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Neoplasia. 2015 Jan;17(1):43-54. doi: 10.1016/j.neo.2014.11.002.

Suppression of tumor growth in mice by rationally designed pseudopeptide inhibitors of fibroblast activation protein and prolyl oligopeptidase.

Author information

1
William K. Warren Medical Research Center, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. Electronic address: ken-jackson@ouhsc.edu.
2
William K. Warren Medical Research Center, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
3
College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
4
Cardiovascular Biology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
5
Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

Abstract

Tumor microenvironments (TMEs) are composed of cancer cells, fibroblasts, extracellular matrix, microvessels, and endothelial cells. Two prolyl endopeptidases, fibroblast activation protein (FAP) and prolyl oligopeptidase (POP), are commonly overexpressed by epithelial-derived malignancies, with the specificity of FAP expression by cancer stromal fibroblasts suggesting FAP as a possible therapeutic target. Despite overexpression in most cancers and having a role in angiogenesis, inhibition of POP activity has received little attention as an approach to quench tumor growth. We developed two specific and highly effective pseudopeptide inhibitors, M83, which inhibits FAP and POP proteinase activities, and J94, which inhibits only POP. Both suppressed human colon cancer xenograft growth >90% in mice. By immunohistochemical stains, M83- and J94-treated tumors had fewer microvessels, and apoptotic areas were apparent in both. In response to M83, but not J94, disordered collagen accumulations were observed. Neither M83- nor J94-treated mice manifested changes in behavior, weight, or gastrointestinal function. Tumor growth suppression was more extensive than noted with recently reported efforts by others to inhibit FAP proteinase function or reduce FAP expression. Diminished angiogenesis and the accompanying profound reduction in tumor growth suggest that inhibition of either FAP or POP may offer new therapeutic approaches that directly target TMEs.

PMID:
25622898
PMCID:
PMC4309729
DOI:
10.1016/j.neo.2014.11.002
[Indexed for MEDLINE]
Free PMC Article

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