A selective alpha1D-adrenoreceptor antagonist inhibits human prostate cancer cell proliferation and motility “in vitro”

Abstract

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.

1,4-Benzodioxane, an evergreen, versatile scaffold in medicinal chemistry: A review of its recent applications in drug design

“…90,91 Consistently with affinity data, functional studies of the antagonist activity at the 1A-, 1B-and 1D-ARs show that the two combined modifications, fusion of cyclohexane at the benzodioxane and of benzene at the 2,6 dimethoxyphenyl, lead to a potent and selective 1A-AR antagonist (compound 8) (7.98 1A pA2 vs <5 1B pA2 and 5.59 1D pA2) (Figure 6). 89 On the other hand, selective 1D-AR antagonist activity is attained by maintaining the characteristic ortho hetero-disubstituted phenyl group of (S)-WB-4101, but rigidified in the 6-methoxy-2,3-dihydrobenzofuran substructure (9.58 1D pA2 vs 8.49 1B pA2 and 7.88 1A pA2), 92,93 while 8-substitution at the benzodioxane, in particular with methoxyl, confers significantly selective 1B-AR antagonism (9.58 1B pA2 vs 8.55 1A pA2 and 7.93 1D pA2) (compounds 9 and 10) (Figure 6). 94 (S)-WB4101, 7 and 9 show also intrinsic relaxant activity on non-vascular smooth muscle and moderate negative inotropic effect, which parallel the calcium antagonist effects suggesting a direct interaction with L-type Ca 2+ channels.…”

The downregulation of NCXs is positively correlated with the prognosis of stage II–IV colon cancer

“…The contradictory results may be due to different tissue specificities. Ca 2+ protein alpha 1D is expressed in a variety of malignant tumors and promotes tumor progression [ 52 ]. Inhibiting NCX1/3 and promoting the release of calcium from the endoplasmic reticulum can increase [Ca 2+ ]i, upregulate Ca 2+ protein alpha 1D, and promote the migration of HCT116 colon cancer cells [ 35 ].…”

Drug Repositioning of the α1-Adrenergic Receptor Antagonist Naftopidil: A Potential New Anti-Cancer Drug?

“…Indeed, naftopidil cytostatic and cytotoxic properties are reached at high concentrations in vitro and reducing effective concentrations through more effective compounds would facilitate is use in clinic. It is interesting to note that Colciago et al, synthesised a compound derived from WB4101: A175, that binds with a strong affinity α 1D -AR [ 98 ]. They demonstrated that this compound had an anti-proliferative effect in androgen-insensitive prostate cancer cells PC3 that strongly expressed α 1D -AR at the mRNA level but had no effect on DU145 cells that did not express this receptor.…”