title: Arsenic trioxide is highly cytotoxic to small cell lung carcinoma cells.
abstract: Small cell lung carcinoma (SCLC) is an extremely aggressive form of cancer and current treatment protocols are insufficient. SCLC have neuroendocrine characteristics and show phenotypical similarities to the childhood tumor neuroblastoma. As multidrug-resistant neuroblastoma cells are highly sensitive to arsenic trioxide (As2O3) in vitro and in vivo, we here studied the cytotoxic effects of As2O3 on SCLC cells. As2O3 induced pronounced cell death in SCLC cells at clinically relevant concentrations, and also at hypoxia. SCLC cells were more sensitive than non-SCLC cells to As2O3. Cell death was mainly due to necrosis, although apoptotic responses were also seen. A significant in vivo effect of As2O3 on SCLC growth was shown in a nude mice-xenograft model, although a fraction of the treated tumor-bearing animals did not respond. The nonresponding SCLC tumors differed in morphology and cell organization compared with treatment-responsive tumors, which in turn, showed decreased vascularization and higher expression of neuroendocrine markers compared with control tumors. Our results suggest a potential clinical application of As2O3 in SCLC therapy. In addition to cell death induction, antiangiogenic induction of differentiation may also be part of the in vivo effect of As2O3 on SCLC growth, as suggested by an increase in neuroendocrine markers in cultured cells.
authors.affiliation: Center for Molecular Pathology, CREATE Health, Department of Laboratory Medicine, Lund University, University Hospital MAS, Entrance 78, SE-205 02 Malmö, Sweden. helen.pettersson@med.lu.se
authors.forename: Helen M
authors.initials: HM
authors.lastname: Pettersson
authors.forename: Alexander
authors.initials: A
authors.lastname: Pietras
authors.forename: Matilda
authors.initials: M
authors.lastname: Munksgaard Persson
authors.forename: Jenny
authors.initials: J
authors.lastname: Karlsson
authors.forename: Leif
authors.initials: L
authors.lastname: Johansson
authors.forename: Maria C
authors.initials: MC
authors.lastname: Shoshan
authors.forename: Sven
authors.initials: S
authors.lastname: Påhlman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D010087:Oxides / Q000627:therapeutic use / Q000633:toxicity*; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D015415:Biomarkers; D010087:Oxides; D051028:bcl-2-Associated X Protein; D053148:Caspase 3; D000077237:Arsenic Trioxide