|
|
Prepublished online as a Blood First Edition Paper on May 8, 2003; DOI 10.1182/blood-2003-01-0208.
Submitted January 23, 2003
Accepted April 26, 2003
Hematopoietic stimulation by a dipeptidyl peptidase inhibitor reveals a novel regulatory mechanism and therapeutic treatment for blood cell deficiencies
Barry Jones*, Sharlene Adams, Glenn T Miller, Michael I Jesson, Takeshi Watanabe, and Barbara P Wallner
Point Therapeutics, Inc., Boston, MA, USA
Department of Molecular Immunology, Kyushu University, Higashi-ku, Fukuoka, Japan
Biotransplant, Inc., Boston, MA, USA
* Corresponding author; email: bjones{at}pther.com.
In hematopoiesis, cytokine levels modulate blood cell replacement, self-renewal of stem cells, and responses to disease. Feedback pathways regulating cytokine levels and targets for therapeutic intervention remain to be determined. Amino boronic dipeptides are orally bioavailable inhibitors of dipeptidyl peptidases. Here we show that the high affinity inhibitor Val-boro-Pro (PT-100) can stimulate the growth of hematopoietic progenitor cells in vivo, and accelerate neutrophil and erythrocyte regeneration in mouse models of neutropenia and acute anemia. Hematopoietic stimulation by PT-100 correlated with increased cytokine levels in vivo. In vitro, PT-100 promoted growth of primitive hematopoietic progenitor cells by increasing G-CSF, IL-6, and IL-11 production by bone marrow stromal cells. Two molecular targets of PT-100 are expressed by stromal cells: CD26/DPP-IV and the closely related fibroblast activation protein (FAP). Since PT-100 was active in the absence of CD26, FAP appears to be the hematopoietic target for PT-100. Interaction of PT-100 with the catalytic site seems to be required, because amino-terminal acetylation of PT-100 abrogated both enzyme inhibition and hematopoietic stimulation. PT-100 is a therapeutic candidate for treatment of neutropenia and anemia. The data support the increasing evidence that dipeptidyl peptidases can regulate complex biological systems by the proteolysis of signaling peptides.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
D. J. Drucker
Dipeptidyl Peptidase-4 Inhibition and the Treatment of Type 2 Diabetes: Preclinical biology and mechanisms of action
Diabetes Care,
June 1, 2007;
30(6):
1335 - 1343.
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. D Green, P. R Flatt, and C. J Bailey
Dipeptidyl peptidase IV (DPP IV) inhibitors: a newly emerging drug class for the treatment of type 2 diabetes
Diabetes and Vascular Disease Research,
December 1, 2006;
3(3):
159 - 165.
[Abstract]
[PDF]
|
|
|
|
|
|
|
C. Y. Edosada, C. Quan, C. Wiesmann, T. Tran, D. Sutherlin, M. Reynolds, J. M. Elliott, H. Raab, W. Fairbrother, and B. B. Wolf
Selective Inhibition of Fibroblast Activation Protein Protease Based on Dipeptide Substrate Specificity
J. Biol. Chem.,
March 17, 2006;
281(11):
7437 - 7444.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. D. Cheng, M. Valianou, A. A. Canutescu, E. K. Jaffe, H.-O. Lee, H. Wang, J. H. Lai, W. W. Bachovchin, and L. M. Weiner
Abrogation of fibroblast activation protein enzymatic activity attenuates tumor growth
Mol. Cancer Ther.,
March 1, 2005;
4(3):
351 - 360.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Adams, G. T. Miller, M. I. Jesson, T. Watanabe, B. Jones, and B. P. Wallner
PT-100, a Small Molecule Dipeptidyl Peptidase Inhibitor, Has Potent Antitumor Effects and Augments Antibody-Mediated Cytotoxicity via a Novel Immune Mechanism
Cancer Res.,
August 1, 2004;
64(15):
5471 - 5480.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
