Title |
A d-amino acid containing peptide as a potent, noncovalent inhibitor of α5β1 integrin in human prostate cancer invasion and lung colonization
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Published in |
Clinical & Experimental Metastasis, January 2014
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DOI | 10.1007/s10585-013-9634-1 |
Pubmed ID | |
Authors |
Donna M. Veine, Hongren Yao, Daniel R. Stafford, Kevin S. Fay, Donna L. Livant |
Abstract |
Primary tumors often give rise to disseminated tumor cells (DTC's), which acquire full malignancy after invading distant site(s). Thus, DTC's may be a productive target for preventing prostate cancer metastasis progression. Our prior research showed that PHSCN peptide (Ac-PHSCN-NH2) targets activated α5β1 integrin to prevent invasion and metastasis in preclinical adenocarcinoma models, and disease progression in Phase I clinical trial. Here, we report that D-stereoisomer replacement of histidine and cysteine in PHSCN produces a highly potent derivative, Ac-PhScN-NH2 (PhScN). PhScN was 27,000- to 150,000-fold more potent as an inhibitor of basement membrane invasion by DU 145 and PC-3 prostate cancer cells. A large increase in invasion-inhibitory potency occurred after covalent modification of the sulfhydryl group in PHSCN to prevent disulfide bond formation; while the potency of covalently modified PhScN was not significantly increased. Thus PhScN and PHSCN invasion inhibition occurs by a noncovalent mechanism. These peptides also displayed similar cell surface binding dissociation constants (Kd), and competed for the same site. Consistent with its increased invasion-inhibitory potency, PhScN was also a highly potent inhibitor of lung extravasation and colonization in athymic nude mice: it was several hundred- or several thousand-fold more potent than PHSCN at blocking extravasation by PC-3 or DU 145 cells, and 111,000- or 379,000-fold more potent at inhibiting lung colonization, respectively. Furthermore, systemic 5 mg/kg PhScN monotherapy was sufficient to cause complete regression of established, intramuscular DU 145 tumors. PhScN thus represents a potent new family of therapeutic agents targeting metastasis by DTC's to prevent parallel progression in prostate cancer. |
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Geographical breakdown
Country | Count | As % |
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Unknown | 29 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Bachelor | 7 | 24% |
Researcher | 7 | 24% |
Student > Doctoral Student | 3 | 10% |
Student > Ph. D. Student | 2 | 7% |
Student > Postgraduate | 2 | 7% |
Other | 3 | 10% |
Unknown | 5 | 17% |
Readers by discipline | Count | As % |
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Medicine and Dentistry | 7 | 24% |
Biochemistry, Genetics and Molecular Biology | 2 | 7% |
Computer Science | 2 | 7% |
Unspecified | 1 | 3% |
Other | 2 | 7% |
Unknown | 8 | 28% |