Anthrax Lethal Toxin Inhibits Growth of and Vascular Endothelial Growth Factor Release from Endothelial Cells Expressing the Human Herpes Virus 8 Viral G Protein–Coupled Receptor

Depeille, Philippe; Young, John J.; Boguslawski, Elissa A.; Berghuis, Bree D.; Kort, Eric J.; Resau, James H.; Frankel, Arthur E.; Duesbery, Nicholas S.

doi:10.1158/1078-0432.ccr-07-0732

Cited by 19 publications

(23 citation statements)

References 41 publications

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“…Histological analysis determined that PA-L1/LF-treated xenografts contained viable tumor cells with a marked absence of necrosis or apoptosis. A similar anti-angiogenic effect has been noted in tumors treated with wild-type PA and LF (12, 14). Therefore, these findings demonstrate that the inhibition of a non-tumor cell compartment such as endothelial cells, and not direct tumor cell cytotoxicity, is the primary in vivo inhibitory mechanism of LF (12, 14, 17, 22).…”

Section: Discussionsupporting

confidence: 72%

Inhibition of Tumor Angiogenesis by the Matrix Metalloproteinase–Activated Anthrax Lethal Toxin in an Orthotopic Model of Anaplastic Thyroid Carcinoma

Alfano

Leppla

Liu

et al. 2010

Molecular Cancer Therapeutics

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Patients with anaplastic thyroid carcinoma (ATC) typically succumb to their disease months after diagnosis despite aggressive therapy. A large percentage of ATCs have been shown to harbor the V600E B-Raf point mutation, leading to the constitutive activation of the mitogen-activated protein kinase pathway. ATC invasion, metastasis, and angiogenesis are in part dependent on the gelatinase class of matrix metalloproteinases (MMP). The explicit targeting of these two tumor markers may provide a novel therapeutic strategy for the treatment of ATC. The MMP-activated anthrax lethal toxin (LeTx), a novel recombinant protein toxin combination, shows potent mitogen-activated protein kinase pathway inhibition in gelatinase-expressing V600E B-Raf tumor cells in vitro. However, preliminary in vivo studies showed that the MMP-activated LeTx also exhibited dramatic antitumor activity against xenografts that did not show significant antiproliferative responses to the LeTx in vitro. Here, we show that the MMP-activated LeTx inhibits orthotopic ATC xenograft progression in both toxin-sensitive and toxin-resistant ATC cells via reduced endothelial cell recruitment and subsequent tumor vascularization. This in turn translates to an improved long-term survival that is comparable with that produced by the multikinase inhibitor sorafenib. Our results also indicate that therapy with the MMP-activated LeTx is extremely effective against advanced tumors with well-established vascular networks. Taken together, these results suggest that the MMP-activated LeTx-mediated endothelial cell targeting is the primary in vivo antitumor mechanism of this novel toxin. Therefore, the MMP-activated LeTx could be used not only in the clinical management of V600E B-Raf ATC but potentially in any solid tumor. Mol Cancer Ther; 9(1); 190-201. ©2010 AACR.

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Section: Discussionsupporting

confidence: 72%

Inhibition of Tumor Angiogenesis by the Matrix Metalloproteinase–Activated Anthrax Lethal Toxin in an Orthotopic Model of Anaplastic Thyroid Carcinoma

Alfano

Leppla

Liu

et al. 2010

Molecular Cancer Therapeutics

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“…The results of this and our earlier studies imply that MKK inhibitors such as LeTx may be effective therapeutic agents for the treatment of not only fibrosarcomas but also a broad spectrum of sarcomas and carcinomas, including malignant fibrous histiocytomas, leiomyosarcomas, and liposarcomas; melanoma (19,20); and Kaposi's sarcoma (40). Based on this, we propose that MKK inhibition by LeTx is a broadly effective strategy for targeting tumor vascularization and by extension other neovascular diseases such as various retinopathies.…”

Section: Discussionsupporting

confidence: 58%

“…Insight into their in vivo functions may be inferred from the effects of MKK inhibitors on tumor vascularization. For example, we have shown previously that anthrax lethal factor substantially inhibits vascularization in mouse xenograft studies (11,40). Also, expression of an inactive Raf-1 mutant in endothelial cells blocks the growth and vascularization of melanomas in mice (41).…”

Section: Discussionmentioning

confidence: 97%

Mitogen-activated protein kinase kinase signaling promotes growth and vascularization of fibrosarcoma

