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

• Published in: Cell death & disease 2014-09, Vol.5 (9), p.e1423-e1423
• Main Authors: Loriot, Y, Mordant, P, Dugue, D, Geneste, O, Gombos, A, Opolon, P, Guegan, J, Perfettini, J-L, Pierre, A, Berthier, L K, Kroemer, G, Soria, J C, Depil, S, Deutsch, E
• Format: Article
• Language: English
• Subjects: 631/67/1059/485; 631/67/1059/99; 631/67/1612/2143; 631/80/82/23; Animals; Antibodies; Apoptosis - drug effects; Apoptosis - radiation effects; bcl-X Protein - antagonists & inhibitors; bcl-X Protein - genetics; bcl-X Protein - metabolism; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Proliferation - drug effects; Cell Proliferation - radiation effects; Cisplatin - administration & dosage; Combined Modality Therapy; Female; Heterocyclic Compounds, 3-Ring - administration & dosage; Humans; Immunology; Life Sciences; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - radiotherapy; Mice; Mice, Nude; NF-kappa B - genetics; NF-kappa B - metabolism; Original; original-article; 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
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2014.365

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-X L 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- κ B pathway. These data underline the possibility of combining IR and Bcl-2/Bcl-X L inhibition in the treatment of SCLC as they underscore the importance of administering conventional and targeted therapies in an optimal sequence.