Verotoxin Induces Rapid Elimination of Human Renal Tumor Xenografts in SCID Mice

Ishitoya, Satoshi; Kurazono, Hisao; Nishiyama, Hiroyuki; Nakamura, Eijiro; Kamoto, Toshiyuki; Habuchi, Tomonori; Terai, Akito; Ogawa, Osamu; Yamamoto, Shingo

doi:10.1097/01.ju.0000100110.11129.85

Cited by 56 publications

(50 citation statements)

References 15 publications

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“…Shiga toxin as a cytotoxic agent has been tested in xenograft tumor models in mice (11,(22)(23)(24)(25). Furthermore, it eliminates clonogenic tumor cells in purging applications (26).…”

Section: Introductionmentioning

confidence: 99%

In vivo Tumor Targeting Using a Novel Intestinal Pathogen-Based Delivery Approach

et al. 2006

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Efficient methods for tumor targeting are eagerly awaited and must satisfy several challenges: molecular specificity, transport through physiologic barriers, and capacity to withstand extracellular or intracellular degradation and inactivation by the immune system. Through interaction with its hosts, the intestinal pathogen-produced Shiga toxin has evolved molecular properties that are of interest in this context. Its nontoxic B-subunit binds to the cellular toxin receptor, glycosphingolipid Gb 3 , which is highly expressed on human cancers and has recently been reported to be involved in the formation of metastasis in colorectal cancers. Its function as a target for cancer therapy has already been addressed in xenograft experiments. We here show that after oral or i.v. injections in mice, the B-subunit targets spontaneous digestive Gb 3 -expressing adenocarcinomas. The nontumoral mucosa is devoid of labeling, with the exception of rare enteroendocrine and CD11b-positive cells. As opposed to other delivery tools that are often degraded or recycled on cancer cells, the B-subunit stably associates with these cells due to its trafficking via the retrograde transport route. This can be exploited for the in vivo delivery of contrast agents to tumors, as exemplified using fibered confocal fluorescence endoscopy and positron emission tomography (PET) imaging. In conclusion, the data presented in this manuscript lay the groundwork for a novel delivery technology that, in addition to its use for molecular imaging applications such as noninvasive PET, could also be exploited for targeted tumor therapies.

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“…Shiga toxin as a cytotoxic agent has been tested in xenograft tumor models in mice (11,(22)(23)(24)(25). Furthermore, it eliminates clonogenic tumor cells in purging applications (26).…”

Section: Introductionmentioning

confidence: 99%

In vivo Tumor Targeting Using a Novel Intestinal Pathogen-Based Delivery Approach

et al. 2006

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“…The B part consists of five identical sub-units, which can all bind to the Gb3 receptor in which the A sub-unit is internalised and cytotoxic through ribosome inactivation (Endo et al, 1988;Olsnes and Sandvig, 1988;Saxena et al, 1989;O'Brien et al, 1992;Gariepy, 2001;Sandvig et al, 2002). VT-1 has shown efficacy against meningioma, astrocytoma, as well as renal tumour xenografts in mice (Arab et al, 1999;Salhia et al, 2002;Ishitoya et al, 2004). The B part of VT-1 has also been suggested as a novel approach to deliver other anti-tumour agents (Vingert et al, 2006).…”

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confidence: 99%

Cisplatin-induced expression of Gb3 enables verotoxin-1 treatment of cisplatin resistance in malignant pleural mesothelioma cells

et al. 2009

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BACKGROUND: A major problem with cisplatin treatment is the development of acquired-drug resistance of the tumour cells. Verotoxin-1 (VT-1) exerts its cytotoxicity by targeting the membrane glycolipid globotriasosylceramide (Gb3), a molecule associated with drug resistance. Cisplatin-and VT-1-induced apoptosis involves mitogen-activated protein kinase (MAPK) activation, and deactivation of MAPKs is associated with cisplatin resistance. This study aimed to investigate whether a sub-toxic concentration of VT-1 could enhance cisplatin-induced apoptosis and overcome acquired-cisplatin resistance in cultured cancer cell lines. METHOD: P31 and H1299 cells with corresponding cisplatin-resistant sub-lines (P31res/H1299res) were incubated with VT-1 and/or cisplatin followed by determination of Gb3 expression, cell viability, apoptosis, and signalling pathways. RESULTS: Cells from the resistant sub-lines had elevated Gb3 expression compared with the parental cell lines, and cisplatin further increased Gb3 expression, whereas VT-1 reduced the percentage of Gb3-expressing cells. Combination of cisplatin and sub-toxic concentrations of VT-1 led to a super-additive increase of cytotoxicity and TUNEL staining, especially in the cisplatin-resistant sublines. Blockade of Gb3 synthesis by a Gb3 synthesis inhibitor not only led to eradicated TUNEL staining of P31 cells, but also sensitised P31res cells to the induction of apoptosis by cisplatin alone. Cisplatin-and VT-1-induced apoptosis involved the MAPK pathways with increased C-Jun N-terminal kinase and MAPK kinase-3 and -6 phosphorylation. CONCLUSIONS: We show the presence of Gb3 in acquired-cisplatin resistance in P31res and H1299res cells. Cisplatin up-regulated Gb3 expression in all cells and thus sensitised the cells to VT-1-induced cytotoxicity. A strong super-additive effect of combined cisplatin and a sub-toxic concentration of VT-1 in cisplatin-resistant malignant pleural mesothelioma cells were observed, indicating a new potential clinical-treatment approach.

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“…It was shown that intratumoral injection of Shiga toxin inhibits tumor growth. [102][103][104] Another potential application of Shiga toxin is the control of tumor neo-angiogenesis 105 and purging of residual tumor burden from a human B-cell lymphoma xenograft, while sparing normal hematopoietic precursor cells. 106 As a further refinement of the cancer cell targeting approach, it might be suggested to replace the catalytic A-subunit of Shiga toxin by contrast agents for noninvasive tumor imaging or by therapeutic compounds that have preferential effects on cancer cells.…”

Section: Therapeutic Applications Of Toxin Traffickingmentioning

confidence: 99%

Protein toxins: intracellular trafficking for targeted therapy

2005

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The immunotoxin approach is based on the use of tumortargeting ligands or antibodies that are linked to the catalytic (toxic) moieties of bacterial or plant protein toxins. In this review, we first discuss the current state of clinical development of immunotoxin approaches describing the results obtained with the two toxins most frequently used: diphtheria and Pseudomonas toxin-derived proteins. In the second part of the review, a novel concept will be presented in which the roles are inverted: nontoxic receptor-binding toxin moieties are used for the targeting of therapeutic and diagnostic compounds to cancer or immune cells. The cell biological basis of these novel types of toxin-based therapeutics will be discussed, and we will summarize ongoing preclinical and clinical testing.

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Verotoxin Induces Rapid Elimination of Human Renal Tumor Xenografts in SCID Mice

Abstract: These results suggest that VTs could be candidates for antineoplastic agents against Gb3 expressing tumors for clinical use.

Cited by 56 publications

References 15 publications

In vivo Tumor Targeting Using a Novel Intestinal Pathogen-Based Delivery Approach

In vivo Tumor Targeting Using a Novel Intestinal Pathogen-Based Delivery Approach

Cisplatin-induced expression of Gb3 enables verotoxin-1 treatment of cisplatin resistance in malignant pleural mesothelioma cells

Protein toxins: intracellular trafficking for targeted therapy

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