Cisplatin enhances the antitumor effect of tumor necrosis factor-related apoptosis-inducing ligand gene therapy via recruitment of the mitochondria-dependent death signaling pathway

Abstract

Despite adequately expressing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors DR4/DR5, malignant cells are frequently refractory to the cytotoxic effect of this apoptosis-inducing ligand. The susceptibility of cancer cells to TRAIL can be potentiated by cisplatin (CDDP). This study was designed to evaluate the ability of cisplatin to enhance the cytotoxic effect of TRAIL gene therapy using the recombinant adenovirus-mediated tumor-selective expression of membrane-bound green fluorescence protein (GFP)-TRAIL fusion protein (AdVgTRAIL) on thoracic cancer cells and to elucidate the putative mechanisms responsible for this synergistic combination effect. While causing little death of cultured thoracic cancer cells by itself, AdVgTRAIL in combination with CDDP, on the other hand, mediated profound supra-additive cytotoxicity and apoptosis via a strong bystander effect. CDDP/AdVgTRAIL-induced cytotoxicity was completely abrogated either by the pancaspase inhibitor zVAD-fmk or by the selective caspase 9 inhibitor or by transient knockdown of caspase 9 by siRNA, indicating that this process was caspase-mediated and mitochondria-dependent. This was confirmed by the observation that Bcl2 overexpression protected the cells from combinationinduced cytotoxicity. Robust activation of caspase 8 activity in combination-treated cells was blocked by overexpression of Bcl2, indicating that caspase 8 activation was secondary to the mitochondria-mediated amplification feedback loop. Combining CDDP with AdVgTRAIL greatly enhances its tumoricidal efficacy in cultured thoracic cancer cells in vitro. The two agents interact to mediate profound activation of caspase cascade via recruitment of the mitochondria and positive feedback loop. The CDDP/ AdVgTRAIL combination also exhibits a strong antitumor effect in in vivo animal model of human cancer xenografts.

The Synthetic Cannabinoid WIN 55,212-2 Sensitizes Hepatocellular Carcinoma Cells to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-Induced Apoptosis by Activating p8/CCAAT/Enhancer Binding Protein Homologous Protein (CHOP)/Death Receptor 5 (DR5) Axis

“…Thus, it is important to find therapeutic agents capable of sensitizing resistant cancer cells to TRAIL-induced apoptosis. There are many studies demonstrating that the combination of different anticancer agents with TRAIL induces additive or synergistic tumor cell death (Griffith and Kemp, 2003;Elrod and Sun, 2008;Shamimi-Noori et al, 2008;Siegelin et al, 2009). It has been demonstrated that the efficacy of histone deacetylase inhibitors in sensitizing hepatocellular carcinoma (HCC) cells to TRAIL induced apoptosis (Carlisi et al, 2009).…”

Cisplatin sensitizes human hepatocellular carcinoma cells, but not hepatocytes and mesenchymal stem cells, to TRAIL within a therapeutic window partially depending on the upregulation of DR5

“…Activation of this pathway involved the cleavage of BH3 interacting death domain and mitochondrial outer membrane permeabilization, resulting in the release of cytochrome c from mitochondria, which sequentially activates caspase-9 and -3. Shamimi-Noori S et al revealed that cisplatin/TRAIL-induced cytotoxicity of thoracic cancer cells was completely abrogated either by the selective caspase-9 inhibitor or by transient knockdown of caspase-9 by siRNA, indicating that this apoptotic process was caspase-mediated and mitochondria-dependent (22). In the present study, we investigated the signaling cascades of apoptosis after the combination of TRAIL and cisplatin by Western blotting.…”

The expression of TRAIL and its receptors in gastric cancer and the apoptotic effect of rh-TRAIL on SGC7901 cells

“…In our study, the inhibitory rates of combinations of TRAIL plus chemotherapeutic drugs were higher than TRAIL alone and chemotherapeutic drug alone (P=0.000), which suggested that concomitant TRAIL and chemotherapeutic drugs could shed light on the synergy effect in inducing tumor cell apoptosis. Shamimi-Noori et al (37) demonstrated that DDP interacted with TRAIL to mediate profound activation of caspase cascade via recruitment of the mitochondriadependent death signaling pathway, whereas the increased effectiveness of caspase-8 recruitment to and activation at the death-inducing signaling complex (DISC) and the consequent shift in the ratio of caspase-8 to cellular FLICEinhibitory protein (cFLIP) at the DISC may be a potential mechanism for TRAIL sensitization by 5-FU (38). In addition, some other drugs, such as phosphatidylinositol 3-kinase inhibitor, and non-steroidal anti-inflammatory drugs also enhanced the apoptotic effect of TRAIL (39,40).…”