Inhibition of human prostate cancer growth, osteolysis and angiogenesis in a bone metastasis model by a novel mechanism-based selective gelatinase inhibitor.
Metastasis to the bone is a major clinical complication in patients with prostate cancer (PC). However, therapeutic options for treatment of PC bone metastasis are limited. Gelatinases are members of the matrix metalloproteinase (MMP) family and have been shown to play a key role in PC metastasis. Herein, we investigated the effect of SB-3CT, a covalent mechanism-based MMP inhibitor with high selectivity for gelatinases, in an experimental model of PC bone metastases. Intraperitoneal (i.p.) treatment with SB-3CT (50 mg/kg) inhibited intraosseous growth of human PC3 cells within the marrow of human fetal femur fragments previously implanted in SCID mice, as demonstrated by histomorphometry and Ki-67 immunohistochemistry. The anti-osteolytic effect of SB-3CT was confirmed by radiographic images. Treatment with SB-3CT also reduced intratumoral vascular density and bone degradation in the PC3 bone tumors. A direct inhibition of bone marrow endothelial cell invasion and tubule formation in Matrigel by SB-3CT in vitro was also demonstrated. The use of the highly selective gelatinase inhibitors holds the promise of effective intervention of metastases of PC to the bone.
Bonfil
R Daniel
RD
Department of Urology, Wayne State University School of Medicine and The Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, USA. dbonfil@med.wayne.edu
Sabbota
Aaron
A
Nabha
Sanaa
S
Bernardo
M Margarida
MM
Dong
Zhong
Z
Meng
Hong
H
Yamamoto
Hamilto
H
Chinni
Sreenivasa R
SR
Lim
Int Taek
IT
Chang
Mayland
M
Filetti
Lusia C
LC
Mobashery
Shahriar
S
Cher
Michael L
ML
Fridman
Rafael
R
D000818:Animals; D001859:Bone Neoplasms / Q000503:physiopathology / Q000517:prevention & control* / Q000556:secondary*; D005354:Fibrosarcoma / Q000473:pathology; D018093:Gelatinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006573:Heterocyclic Compounds, 1-Ring / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D007263:Infusions, Parenteral; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010014:Osteolysis / Q000517:prevention & control; D011471:Prostatic Neoplasms / Q000473:pathology*; D013450:Sulfones / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D006573:Heterocyclic Compounds, 1-Ring; C429533:SB 3CT compound; D013450:Sulfones; D018093:Gelatinases