title: Debio 1143, an antagonist of multiple inhibitor-of-apoptosis proteins, activates apoptosis and enhances radiosensitization of non-small cell lung cancer cells in vitro.
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.
authors.affiliation: Department of Radiation Oncology, Tianjin Medical University Cancer Hospital Tianjin, China ; Department of Radiation Oncology, Thomas Jefferson University Philadelphia, PA, USA.
authors.forename: Ningbo
authors.initials: N
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology, Thomas Jefferson University Philadelphia, PA, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Tao
authors.affiliation: Department of Radiation Oncology, Thomas Jefferson University Philadelphia, PA, USA.
authors.forename: Justin M Le
authors.initials: JM
authors.lastname: Blanc
authors.affiliation: Department of Radiation Oncology, Thomas Jefferson University Philadelphia, PA, USA.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Zaorsky
authors.affiliation: Department of Radiation Oncology, Thomas Jefferson University Philadelphia, PA, USA.
authors.forename: Yunguang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Debiopharm SA Lausanne, Switzerland.
authors.forename: Grégoire
authors.initials: G
authors.lastname: Vuagniaux
authors.affiliation: Department of Radiation Oncology, Thomas Jefferson University Philadelphia, PA, USA.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Dicker
authors.affiliation: Department of Radiation Oncology, Thomas Jefferson University Philadelphia, PA, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Lu
keywords: D1143; non-small cell lung cancer; radiotherapy