Is TRAIL the holy grail of cancer therapy?

Newsom-Davis, Thomas; Prieske, Silvia; Walczak, Henning

doi:10.1007/s10495-009-0321-2

Cited by 117 publications

(104 citation statements)

References 158 publications

(165 reference statements)

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“…Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is currently being tested as therapeutic agent for HCC treatment, but its utility is greatly hampered by the fact tumor cells ultimately develop resistant to the TRAILinduced apoptosis [6,7]. The exact mechanism(s) responsible for resistance to TRAIL is still not completely understood; however, susceptibility to TRAIL-induced apoptosis can be regulated at several levels in the apoptotic signaling cascades [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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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“…Furthermore, recent studies demonstrated that TRAIL and other death ligands, including CD95/ FasL and TNF, could sensitize tumor cells for ionizing radiationand drug-induced apoptosis. Such a combined modality may circumvent the resistance of tumors against chemo-and radiotherapy (Marini and Belka, 2003;Schmelz et al, 2004;Marini et al, 2005;Fulda, 2009;Newsom-Davis et al, 2009; for review see Daniel et al, 2001). Ligands of the TNF family initiate the extrinsic apoptotic pathway through binding to cell surface death receptors of the TNF receptor superfamily.…”

Section: Introductionmentioning

confidence: 99%

Endogenous Bak inhibitors Mcl-1 and Bcl-x_L: differential impact on TRAIL resistance in Bax-deficient carcinoma

Gillissen¹,

Wendt²,

Richter³

et al. 2010

J Exp Med

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“…Indeed, it is well established that resistance can be relieved by a poorly understood phenomenon generally referred to as 'sensitization'. A plethora of sensitizing agents, including ionizing radiation, chemotherapeutic drugs, cytokines as well as HDAC, proteosome or phosphatidylinositol-3-kinase (PI3K)/Akt inhibitors can reverse the TRAIL-resistant phenotype (Figure 3) (Altucci et al, 2001(Altucci et al, , 2005Clarke et al, 2004;Insinga et al, 2005;Nebbioso et al, 2005;Newsom-Davis et al, 2009). Furthermore, administration of inhibitors of the canonical nuclear factor-kB pathway, which has been shown to regulate resistance to TRAIL-induced apoptosis, induces sensitization of cancer cells to TRAIL (Ravi et al, 2001).…”

Section: Novel Paradigms For Cancer Therapy V Pavet Et Almentioning

confidence: 99%

Towards novel paradigms for cancer therapy

et al. 2010

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Cancer is a complex progressive multistep disorder that results from the accumulation of genetic and epigenetic abnormalities, which lead to the transformation of normal cells into malignant derivatives. Despite enormous progress in the understanding of cancer biology including the decryption of multiple regulatory networks governing cell growth and death, and despite the possibility of analyzing (epi)genetic deregulation at the genome-wide scale, cancertargeted therapy is still the exception. In fact, to date there are still far too few examples of therapies leading to cure; treatment-derived toxicity is a major issue, and cancer remains to be one of the largest causes of death worldwide. The purpose of this review is to discuss the state of the art of cancer therapy with respect to the key issue of any treatment, namely its target selectivity. Therefore, we recapitulate and discuss current concepts and therapies targeting tumorspecific features, including oncofusion proteins, aberrant kinase activities and epigenetic tumor makeup. We analyze strategies designed to induce tumor-selective death such as the use of oncolytic virus, tumoricidal proteins (NS1, Eorf4, apoptin, HAMLET (human a-lactalbumin made lethal to tumor cells)) and activation of signaling pathways involved in tumor surveillance. We emphasize the potential of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway, an essential component of the evolutionary developed defense systems that eradicate malignant cells. Finally, we discuss the necessity of targeting tumor-initiating cells (TICs) to avoid relapse and increase the chances of complete remission, and describe emerging concepts that might provide novel avenues for cancer therapy.

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Is TRAIL the holy grail of cancer therapy?

Cited by 117 publications

References 158 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

Endogenous Bak inhibitors Mcl-1 and Bcl-x_L: differential impact on TRAIL resistance in Bax-deficient carcinoma

Towards novel paradigms for cancer therapy

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Is TRAIL the holy grail of cancer therapy?

Cited by 117 publications

References 158 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

Endogenous Bak inhibitors Mcl-1 and Bcl-xL: differential impact on TRAIL resistance in Bax-deficient carcinoma

Towards novel paradigms for cancer therapy

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Endogenous Bak inhibitors Mcl-1 and Bcl-x_L: differential impact on TRAIL resistance in Bax-deficient carcinoma