Medical College of Wisconsin
CTSICores SearchResearch InformaticsREDCap

Debio 1143, an antagonist of multiple inhibitor-of-apoptosis proteins, activates apoptosis and enhances radiosensitization of non-small cell lung cancer cells in vitro. Am J Cancer Res 2014;4(6):943-51

Date

12/19/2014

Pubmed ID

25520882

Pubmed Central ID

PMC4266726

Abstract

Inhibitors of apoptosis (IAPs) limit the effectiveness of radiation in non-small cell lung cancer (NSCLC). Debio 1143 (D1143) is an antagonist of IAPs. The purpose of this study was to investigate the potential of D1143 as a radiosensitizer in NSCLC. MTS assays were performed in two NSCLC cell lines: HCC193 and H460. Extent of apoptotic cell death was characterized by Annexin V assay and Western blot for cleaved caspase-3, -8, and IAPs. TNF-α release was determined by ELISA. Radiosensitivities were compared with dose enhancement ratios (DERs). HCC193 cells D1143 IC50 was 1 μM. HCC193 cells demonstrated noticeable cleaved caspase-3, -8, and a decrease in IAP levels with 2.5 μM D1143; H460 cells, with 10 μM; both in a time-dependent manner. Additionally, HCC193 cells exhibited an increase in TNF-α. D1143 radiosensitized cells: HCC193, 2.5 μM D1143, 24 h incubation, DER of 2.19, p = 0.001; H460 cells, 10 μM D1143, 48 h incubation, DER of 1.29, p = 0.082. Treatment of H460 cells with radiation therapy, TNF-α, and D1143 further radiosensitized the cells (DER of 1.92, p = 0.026). D1143 significantly enhanced the radiosensitization of HCC193 and H460 cells in vitro. TNF-α contributed to the sensitization in the more sensitive cell line (HCC193). More research is warranted to test the mechanism of D1143, and to assess its potential in vivo in the clinical setting.

Author List

Liu N, Tao Z, Blanc JM, Zaorsky NG, Sun Y, Vuagniaux G, Dicker AP, Lu B

Author

Yunguang Sun MD, PhD Assistant Professor in the Pathology department at Medical College of Wisconsin




jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a