title: Chemosensitizing effect of podophyllotoxin acetate on topoisomerase inhibitors leads to synergistic enhancement of lung cancer cell apoptosis.
abstract: Podophyllotoxin acetate (PA) acts as a radiosensitizer against non-small cell lung cancer (NSCLC) in vitro and in vivo. In this study, we examined its potential role as a chemosensitizer in conjunction with the topoisomerase inhibitors etoposide (Eto) and camptothecin (Cpt). The effects of combinations of PA and Eto/Cpt were examined with CompuSyn software in two NSCLC cell lines, A549 and NCI-H1299. Combination index (CI) values indicated synergistic effects of PA and the topoisomerase inhibitors. The intracellular mechanism underlying synergism was further determined using propidium iodide uptake, immunoblotting and electrophoretic mobility shift assay (EMSA). Combination of PA with Eto/Cpt promoted disruption of the dynamics of actin filaments, leading to subsequent enhancement of apoptotic cell death via induction of caspase-3, -8, and -9, accompanied by increased phosphorylation of p38. Conversely, suppression of p38 phosphorylation blocked the apoptotic effect of the drug combinations. Notably, CREB-1, a transcription factor, was constitutively activated in both cell types, and synergistically inhibited upon combination treatment. Our results collectively indicate that PA functions as a chemosensitizer by enhancing apoptosis through activation of the p38/caspase axis and suppression of CREB-1.
authors.affiliation: Department of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Nowon-Gu, Seoul, Republic of Korea.
authors.forename: Wan Gi
authors.initials: WG
authors.lastname: Hong
authors.affiliation: Department of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Nowon-Gu, Seoul, Republic of Korea.
authors.forename: Jeong Hyun
authors.initials: JH
authors.lastname: Cho
authors.affiliation: Department of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Nowon-Gu, Seoul, Republic of Korea.
authors.forename: Sang-Gu
authors.initials: SG
authors.lastname: Hwang
authors.affiliation: Graduate School of Biotechnology, Kyung Hee University, Yongin-si, Geonggi-do, Republic of Korea.
authors.forename: Eunah
authors.initials: E
authors.lastname: Lee
authors.affiliation: Department of Biological Science, College of Biological Science, Konkuk University, Seoul, Republic of Korea.
authors.forename: Jaeseok
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Food and Microbial Technology, College of Natural Sciences, Seoul Women's University, Seoul, Republic of Korea.
authors.forename: Jong-Il
authors.initials: JI
authors.lastname: Kim
authors.affiliation: Department of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Nowon-Gu, Seoul, Republic of Korea.
authors.forename: Hong-Duck
authors.initials: HD
authors.lastname: Um
authors.affiliation: Department of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Nowon-Gu, Seoul, Republic of Korea.
authors.forename: Jong Kuk
authors.initials: JK
authors.lastname: Park
mesh_terms: D000072283:A549 Cells; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011034:Podophyllotoxin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D059003:Topoisomerase Inhibitors / Q000494:pharmacology*
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D059003:Topoisomerase Inhibitors; C000613972:podophyllotoxin acetate; D020928:Mitogen-Activated Protein Kinases; D011034:Podophyllotoxin