New approaches are needed to the
therapy of advanced
prostate cancer. This study determined the effect of
growth hormone-releasing hormone (GHRH) antagonists,
JMR-132 and
JV-1-38 on growth of PC3
tumors as well as on angiogenesis and
metastasis through the evaluation of various factors that contribute largely to the progression of
prostate cancer. Human PC3
androgen-independent
prostate cancer cells were injected subcutaneously into nude mice. The treatment with
JMR-132 (10 μg/day) or
JV-1-38 (20 μg/day) lasted 41 days. We also evaluated the effects of
JMR-132 and
JV-1-38 on proliferation, cell adhesion and migration in PC-3 cells in vitro. Several techniques (Western blot, reverse transcription polymerase chain reaction, immunohistochemistry, ELISA and zymography) were used to evaluate the expression levels of
GHRH receptors and its splice variants, GHRH,
vascular endothelial growth factor (
VEGF),
hypoxia inducible factor (HIF)-1α,
metalloproteinases (
MMPs) -2 and -9, β-
catenin and
E-cadherin. GHRH antagonists suppressed the proliferation of PC-3 cells in vitro and significantly inhibited growth of PC3
tumors.
After treatment with these analogues, we found an increase in expression of
GHRH receptor accompanied by a decrease of GHRH levels, a reduction in both
VEGF and HIF-1α expression and in active forms of MMP-2 and MMP-9, a significant increase in levels of membrane-associated β-
catenin and a significant decline in
E-cadherin. These results support that the blockade of
GHRH receptors can modulate elements involved in angiogenesis and
metastasis. Consequently, GHRH antagonists could be considered as suitable candidates for therapeutic trials in the management of
androgen-independent
prostate cancer.