Chemotherapeutic Agents Augment TRAIL-Induced Apoptosis in Human Hepatocellular Carcinoma Cell Lines

Yamanaka, Takenari; Shiraki, Katsuya; Sugimoto, Kazushi; Ito, Takeshi; Fujikawa, Katsuhiko; M, Ito; Takase, Koujiro; Moriyama, Masami; Nakano, Takeshi; Suzuki, Atsushi

doi:10.1053/jhep.2000.16266

Cited by 189 publications

(183 citation statements)

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“…Considerable number of tumor cells, including HCC cells, exhibit resistance to the proapoptotic effect of TRAIL, but their sensitivity to TRAIL can be increased by combining TRAIL with several compounds, including chemotherapeutic agents, proteasome inhibitors and HDAC inhibitors [37][38][39][40]. In the present report, we conclusively demonstrate that emodin, a methyl-anthraquinone can sensitize HCC cells to TRAIL-induced apoptosis.…”

Section: Discussionsupporting

confidence: 63%

An anthraquinone derivative, emodin sensitizes hepatocellular carcinoma cells to TRAIL induced apoptosis through the induction of death receptors and downregulation of cell survival proteins

et al. 2013

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Recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is currently under clinical trials for cancer, however many tumor cells, including hepatocellular carcinoma (HCC) develop resistance to TRAIL-induced apoptosis. Hence, novel agents that can alleviate TRAIL-induced resistance are urgently needed. In the present report, we investigated the potential of emodin to enhance apoptosis induced by TRAIL in HCC cells. As observed by MTT cytotoxicity assay and the externalization of the membrane phospholipid phosphatidylserine, we found that emodin can significantly potentiate TRAIL-induced apoptosis in HCC cells. When investigated for the mechanism(s), we observed that emodin can downregulate the expression of various cell survival proteins, and induce the cell surface expression of both TRAIL receptors, death receptors (DR) 4 as well as 5. In addition, emodin increased the expression of C/EBP homologous protein (CHOP) in a time-dependent manner. Knockdown of CHOP by siRNA decreased the induction of emodin-induced DR5 expression and apoptosis. Emodin-induced induction of DR5 was mediated through the generation of reactive oxygen species (ROS), as N-acetylcysteine blocked the induction of DR5 and the induction of apoptosis. Also, the knockdown of X-linked inhibitor of apoptosis protein by siRNA significantly reduced the sensitization effect of emodin on TRAILinduced apoptosis. Overall, our experimental results clearly indicate that emodin can indeed potentiate TRAIL-induced Aruljothi Subramaniam and Ser Yue Loo contributed equally to this work.

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Section: Discussionsupporting

confidence: 63%

An anthraquinone derivative, emodin sensitizes hepatocellular carcinoma cells to TRAIL induced apoptosis through the induction of death receptors and downregulation of cell survival proteins

et al. 2013

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“…However, various tumor cells, including HCC cells, are resistant to the apoptotic effects of TRAIL [Yamanaka et al, 2000;Pei et al, 2004;Kim et al, 2006]. This resistance could be caused by a variety of factors.…”

Section: Discussionmentioning

confidence: 99%

“…intrinsic or acquired TRAIL resistance [Yamanaka et al, 2000;Shankar and Srivastava, 2004]. Therefore, studies aimed at improving our understanding of the molecular mechanisms underlying TRAIL-resistance and identifying sensitizing agents capable of overcoming this resistance may facilitate the establishment of TRAIL-based combined regimens for the improved treatment of HCC.…”

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confidence: 99%

Quercetin sensitizes human hepatoma cells to TRAIL‐induced apoptosis via Sp1‐mediated DR5 up‐regulation and proteasome‐mediated c‐FLIP_S down‐regulation

Kim

Park

et al. 2008

J of Cellular Biochemistry

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This study demonstrates that combined treatment with subtoxic doses of quercetin (3 0 ,3 0 ,4 0 ,5,7-pentahydroxyflavone), a flavonoid found in many fruits and vegetables, plus tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces rapid apoptosis in TRAIL-resistant hepatocellular carcinoma (HCC) cells. Effective induction of apoptosis by the combined treatment with quercetin and TRAIL was not blocked by overexpression of Bcl-xL, which is known to confer resistance to various chemotherapeutic agents. These results suggest that this combined treatment may provide an attractive strategy for treating resistant HCCs. While the proteolytic processing of procaspase-3 by TRAIL was partially blocked in various HCC cells treated with TRAIL alone, co-treatment with quercetin efficiently recovered TRAIL-induced caspase activation. We found that quercetin treatment of HCC cells significantly up-regulated the mRNA and protein levels of DR5, a death receptor of TRAIL, in a transcription factor Sp1-dependent manner. Furthermore, treatment with quercetin significantly decreased the protein levels of c-FLIP, an inhibitor of caspase-8, through proteasome-mediated degradation. Finally, administration of small interfering RNA against DR5 or overexpression of c-FLIP S , but not c-FLIP L , significantly attenuated quercetin-stimulated TRAIL-induced apoptosis. Collectively, these findings show that quercetin recovers TRAIL sensitivity in various HCC cells via up-regulation of DR5 and down-regulation of c-FLIP S . J. Cell. Biochem. 105: 1386-1398. ß 2008 KEY WORDS: QUERCETIN; TRAIL; HEPATOMA; DR5; c-FLIP S H epatocellular carcinoma (HCC) is the fifth most frequent neoplasm worldwide (>500,000 death/year) [Bruix et al., 2004]. Most hepatocellular carcinoma patients are diagnosed at advanced stages that are unsuitable for the current curative therapies of resection and transplantation [Avila et al., 2006]. The current chemotherapeutic options yield poor responses and low patient survival, making them ineffective for treatment of advanced HCC [Avila et al., 2006]. Therefore, new therapeutic alternatives are needed for more effective treatment of this malignancy.Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF family, is considered a promising anticancer agent due to its ability to induce apoptosis in a variety of tumor cell types while having only negligible effects on normal cells [Ashkenazi et al., 1999]. Binding of TRAIL to either DR4 or DR5, two death receptors of TRAIL, leads to oligomerization and clustering of their intracellular death domains. The subsequent interaction of DR4 or DR5 with the adaptor molecule, FADD (Fas-associated death domain), via their respective death domains leads to recruitment and activation of caspase-8 [ Thomas et al., 2004]. Finally, caspase-8 activates the executioner caspases (e.g., caspase-3 and caspase-7), leading to apoptotic cell death [Srivastava, 2001]. Although TRAIL has garnered considerable attention as a novel anticancer agent...

