Potent inhibition of tumor angiogenesis by the matrix metalloproteinase-activated anthrax lethal toxin - Implications for broad anti-tumor efficacy

被引:25
作者
Alfano, Randall W. [1 ]
Leppla, Stephen H. [2 ]
Liu, Shihui [2 ]
Bugge, Thomas H. [3 ]
Duesbery, Nicholas S. [4 ]
Frankel, Arthur E. [1 ]
机构
[1] Scott & White Mem Hosp & Clin, Inst Canc Res, Temple, TX 76502 USA
[2] NIAID, Lab Bacterial Dis, Natl Inst Hlth, Bethesda, MD 20892 USA
[3] Natl Inst Dental & Craniofacial Res, Oral & Pharyngeal Canc Branch, Natl Inst Hlth, Bethesda, MD USA
[4] Van Andel Res Inst, Lab Canc & Dev Cell Biol, Grand Rapids, MI USA
基金
美国国家卫生研究院;
关键词
angiogenesis; anthrax lethal toxin; B-RAF; lethal factor; matrix metalloproteinase; protective antigen;
D O I
10.4161/cc.7.6.5627
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Angiogenesis is a critical step in solid tumor progression. The mitogen-activated protein kinase ( MAPK) signaling pathways are central to this process, and thus present attractive targets for angiogenesis inhibition. Anthrax Lethal Toxin ( LeTx), secreted from the gram positive Bacillus anthracis, demonstrates potent MAPK pathway inhibition. In vivo efficacy studies revealed that LeTx has broad anti-tumor efficacy via the targeting of angiogenesis. However, specificity in animal models was limited due to the presence of receptors on many normal tissues and the ubiquitous expression of furin in tissues. Further, half-life of LeTx was short due to circulating furin-like proteases. Gelatinases are expressed on tumor angiogenic sprouts and only to a limited extent in normal tissues or blood. In order to circumvent nonspecific LeTx activation, enhance tumor vascular targeting, and improve plasma half-life, a substrate preferably cleaved by gelatinases was substituted for the furin LeTx activation site. The MMP-activated LeTx showed potent angiogenic inhibition in vivo in the absence of systemic toxicity. Based on these studies, this attenuated toxin has clinical potential as a broad anti-tumor agent.
引用
收藏
页码:745 / 749
页数:5
相关论文
共 58 条
[1]   Systemic anthrax lethal toxin therapy produces regressions of subcutaneous human melanoma tumors in athymic nude mice [J].
Abi-Habib, Ralph J. ;
Singh, Ravibhushan ;
Leppla, Stephen H. ;
Greene, John J. ;
Ding, Yan ;
Berghuis, Bree ;
Duesbery, Nicholas S. ;
Frankel, Arthur E. .
CLINICAL CANCER RESEARCH, 2006, 12 (24) :7437-7443
[2]   BRAF status and mitogen-activated protein/extracellular signal-regulated kinase kinase 1/2 activity indicate sensitivity of melanoma cells to anthrax lethal toxin [J].
Abi-Habib, RJ ;
Urieto, JO ;
Liu, SH ;
Leppla, SH ;
Duesbery, NS ;
Frankel, AE .
MOLECULAR CANCER THERAPEUTICS, 2005, 4 (09) :1303-1310
[3]   Anthrax toxin triggers endocytosis of its receptor via a lipid raft-mediated clathrin-dependent process [J].
Abrami, L ;
Liu, SH ;
Cosson, P ;
Leppla, SH ;
van der Goot, FG .
JOURNAL OF CELL BIOLOGY, 2003, 160 (03) :321-328
[4]   Anthrax lethal toxin: a weapon of multisystem destruction [J].
Agrawal, A ;
Pulendran, B .
CELLULAR AND MOLECULAR LIFE SCIENCES, 2004, 61 (22) :2859-2865
[5]  
ARORA N, 1992, J BIOL CHEM, V267, P15542
[6]   Inhibition of mitogen-activated protein kinase signalling by Bacillus anthracis lethal toxin causes destabilization of interleukin-8 mRNA [J].
Batty, S ;
Chow, EMC ;
Kassam, A ;
Der, SD ;
Mogridge, J .
CELLULAR MICROBIOLOGY, 2006, 8 (01) :130-138
[7]   Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis [J].
Bergers, G ;
Brekken, R ;
McMahon, G ;
Vu, TH ;
Itoh, T ;
Tamaki, K ;
Tanzawa, K ;
Thorpe, P ;
Itohara, S ;
Werb, Z ;
Hanahan, D .
NATURE CELL BIOLOGY, 2000, 2 (10) :737-744
[8]   Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance [J].
Boehm, T ;
Folkman, J ;
Browder, T ;
OReilly, MS .
NATURE, 1997, 390 (6658) :404-407
[9]   Inhibition of human prostate cancer growth, osteolysis and angiogenesis in a bone metastasis model by a novel mechanism-based selective gelatinase inhibitor [J].
Bonfil, RD ;
Sabbota, A ;
Nabha, S ;
Bernardo, MM ;
Dong, Z ;
Meng, H ;
Yamamoto, H ;
Chinni, SR ;
Lim, IT ;
Chang, M ;
Filetti, LC ;
Mobashery, S ;
Cher, ML ;
Fridman, R .
INTERNATIONAL JOURNAL OF CANCER, 2006, 118 (11) :2721-2726
[10]   Role of anti-angiogenesis agents in treating NSCLC: Focus on bevacizumab and VEGFR tyrosine kinase inhibitors [J].
Cabebe E. ;
Wakelee H. .
Current Treatment Options in Oncology, 2007, 8 (1) :15-27