Human brain-cell death induced by tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL)

Nitsch, Robert; Bechmann, Ingo; Deisz, Rudolf A.; Haas, Dorit; Lehmann, Thomas N; Wendling, Uwe; Zipp, Frauke

doi:10.1016/s0140-6736(00)02659-3

Cited by 279 publications

(192 citation statements)

References 5 publications

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“…Whereas the therapeutic index of TRAIL appears to be high, TRAIL may not be completely devoid of side effects on normal human cells and tissues such as astrocytes, 50 brain tissue, 40 hepatocytes, 23 and keratinocytes. 30 Thus, instead of adding TRAIL to TK -bearing tumor cells, one could transfer the TRAIL gene into the tumor cells -an approach shown to induce tumor cell apoptosis.…”

Section: Discussionmentioning

confidence: 99%

TRAIL enhances thymidine kinase/ganciclovir gene therapy of neuroblastoma cells

et al. 2002

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The clinical benefit of suicide gene therapy of tumors has been marginal, mostly due to the low gene transfer efficiency in vivo. The death -inducing ligand, TRAIL, effectively kills many tumor cell types, while sparing most normal tissues. We hypothesized that TRAIL may enhance HSV thymidine kinase / ganciclovir ( TK / GCV ) gene therapy of tumor cells by augmenting both target and bystander cell kill. Human SH -EP neuroblastoma cells expressing TK as well as bystander cells were effectively killed by apoptosis, and their clonogenicity was ablated following GCV. Human TRAIL enhanced TK / GCV -induced cell death and decreased clonogenicity of TK -expressing cells and also of bystander cells. Cooperation between TRAIL and TK / GCV depended both on caspase activation and on mitochondrial apoptogenic function because both the broad -spectrum caspase inhibitor zVAD.fmk and overexpression of Bcl -2 decreased enhancement of cell kill by TRAIL. Facilitation of TRAIL signalling by up -regulation of TRAIL receptors did not contribute to enhancement because cell surface expression of the agonistic TRAIL receptors 1 and 2 was not increased by TK / GCV. In conclusion, the concerted activation of caspases and the mitochondrial amplification of caspase activation by TK / GCV may explain the cooperative effect of TK / GCV and TRAIL on the kill of neuroblastoma cells. Because combined treatment also augmented the bystander cell kill, the addition of TRAIL may increase the efficacy of TK / GCV gene therapy of neuroblastoma.

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Section: Discussionmentioning

confidence: 99%

TRAIL enhances thymidine kinase/ganciclovir gene therapy of neuroblastoma cells

et al. 2002

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“…3,4 TRAIL exhibits antitumor activity in tumor xenograft models 3,4 and when administered in vivo, TRAIL shows little toxicity to normal tissues in mice and in non-human primates. 4,5 However, it was reported that normal human hepatocytes, astrocytes and other brain cells were killed by recombinant soluble human TRAIL in vitro, 3,6,7 which raised concern about the safety of TRAIL in cancer therapy. Recently, it was demonstrated that the method of preparing recombinant soluble ligand might be important for assessing the results of experiments with TRAIL.…”

Section: Introductionmentioning

confidence: 99%

Human normal hepatocytes are susceptible to apoptosis signal mediated by both TRAIL-R1 and TRAIL-R2

et al. 2003

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptosis in tumor cells without toxicity to normal cells, but some recombinant versions of TRAIL caused hepatocyte death. We generated fully human monoclonal antibodies (mAbs) that bind specifically to TRAIL receptor 1 (TRAIL-R1) and TRAIL receptor 2 (TRAIL-R2), which mediate apoptosis signal when they ligate with TRAIL, to investigate the contribution of each receptor to induce tumor cell apoptosis and hepatocyte toxicity. All of mAbs to TRAIL-R1 and TRAIL-R2 induced cell death in several cancer cell lines susceptible to TRAIL but not in human umbilical vein endothelial cells in vitro. Both anti-TRAIL-R1 mAbs and anti-TRAIL-R2 mAbs also caused cell death in hepatocytes. However, a subset of mAbs to TRAIL-R2, which was characterized by the TRAIL blocking activity, did not show strong hepatocyte toxicity. These results indicate that human normal hepatocytes are susceptible to both TRAIL-R1-and TRAIL-R2-mediated apoptosis signal.

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“…Although biological effects of TRAIL were initially thought to be restricted to its typical tumour cell toxicity (Sheridan et al, 1997), numerous data report its proapoptotic effects on normal human cells, including brain cells (Nitsch et al, 2000). Interestingly, human glioblastoma cells, such as A172, U87MG and U373MG, display differential responsiveness to TRAIL-related cytotoxicity in vitro and in vivo (Pollack et al, 2001;Nabors et al, 2003;Kasuga et al, 2004), and also release substantial amounts of VEGF in response to hypoxia (Acker and Plate, 2004).…”

mentioning

confidence: 99%

TRAIL inhibits angiogenesis stimulated by VEGF expression in human glioblastoma cells

et al. 2006

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Tumour growth is tightly related to new blood vessel formation, tissue remodelling and invasiveness capacity. A number of tissular factors fuel the growth of glioblastoma multiforme, the most aggressive brain neoplasm. In fact, gene array analyses demonstrated that the proapoptotic cytokine tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) inhibited mRNA expression of VEGF, along with those of matrix metalloproteinase-2 (MMP-2), its inhibitor tissue inhibitor of matrix metalloproteinases-2 (TIMP-2), as well as the tumour invasiveness-related gene secreted protein acid rich in cysteine (SPARC) in different human glioblastoma cell lines. Particularly, VEGF mRNA and protein expression and release from glioblastoma cells were also inhibited by TRAIL. The latter also exerted antimitogenic effects on human umbilical vein endothelial cells (HUVECs). With the same cells, TRAIL inhibited new vessel formation in the in vitro matrigel model, as well as it exerted powerful inhibition of blood vessel formation induced by an angiogenic cocktail administered in subcutaneous pellets in vivo in the C57 mouse. Moreover, the expression of MMP-2, its inhibitor TIMP-2 and the tumour invasiveness-related protein SPARC were effectively inhibited by TRAIL in glioblastoma cell lines. In conclusion, our data indicate that TRAIL inhibits the orchestra of factors contributing to glioblastoma biological aggressiveness. Thus, the TRAIL system could be regarded as a molecular target to exploit for innovative therapy of this type of tumour.

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Human brain-cell death induced by tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL)

Cited by 279 publications

References 5 publications

TRAIL enhances thymidine kinase/ganciclovir gene therapy of neuroblastoma cells

TRAIL enhances thymidine kinase/ganciclovir gene therapy of neuroblastoma cells

Human normal hepatocytes are susceptible to apoptosis signal mediated by both TRAIL-R1 and TRAIL-R2

TRAIL inhibits angiogenesis stimulated by VEGF expression in human glioblastoma cells

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