Cancer gene therapy using a novel secretable trimeric TRAIL

Cy, Kim; Jeong, Moonsup; Mushiake, Hajime; Bm, Kim; Wb, Kim; Jp, Ko; Mh, Kim; Kim, Mi‐Hyun; Kim, Tae Hyeon; Robbins, P. D.; Tr, Billiar; Dw, Seol

doi:10.1038/sj.gt.3302658

Cited by 56 publications

(46 citation statements)

References 38 publications

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“…This administration mode is not suited to target disseminated cancers, and the limitations of intratumoral injections and MSCsexpressing membrane-bound full-length TRAIL were highlighted in a recent study that demonstrated the requirement for substantial intratumoral presence of MSCs to afford growth inhibition in a colorectal carcinoma model [42]. Therefore, we designed an adenoviral vector that expressed a secretable form of trimeric TRAIL, which has superior apoptosis-inducing activity over normal TRAIL [43,44]. MSCs transduced with this vector and injected intravenously could actively seek and destroy tumor cells at sites that may have otherwise been inaccessible or undetectable.…”

Section: Discussionmentioning

confidence: 99%

Targeting of XIAP Combined with Systemic Mesenchymal Stem Cell-Mediated Delivery of sTRAIL Ligand Inhibits Metastatic Growth of Pancreatic Carcinoma Cells

et al. 2010

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Disseminating tumors are one of the gravest medical problems. Here, we combine the tumor-specific apoptosis-inducing activity of tumor necrosis factor-related apoptosisinducing ligand (TRAIL) with the ability of mesenchymal stem cells (MSCs) to infiltrate both tumor and lymphatic tissues to target primary tumors as well as disseminated cancer cells in a human pancreatic cancer mouse model. Furthermore, we targeted X-linked inhibitor of apoptosis protein (XIAP) by RNA interference (RNAi) inside the cancer cells to make use of the apoptosis sensitization as well the antimetastatic effect that is afforded by XIAP silencing. We generated MSCs, termed MSC.sTRAIL, that express and secrete a trimeric form of soluble TRAIL (sTRAIL). MSC.sTRAIL triggered limited apoptosis in human pancreatic carcinoma cells that were resistant to soluble recombinant TRAIL, which is most likely due to the enhanced effect of the direct, cell-mediated delivery of trimeric TRAIL. MSC.sTRAIL-mediated cell death was markedly increased by concomitant knockdown of XIAP by RNAi in the cancer cells. These findings were confirmed in xenograft models, in which tumors from the parental pancreatic carcinoma cells showed only growth retardation on treatment with MSC.sTRAIL, whereas tumors with silenced XIAP that were treated with MSC.sTRAIL went into remission. Moreover, animals with XIAP-negative xenografts treated with MSC.sTRAIL were almost free of lung metastasis, whereas animals treated with control MSCs showed substantial metastatic growth in the lungs. In summary, this is the first demonstration that a combined approach using systemic MSC-mediated delivery of sTRAIL together with XIAP inhibition suppresses metastatic growth of pancreatic carcinoma.

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Section: Discussionmentioning

confidence: 99%

Targeting of XIAP Combined with Systemic Mesenchymal Stem Cell-Mediated Delivery of sTRAIL Ligand Inhibits Metastatic Growth of Pancreatic Carcinoma Cells

et al. 2010

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“…Although the mechanism for this cancer-selective action of TRAIL is poorly understood, it is recognized that TRAIL has a potential to become a promising antitumor therapy reagent. 18 Recently, it was reported that adenoviral transduction of a human cancer cell line with TRAIL gene induced apoptosis in vitro and also inhibited tumor growth in vivo. Moreover, the transduction with the TRAIL gene led to a bystander effect as non-transduced neighboring cancer cells underwent apoptosis as well.…”

Section: Introductionmentioning

confidence: 99%

Adenoviral mediated transduction of adenoid cystic carcinoma by human TRAIL gene driven with hTERT tumor specific promoter induces apoptosis

Zang¹,

Miao²,

Mu³

et al. 2009

Cancer Biology & Therapy

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“…The level of TRAIL in the medium in this study was low, suggesting that the bystander effect beyond neighbouring cells is limited. Kim et al 45 presented recently an adenoviral vector expressing a soluble trimeric form of TRAIL (stTRAIL). This adenoviral vector increased stimulation of apoptosis and induce tumor eradication more effectively in vivo compared to the vector expressing fulllength TRAIL.…”

Section: Discussionmentioning

confidence: 99%

Photochemically mediated delivery of AdhCMV-TRAIL augments the TRAIL-induced apoptosis in colorectal cancer cell lines

Engesæter

Bonsted²,

Lillehammer³

et al. 2006

Cancer Biology & Therapy

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Tumor targeting is an important issue in cancer gene therapy. We have developed a light-specific transduction method, named photochemical internalization (PCI), to enhance gene expression from adenoviral vectors selectively in illuminated areas. Tumor necrosis factor related apoptosis inducing ligand (TRAIL) has been shown to induce apoptosis in cancer cells, and the aim of this study was to investigate the potential of PCI to enhance transgene expression from AdhCMV-TRAIL and evaluate its impact on apoptotic induction in the two human colorectal cancer cell lines HCT116 and WiDr. PCI-mediated delivery of AdhCMV-TRAIL enabled an increased expression of TRAIL, induced a synergistic reduction in cell viability compared to the individual action of AdhCMV-TRAIL and photochemical treatment, and enhanced the induction of apoptosis demonstrated by an increase in cytoplasmic histone-associated DNA fragments, caspase-8 and caspase-3 activation, PARP cleavage and a decrease in the mitochondrial membrane potential. The synergistic effect could be related to the enhanced TRAIL expression in PCI-treated samples and a modest sensitization of the cancer cells to TRAIL induced apoptosis due to the photochemical treatment. Furthermore, an increased cleavage of Bid and a cell line dependent reduction in the expression levels of anti-apoptotic Bcl-2 family members were observed and could possibly contribute to the enhanced apoptotic level in samples exposed to the combined treatment. The presented results indicate that photochemically mediated delivery of AdhCMV-TRAIL allows a selective enhancement in cell killing, and suggest that PCI may be relevant and advantageous for therapeutic gene delivery in vivo.

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Cancer gene therapy using a novel secretable trimeric TRAIL

Cited by 56 publications

References 38 publications

Targeting of XIAP Combined with Systemic Mesenchymal Stem Cell-Mediated Delivery of sTRAIL Ligand Inhibits Metastatic Growth of Pancreatic Carcinoma Cells

Targeting of XIAP Combined with Systemic Mesenchymal Stem Cell-Mediated Delivery of sTRAIL Ligand Inhibits Metastatic Growth of Pancreatic Carcinoma Cells

Adenoviral mediated transduction of adenoid cystic carcinoma by human TRAIL gene driven with hTERT tumor specific promoter induces apoptosis

Photochemically mediated delivery of AdhCMV-TRAIL augments the TRAIL-induced apoptosis in colorectal cancer cell lines

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