Ding¹,

Boguslawski²,

Berghuis

et al. 2008

Molecular Cancer Therapeutics

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We hypothesized that signaling through multiple mitogenactivated protein kinase (MAPK) kinase (MKK) pathways is essential for the growth and vascularization of softtissue sarcomas, which are malignant tumors derived from mesenchymal tissues. We tested this using HT-1080, NCI, and Shac fibrosarcoma-derived cell lines and anthrax lethal toxin (LeTx), a bacterial toxin that inactivates MKKs. Western blots confirmed that LeTx treatment reduced the levels of phosphorylated extracellular signal-regulated kinase and p38 MAPK in vitro. Although short treatments with LeTx only modestly affected cell proliferation, sustained treatment markedly reduced cell numbers. LeTx also substantially inhibited the extracellular release of angioproliferative factors including vascular endothelial growth factor, interleukin-8, and basic fibroblast growth factor. Similar results were obtained with cell lines derived from malignant fibrous histiocytomas, leiomyosarcomas, and liposarcomas. In vivo, LeTx decreased MAPK activity and blocked fibrosarcoma growth. Growth inhibition correlated with decreased cellular proliferation and extensive necrosis, and it was accompanied by a decrease in tumor mean vessel density as well as a reduction in serum expression of angioproliferative cytokines. Vital imaging using high-resolution ultrasound enhanced with contrast microbubbles revealed that the effects of LeTx on tumor perfusion were remarkably rapid (<24 h) and resulted in a marked reduction of perfusion within the tumor but not in nontumor tissues. These results are consistent with our initial hypothesis and lead us to propose that MKK inhibition by LeTx is a broadly effective strategy for targeting neovascularization in fibrosarcomas and other similar proliferative lesions. [Mol Cancer Ther 2008;7(3):648 -58]

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“…Activated ERK or elevated ERK expression has been detected in a variety of human tumors, including breast carcinoma, glioblastoma, and primary tumor cells derived from kidney, colon, and lung tissues (13)(14)(15)(16). Sustained activation of ERK has been established as a requirement for angiogenesis (17)(18)(19)(20)(21). Overexpression of MKK was also found in human RCC cases (52%; ref.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of MAPK Kinase Signaling Pathways Suppressed Renal Cell Carcinoma Growth and Angiogenesis In vivo

Ding²,

et al. 2008

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The mitogen-activated protein kinase (MAPK) signaling pathways play essential roles in cell proliferation and differentiation. Recent studies also show the activation of MAPK signaling pathways in tumorigenesis, metastasis, and angiogenesis of multiple human malignancies, including renal cell carcinoma (RCC). To assess the role of this pathway in regulating the proliferation and survival of RCC cells, we first examined the expression of MAPK kinase (MKK) and MAPK in clear cell RCC and confirmed the overexpression of MKK1 and extracellular signal-regulated kinase 2 (ERK2) in these tumors. We then tested the effects of pharmacologic inhibition of MKK on human RCC cell lines, both in vitro and in vivo, using anthrax lethal toxin (LeTx), which cleaves and inactivates several MKKs. Western blotting showed that the phosphorylation levels of ERK, c-Jun-NH 2 kinase, and p38 MAPK decreased after 72 h of LeTx treatment. Exposure to LeTx for 72 h reduced cell proliferation by 20% without significant effects on cell cycle distribution and apoptosis. Anchorageindependent growth of RCC cells was dramatically inhibited by LeTx. In vivo studies showed that tumor growth of RCC xenografts could be suppressed by LeTx. Extensive necrosis and decreased tumor neovascularization were observed after LeTx treatment. LeTx also showed direct inhibition of proliferation of endothelial cells in vitro. Our results suggest that suppression of one or more MAPK signaling pathways may inhibit RCC growth through the disruption of tumor vasculature. [Cancer Res 2008;68(1):81-8]

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Anthrax Lethal Toxin Inhibits Growth of and Vascular Endothelial Growth Factor Release from Endothelial Cells Expressing the Human Herpes Virus 8 Viral G Protein–Coupled Receptor

Cited by 19 publications

References 41 publications

Inhibition of Tumor Angiogenesis by the Matrix Metalloproteinase–Activated Anthrax Lethal Toxin in an Orthotopic Model of Anaplastic Thyroid Carcinoma

Inhibition of Tumor Angiogenesis by the Matrix Metalloproteinase–Activated Anthrax Lethal Toxin in an Orthotopic Model of Anaplastic Thyroid Carcinoma

Mitogen-activated protein kinase kinase signaling promotes growth and vascularization of fibrosarcoma

Inhibition of MAPK Kinase Signaling Pathways Suppressed Renal Cell Carcinoma Growth and Angiogenesis In vivo

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