Dataset Information

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-? release was determined by ELISA. Radiosensitivities were compared with dose enhancement ratios (DERs). HCC193 cells D1143 IC50 was 1 ?M. HCC193 cells demonstrated noticeable cleaved caspase-3, -8, and a decrease in IAP levels with 2.5 ?M D1143; H460 cells, with 10 ?M; both in a time-dependent manner. Additionally, HCC193 cells exhibited an increase in TNF-?. D1143 radiosensitized cells: HCC193, 2.5 ?M D1143, 24 h incubation, DER of 2.19, p = 0.001; H460 cells, 10 ?M D1143, 48 h incubation, DER of 1.29, p = 0.082. Treatment of H460 cells with radiation therapy, TNF-?, 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-? 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.

SUBMITTER: Liu N

PROVIDER: S-EPMC4266726 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Debio 1143, an antagonist of multiple inhibitor-of-apoptosis proteins, activates apoptosis and enhances radiosensitization of non-small cell lung cancer cells in vitro.

Liu Ningbo N Tao Zhen Z Blanc Justin M Le JM Zaorsky Nicholas G NG Sun Yunguang Y Vuagniaux Grégoire G Dicker Adam P AP Lu Bo B

American journal of cancer research 20141119 6

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 w ...[more]

PMID: 25520882

Similar Datasets

Project description:Antiretroviral therapy (ART) suppresses HIV replication, but does not cure the infection because replication-competent virus persists within latently infected CD4+ T cells throughout years of therapy. These reservoirs contain integrated HIV-1 genomes and can resupply active virus. Thus, the development of strategies to eliminate the reservoir of latently infected cells is a research priority of global significance. In this study, we tested efficacy of a new inhibitor of apoptosis protein antagonist (IAPa) called Debio 1143 at reversing HIV latency and investigated its mechanisms of action. Debio 1143 activates HIV transcription via NF-kB signaling by degrading the ubiquitin ligase baculoviral IAP repeat-containing 2 (BIRC2), a repressor of the non-canonical NF-kB pathway. Debio 1143-induced BIRC2 degradation results in the accumulation of NF-?B-inducing kinase (NIK) and proteolytic cleavage of p100 into p52, leading to nuclear translocation of p52 and RELB. Debio 1143 greatly enhances the binding of RELB to the HIV-1 LTR. These data indicate that Debio 1143 activates the non-canonical NF-kB signaling pathway by promoting the binding of RELB:p52 complexes to the HIV-1 LTR, resulting in the activation of the LTR-dependent HIV-1 transcription. Importantly, Debio 1143 reverses viral latency in HIV-1 latent T cell lines. Using knockdown (siRNA BIRC2), knockout (CRIPSR NIK) and proteasome machinery neutralization (MG132) approaches, we found that Debio 1143-mediated HIV latency reversal is BIRC2 degradation- and NIK stabilization-dependent. Debio 1143 also reverses HIV-1 latency in resting CD4+ T cells derived from ART-treated patients or HIV-1-infected humanized mice under ART. Interestingly, daily oral administration of Debio 1143 in cancer patients at well-tolerated doses elicited BIRC2 target engagement in PBMCs and induced a moderate increase in cytokines and chemokines mechanistically related to NF-kB signaling. In conclusion, we provide strong evidences that the IAPa Debio 1143, by initially activating the non-canonical NF-kB signaling and subsequently reactivating HIV-1 transcription, represents a new attractive viral latency reversal agent (LRA).

Dataset Information

Debio 1143, an antagonist of multiple inhibitor-of-apoptosis proteins, activates apoptosis and enhances radiosensitization of non-small cell lung cancer cells in vitro.

Publications

Debio 1143, an antagonist of multiple inhibitor-of-apoptosis proteins, activates apoptosis and enhances radiosensitization of non-small cell lung cancer cells in vitro.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets