title: Radiosensitization by a novel Bcl-2 and Bcl-XL inhibitor S44563 in small-cell lung cancer.
abstract: Radiotherapy has a critical role in the treatment of small-cell lung cancer (SCLC). The effectiveness of radiation in SCLC remains limited as resistance results from defects in apoptosis. In the current study, we investigated whether using the Bcl-2/Bcl-XL inhibitor S44563 can enhance radiosensitivity of SCLC cells in vitro and in vivo. In vitro studies confirmed that S44563 caused SCLC cells to acquire hallmarks of apoptosis. S44563 markedly enhanced the sensitivity of SCLC cells to radiation, as determined by a clonogenic assay. The combination of S44563 and cisplatin-based chemo-radiation showed a significant tumor growth delay and increased overall survival in mouse xenograft models. This positive interaction was greater when S44563 was given after the completion of the radiation, which might be explained by the radiation-induced overexpression of anti-apoptotic proteins secondary to activation of the NF-κB pathway. These data underline the possibility of combining IR and Bcl-2/Bcl-XL inhibition in the treatment of SCLC as they underscore the importance of administering conventional and targeted therapies in an optimal sequence.
authors.affiliation: 1] Gustave Roussy, Cancer Campus, Grand Paris, 114 rue Edouard Vaillant, Villejuif 94805, France [2] INSERM 1030 "radiosensitivity and human carcinogenesis", 114 rue Edouard Vaillant, Villejuif 94805, France [3] Faculty of Medicine, University of Paris-Sud, DHU TORINO, LABEX LERMIT, SIRIC Socrates, Le Kremlin-Bicêtre, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Loriot
authors.affiliation: 1] Gustave Roussy, Cancer Campus, Grand Paris, 114 rue Edouard Vaillant, Villejuif 94805, France [2] INSERM 1030 "radiosensitivity and human carcinogenesis", 114 rue Edouard Vaillant, Villejuif 94805, France [3] Faculty of Medicine, University of Paris-Sud, DHU TORINO, LABEX LERMIT, SIRIC Socrates, Le Kremlin-Bicêtre, France.
authors.forename: P
authors.initials: P
authors.lastname: Mordant
authors.affiliation: 1] Gustave Roussy, Cancer Campus, Grand Paris, 114 rue Edouard Vaillant, Villejuif 94805, France [2] INSERM 1030 "radiosensitivity and human carcinogenesis", 114 rue Edouard Vaillant, Villejuif 94805, France.
authors.forename: D
authors.initials: D
authors.lastname: Dugue
authors.affiliation: Institut de Recherche Servier Oncology R&D Unit, 125 Chemin De Ronde, Croissy Sur Seine 78290, France.
authors.forename: O
authors.initials: O
authors.lastname: Geneste
authors.affiliation: 1] Gustave Roussy, Cancer Campus, Grand Paris, 114 rue Edouard Vaillant, Villejuif 94805, France [2] INSERM 1030 "radiosensitivity and human carcinogenesis", 114 rue Edouard Vaillant, Villejuif 94805, France.
authors.forename: A
authors.initials: A
authors.lastname: Gombos
authors.affiliation: 1] Gustave Roussy, Cancer Campus, Grand Paris, 114 rue Edouard Vaillant, Villejuif 94805, France [2] INSERM 1030 "radiosensitivity and human carcinogenesis", 114 rue Edouard Vaillant, Villejuif 94805, France.
authors.forename: P
authors.initials: P
authors.lastname: Opolon
authors.affiliation: Institut Gustave Roussy's Genomics Centre, Institut de cancérologie Gustave-Roussy, 114, rue Edouard-Vaillant, Villejuif 94805, France.
authors.forename: J
authors.initials: J
authors.lastname: Guegan
authors.affiliation: 1] Gustave Roussy, Cancer Campus, Grand Paris, 114 rue Edouard Vaillant, Villejuif 94805, France [2] INSERM 1030 "radiosensitivity and human carcinogenesis", 114 rue Edouard Vaillant, Villejuif 94805, France [3] Faculty of Medicine, University of Paris-Sud, DHU TORINO, LABEX LERMIT, SIRIC Socrates, Le Kremlin-Bicêtre, France.
authors.forename: J-L
authors.initials: JL
authors.lastname: Perfettini
authors.affiliation: Institut de Recherche Servier Oncology R&D Unit, 125 Chemin De Ronde, Croissy Sur Seine 78290, France.
authors.forename: A
authors.initials: A
authors.lastname: Pierre
authors.affiliation: Institut de Recherche Servier Oncology R&D Unit, 125 Chemin De Ronde, Croissy Sur Seine 78290, France.
authors.forename: L K
authors.initials: LK
authors.lastname: Berthier
authors.affiliation: 1] INSERM, U848, Villejuif, France [2] Metabolomics Platform, Institut Gustave Roussy, Villejuif, France [3] Centre de Recherche des Cordeliers, Paris, France [4] Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
authors.forename: G
authors.initials: G
authors.lastname: Kroemer
authors.affiliation: 1] Gustave Roussy, Cancer Campus, Grand Paris, 114 rue Edouard Vaillant, Villejuif 94805, France [2] Faculty of Medicine, University of Paris-Sud, DHU TORINO, LABEX LERMIT, SIRIC Socrates, Le Kremlin-Bicêtre, France [3] Inserm 981, Institut de cancérologie Gustave-Roussy, 114, rue Edouard-Vaillant, Villejuif 94805, France.
authors.forename: J C
authors.initials: JC
authors.lastname: Soria
authors.affiliation: Institut de Recherche Servier Oncology R&D Unit, 125 Chemin De Ronde, Croissy Sur Seine 78290, France.
authors.forename: S
authors.initials: S
authors.lastname: Depil
authors.affiliation: 1] Gustave Roussy, Cancer Campus, Grand Paris, 114 rue Edouard Vaillant, Villejuif 94805, France [2] INSERM 1030 "radiosensitivity and human carcinogenesis", 114 rue Edouard Vaillant, Villejuif 94805, France [3] Faculty of Medicine, University of Paris-Sud, DHU TORINO, LABEX LERMIT, SIRIC Socrates, Le Kremlin-Bicêtre, France.
authors.forename: E
authors.initials: E
authors.lastname: Deutsch
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy*; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy*; D013449:Sulfonamides / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D011838:Radiation-Sensitizing Agents; C000599183:S44563; D013449:Sulfonamides; D051020:bcl-X Protein; D002945:Cisplatin