title: Suppression of tumor growth in mice by rationally designed pseudopeptide inhibitors of fibroblast activation protein and prolyl oligopeptidase.
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.
authors.affiliation: 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.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Jackson
authors.affiliation: William K. Warren Medical Research Center, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Christiansen
authors.affiliation: College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Vivek R
authors.initials: VR
authors.lastname: Yadav
authors.affiliation: Cardiovascular Biology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Silasi-Mansat
authors.affiliation: Cardiovascular Biology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: Florea
authors.initials: F
authors.lastname: Lupu
authors.affiliation: College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Vibhudutta
authors.initials: V
authors.lastname: Awasthi
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Roy R
authors.initials: RR
authors.lastname: Zhang
authors.affiliation: William K. Warren Medical Research Center, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: McKee
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015195:Drug Design; D010450:Endopeptidases; D018093:Gelatinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051379:Mice; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D009374:Neoplasms, Experimental; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D000085822:Prolyl Oligopeptidases; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D000970:Antineoplastic Agents; D010450:Endopeptidases; D018093:Gelatinases; D008565:Membrane Proteins; D010455:Peptides; D000085822:Prolyl Oligopeptidases; D011480:Protease Inhibitors; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha; C000705287:PREPL protein, human