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“…While TRAIL alone induces apoptosis in sensitive cancer cell lines, TRAIL activity can be enhanced upon coexposure with various chemotherapeutic agents Keane et al, 1999;Yamanaka et al, 2000;Bouralexis et al, 2001;Evdokiou et al, 2002;Shimoyama et al, 2002). Tumour cells that are resistant to TRAIL can be sensitised by combination treatment with various chemotherapeutic drugs (LeBlanc et al, 2002).…”

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confidence: 99%

HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo

et al. 2005

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Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a variety of tumour cells through activation of TRAIL-R1 and TRAIL-R2 death signalling receptors. Here, we describe the characterisation and activity of HGS-ETR1, the first fully human, agonistic TRAIL-R1 mAb that is being developed as an antitumour therapeutic agent. HGS-ETR1 showed specific binding to TRAIL-R1 receptor. HGS-ETR1 reduced the viability of multiple types of tumour cells in vitro, and induced activation of caspase 8, Bid, caspase 9, caspase 3, and cleavage of PARP, indicating activation of TRAIL-R1 alone was sufficient to induce both extrinsic and intrinsic apoptotic pathways. Treatment of cell lines in vitro with HGS-ETR1 enhanced the cytotoxicity of chemotherapeutic agents (camptothecin, cisplatin, carboplatin, or 5-fluorouracil) even in tumour cell lines that were not sensitive to HGS-ETR1 alone. In vivo administration of HGS-ETR1 resulted in rapid tumour regression or repression of tumour growth in pre-established colon, non-smallcell lung, and renal tumours in xenograft models. Combination of HGS-ETR1 with chemotherapeutic agents (topotecan, 5-fluorouracil, and irinotecan) in three independent colon cancer xenograft models resulted in an enhanced antitumour efficacy compared to either agent alone. Pharmacokinetic studies in the mouse following intravenous injection showed that HGS-ETR1 serum concentrations were biphasic with a terminal half-life of 6.9 -8.7 days and a steady-state volume of distribution of approximately 60 ml kg À1 . Clearance was 3.6 -5.7 ml À1 day À1 kg À1 . These data suggest that HGS-ETR1 is a specific and potent antitumour agent with favourable pharmacokinetic characteristics and the potential to provide therapeutic benefit for a broad range of human malignancies.

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Chemotherapeutic Agents Augment TRAIL-Induced Apoptosis in Human Hepatocellular Carcinoma Cell Lines

Cited by 189 publications

References 48 publications

An anthraquinone derivative, emodin sensitizes hepatocellular carcinoma cells to TRAIL induced apoptosis through the induction of death receptors and downregulation of cell survival proteins

An anthraquinone derivative, emodin sensitizes hepatocellular carcinoma cells to TRAIL induced apoptosis through the induction of death receptors and downregulation of cell survival proteins

Quercetin sensitizes human hepatoma cells to TRAIL‐induced apoptosis via Sp1‐mediated DR5 up‐regulation and proteasome‐mediated c‐FLIP_S down‐regulation

HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo

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Chemotherapeutic Agents Augment TRAIL-Induced Apoptosis in Human Hepatocellular Carcinoma Cell Lines

Cited by 189 publications

References 48 publications

An anthraquinone derivative, emodin sensitizes hepatocellular carcinoma cells to TRAIL induced apoptosis through the induction of death receptors and downregulation of cell survival proteins

An anthraquinone derivative, emodin sensitizes hepatocellular carcinoma cells to TRAIL induced apoptosis through the induction of death receptors and downregulation of cell survival proteins

Quercetin sensitizes human hepatoma cells to TRAIL‐induced apoptosis via Sp1‐mediated DR5 up‐regulation and proteasome‐mediated c‐FLIPS down‐regulation

HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo

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Quercetin sensitizes human hepatoma cells to TRAIL‐induced apoptosis via Sp1‐mediated DR5 up‐regulation and proteasome‐mediated c‐FLIP_S down‐regulation