XIAP and survivin as therapeutic targets for radiation sensitization in preclinical models of lung cancer

Abstract

Survivin and XIAP are members of inhibitors of apoptosis (IAPs) family. They are upregulated in various malignancies. Inactivation of these molecules has resulted in chemosensitization. The purpose of this study was to determine whether inhibition of survivin, XIAP, or both enhances radiotherapy in a lung cancer model. Transient transfection of H460 cells with antisense oligonucleotides (ASOs) against either molecule has specifically reduced their expression, by Western analysis. Results from 3-(4,5-methylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide and clonogenic assays suggest that inhibition of survivin or XIAP greatly decreased cell survival following irradiation. A significantly increased number of apoptotic cells were detected when H460 cells were treated with either antisurvivin, anti-XIAP or both ASOs (P ¼ 0.03, 0.0003 and 0.01, respectively) plus irradiation. H460 xenografts that were treated with ASOs plus radiotherapy demonstrated growth delay beyond 15 days. Growth delay in the groups of combined treatment was greater than that in other groups. However, treatment with ASOs alone did not affect tumor growth delay in mice, but decreased the survival of H460 cells in culture. Antisense treatment did not cause any mortality or weight loss during the 32 days of study. These data suggest that inhibition of survivin or XIAP radiosensitizes H460 lung cancer cells by upregulating apoptosis and downregulating cell survival. Combination of radiotherapy and inhibition of survivin and XIAP through the antisense approach results in improved tumor control by radiotherapy in a mouse model of lung cancer.

Targeting the apoptotic machinery in pancreatic cancers using small-molecule antagonists of the X-linked inhibitor of apoptosis protein

“…by previous reports showing the radiosensitization of cancer cells by XIAP down-regulation (35,38), a finding with clinical implications for a modestly radiosensitive malignancy, such as pancreatic cancer (2). We show here that XIAP is overexpressed in the majority of human pancreatic cancers, as assessed by immunohistochemistry, confirming for the first time data that have been reported previously only in cell line models (13,14).…”

Sensitization of pancreatic carcinoma cells for γ-irradiation-induced apoptosis by XIAP inhibition

“…These data provide convincing evidence that blocking XIAP, for example, by small molecule inhibitors, is a promising novel strategy to restore radiosensitivity of pancreatic carcinoma, a prototype cancer that is notoriously resistant to apoptosis. There is mounting evidence that IAPs are involved in determining sensitivity to radiotherapy in human cancers (Rodel et al, 2003;Cao et al, 2004;Lu et al, 2004). To this end, high levels of XIAP or survivin have been associated with resistance to radiotherapy in lung or colorectal carcinoma (Holcik et al, 2000;Rodel et al, 2003;Cao et al, 2004;Lu et al, 2004).…”

“…There is mounting evidence that IAPs are involved in determining sensitivity to radiotherapy in human cancers (Rodel et al, 2003;Cao et al, 2004;Lu et al, 2004). To this end, high levels of XIAP or survivin have been associated with resistance to radiotherapy in lung or colorectal carcinoma (Holcik et al, 2000;Rodel et al, 2003;Cao et al, 2004;Lu et al, 2004). Inhibition of survivin or XIAP by antisense oligonucleotides was shown to enhance the efficacy of radiotherapy of lung cancer cells by reducing survival and increasing apoptosis Lu et al, 2004).…”

“…Apoptosis signaling may be disrupted by deregulated expression and/or function of antiapoptotic molecules, for example 'inhibitor of apoptosis proteins' (Fulda and Debatin, 2006c). IAPs such as X-linked inhibitor of apoptosis (XIAP), cellular inhibitor of apoptosis protein 1 (cIAP1), cIAP2, survivin or livin are expressed at high levels in many human cancers, which has been associated with treatment resistance, for example, resistance to radiotherapy (Salvesen and Duckett, 2002;Rodel et al, 2003;Cao et al, 2004;Lu et al, 2004). Since IAPs block apoptosis at the core of the apoptotic machinery by inhibiting caspases, therapeutic targeting of IAPs may overcome resistance.…”

Immunohistochemical detection of XIAP and p63 in adenomatous hyperplasia, atypical adenomatous hyperplasia, bronchioloalveolar carcinoma and well-differentiated adenocarcinoma

“…4,5,16,17 XIAP expression in non-small cell lung carcinoma has been reported in cell culture and animal models. [18][19][20][21] However, immunohistochemical studies specifically addressing XIAP expression in human lung adenocarcinoma and alveolar hyperplasias are lacking. An immunocytochemical study of body cavity effusions and washes performed in our laboratory detected XIAP in eight out of nine metastatic non-small cell carcinomas of pulmonary origin, 22 raising the possibility that XIAP may play a role in the pathogenesis or progression of lung adenocarcinoma.…”