Radiosensitization by a novel Bcl-2 and Bcl-XL inhibitor S44563 in small-cell lung cancer

Y Loriot; P Mordant; D Dugue; O Geneste; A Gombos; P Opolon; J Guegan; J-L Perfettini; A Pierre; L K Berthier; G Kroemer; J C Soria; S Depil; E Deutsch

doi:10.1038/cddis.2014.365

Radiosensitization by a novel Bcl-2 and Bcl-XL inhibitor S44563 in small-cell lung cancer

Cell Death Dis. 2014 Sep 18;5(9):e1423. doi: 10.1038/cddis.2014.365.

Authors

Y Loriot¹, P Mordant¹, D Dugue², O Geneste³, A Gombos², P Opolon², J Guegan⁴, J-L Perfettini¹, A Pierre³, L K Berthier³, G Kroemer⁵, J C Soria⁶, S Depil³, E Deutsch¹

Affiliations

¹ 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.
² 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 Institut de Recherche Servier Oncology R&D Unit, 125 Chemin De Ronde, Croissy Sur Seine 78290, France.
⁴ Institut Gustave Roussy's Genomics Centre, Institut de cancérologie Gustave-Roussy, 114, rue Edouard-Vaillant, Villejuif 94805, France.
⁵ 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.
⁶ 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects
Apoptosis / radiation effects
Cell Proliferation / drug effects
Cell Proliferation / radiation effects
Cisplatin / administration & dosage
Combined Modality Therapy
Female
Heterocyclic Compounds, 3-Ring / administration & dosage*
Humans
Lung Neoplasms / drug therapy
Lung Neoplasms / genetics
Lung Neoplasms / metabolism
Lung Neoplasms / radiotherapy*
Mice
Mice, Nude
NF-kappa B / genetics
NF-kappa B / metabolism
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
Proto-Oncogene Proteins c-bcl-2 / genetics
Proto-Oncogene Proteins c-bcl-2 / metabolism
Radiation Tolerance
Radiation-Sensitizing Agents / administration & dosage*
Small Cell Lung Carcinoma / drug therapy
Small Cell Lung Carcinoma / genetics
Small Cell Lung Carcinoma / metabolism
Small Cell Lung Carcinoma / radiotherapy*
Sulfonamides / administration & dosage*
Xenograft Model Antitumor Assays
bcl-X Protein / antagonists & inhibitors*
bcl-X Protein / genetics
bcl-X Protein / metabolism

Substances

Heterocyclic Compounds, 3-Ring
NF-kappa B
Proto-Oncogene Proteins c-bcl-2
Radiation-Sensitizing Agents
S44563
Sulfonamides
bcl-X Protein
Cisplatin