Targeted inhibition of cell-surface serine protease Hepsin blocks prostate cancer bone metastasis.

Abstract

The development of effective therapies inhibiting prostate cancer progression and metastasis may substantially impact prostate cancer mortality and potentially reduce the rates of invasive treatments by enhancing the safety of active surveillance strategies. Hepsin (HPN) is a cell surface serine protease amplified in a subset of human sarcomas (7.2%), as well as in ovarian (10%), lung adeno (5.4%), lung squamous cell (4.5%), adenoid cystic (5%), breast (2.6%), uterine (1.7%) and colon (1.4%) carcinomas. While HPN is not amplified in prostate cancer, it is one of the most prominently overexpressed genes in the majority of human prostate tumors and genetic experiments in mice indicate that Hepsin promotes prostate cancer metastasis, particularly metastasis to the bone marrow. We report here the development, analysis and animal trial of the small-molecule Hepsin inhibitor HepIn-13. Long-term exposure to HepIn-13 inhibited bone, liver and lung metastasis in a murine model of metastatic prostate cancer. These findings indicate that inhibition of Hepsin with small-molecule compounds could provide an effective tool for attenuation of prostate cancer progression and metastasis.

• Authors: Xi Tang, Sumit S Mahajan, Liem T Nguyen, François Béliveau, Richard Leduc, Julian A Simon, Valeri Vasioukhin
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 5 Pg. 1352-62 (Mar 15 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 24657880 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• HepIn-13
• Membrane Proteins
• Naphthalenes
• Pyrimidines
• Serine Proteinase Inhibitors
• Serine Endopeptidases
• hepsin

Topics

• Adenocarcinoma (drug therapy, metabolism, secondary)
• Administration, Oral
• Animals
• Biological Availability
• Bone Neoplasms (prevention & control, secondary)
• HEK293 Cells
• Half-Life
• Humans
• Inhibitory Concentration 50
• Male
• Membrane Proteins (antagonists & inhibitors)
• Mice
• Models, Molecular
• Naphthalenes (pharmacokinetics, pharmacology, therapeutic use)
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Pyrimidines (pharmacokinetics, pharmacology, therapeutic use)
• Serine Endopeptidases (metabolism)
• Serine Proteinase Inhibitors (pharmacokinetics, pharmacology, therapeutic use)