of patients, stimulating the search for new compounds with less toxicity. Recently a small library of substituted 9-aminoacridine derivatives was discovered that displayed topoII catalytic inhibitory properties. In this work we assess their ability to inhibit proliferation and induce cellular death in SCLC. The results indicate effective inhibition of cellular proliferation at EC(50) values in the low μM range. Western blot analysis of p62/LC3 levels, the AKT/mTOR pathway, and the ERK1/2 pathway indicate that autophagy is occurring as the primary mechanism of cell death; furthermore, the Guava Nexin and caspase 3/7 activation assays indicate that apoptosis does not occur. While it is unlikely that the active concentration of these compounds could be achieved in vivo, they show great promise for the use and effectiveness of acridine derivatives in the treatment of SCLC in the future.
authors: Unviersity of Minnesota Medical School, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA.
authors: Etchison
authors: E
authors: Ryan
authors: A Jacobson
authors: AJ
authors: Blake
authors: A
authors: A
authors: Benoit
authors: M Ferguson
authors: MF
authors: David
authors: A Kratzke
authors: AK
authors: Robert
mesh_terms: D000609:Aminoacridines / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology; D004250:DNA Topoisomerases, Type II / Q000737:chemistry / Q000378:metabolism; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000609:Aminoacridines; D000970:Antineoplastic Agents; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020169:Caspases; D004250:DNA Topoisomerases, Type II; D002945:Cisplatin