The progression of prostate cancer (PC) to a metastatic hormone refractory disease
is the major contributor to the overall cancer mortality in men, mainly because the
conventional therapies are generally ineffective at this stage. Thus, other therapeutic
options are needed as alternatives or in addition to the classic approaches to prevent
or delay tumor progression. Catecholamines participate to the control of prostate
cell functions by the activation of alpha1-adrenoreceptors (alpha1-AR) and increased
sympathetic activity has been linked to PC development and evolution. Molecular and
pharmacological studies identified three alpha1-AR subtypes (A, B and D), which differ
in tissue distribution, cell signaling, pharmacology and physiological role. Within
the prostate, alpha1A-ARs mainly control stromal cell functions, while alpha1B- and
alpha1D- subtypes seem to modulate glandular epithelial cell growth. The possible
direct contribution of alpha1D-ARs in tumor biology is supported by their overexpression
in PC. The studies here presented investigate the "in vitro" antitumor action of A175,
a selective alpha1D-AR antagonist we have recently obtained by modifying the potent,
but not subtype-selective alpha1-AR antagonist (S)-WB4101, in the hormone-refractory
PC3 and DU145 PC cell lines. The results indicate that A175 has an alpha1D-AR-mediated
significant and dose-dependent antiproliferative action that possibly involves the
induction of G0/G1 cell cycle arrest, but not apoptosis. In addition, A175 reduces
cell migration and adhesiveness to culture plates. In conclusion, our work clarified
some cellular aspects promoted by alpha1D-AR activity modulation and supports a further
pharmacological approach in the cure of hormone-refractory PC, by targeting specifically
this AR subtype.