Lysosomal β-galactosidase (β-Gal) deficiency causes a group of disorders that include neuronopathic GM1 gangliosidosis and non-neuronopathic Morquio B disease. We have previously proposed the use of small molecule ligands of β-Gal as pharmacological chaperones (PCs) for the treatment of GM1 gangliosidosis brain pathology. Although it is still under development, PC therapy has yielded promising preclinical results in several lysosomal diseases. In this study, we evaluated the effect of bicyclic 1-deoxygalactonojirimycin (DGJ) derivative of the sp(2)-iminosugar type, namely 5N,6S-(N'-butyliminomethylidene)-6-thio-1- deoxygalactonojirimycin (6S-NBI-DGJ), as a novel PC for human mutant β-Gal. In vitro, 6S-NBI-DGJ had the ability to inhibit the activity of human β-Gal in a competitive manner and was able to protect this enzyme from heat-induced degradation. Computational analysis supported that the rigid glycone bicyclic core of 6S-NBI-DGJ binds to the active site of the enzyme, with the aglycone N'-butyl substituent, in a precise E-orientation, located at a hydrophobic region nearby. Chaperone potential profiling indicated significant increases of enzyme activity in 24 of 88 β-Gal mutants, including four common mutations. Finally, oral administration of 6S-NBI-DGJ ameliorated the brain pathology of GM1 gangliosidosis model mice. These results suggest that 6S-NBI-DGJ is a novel PC that may be effective on a broad range of β-Gal mutants.

Competitive inhibitors of either α-galactosidase (α-Gal) or β-galactosidase (β-Gal) with high affinity and selectivity have been accessed by exploiting aglycone interactions with conformationally locked sp(2)-iminosugars. Selected compounds were profiled as potent pharmacological chaperones for mutant lysosomal α- and β-Gal associated with Fabry disease and GM(1) gangliosidosis.

To compare combination therapy with bicalutamide 80 mg and a luteinizing hormone-releasing hormone agonist (LHRH-A) versus LHRH-A alone in Japanese men with untreated advanced prostate cancer. A total of 205 patients with stage C/D prostate cancer were randomized to either LHRH-A þ once-daily oral bicalutamide 80 mg or placebo. Primary study variables have been reported previously. Secondary variables included: time to achieve prostate-specific antigenp4 ng/ ml, time-to-treatment failure (TTTF), time-to-disease progression (TTP), overall survival (OS), adverse events and adverse drug reactions. Following combination therapy with bicalutamide 80 mg, there were significant (Po0.001) advantages over LHRH-A alone in terms of TTTF and TTP, but the difference in the interim OS was not statistically significant. First-line combination therapy with bicalutamide 80 mg in Japanese patients with advanced prostate cancer offers significant benefits over LHRH-A alone, with respect to TTTF and TTP. Follow-up for OS continues.

Abbreviations & Acronyms BPH = benign prostatic hyperplasia BSA = bovine serum albumin DAPI = diamidino-2-phenylindole DMSO = dimethylsulfoxide IC50 = half maximal inhibitory concentration PC = prostate cancer PSA = prostate-specific antigen R1 = receptor 1 RT = room temperature TGF-b = transforming growth factor-b TUNEL = terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling TUR-P = transurethral resection of the prostate Objectives: Quinazoline-based a1-adrenoceptor antagonists are known to inhibit prostate tumor growth through induction of apoptosis. We investigated the effect of a naphthalene-based a1-adrenoceptor antagonist, naftopidil, on prostate cancer incidence, apoptosis of prostatic cell and transforming growth factor-b signaling. Methods: Prescription records were linked to pathological data for men who continued naftopidil (n = 766) or tamsulosin (n = 1015) for 3 months or longer between 2003 and 2010. Prostate cancer incidence was analyzed by log-rank test and the Cox proportional hazards model. Apoptosis and cell cycle arrest in human tissues were assessed by immunohistochemical detection of Bcl2 and p21, respectively. Growth inhibition and apoptosis treatment with naftopidil and tamsulosin were assessed in cancer cell lines. Interference with transforming growth factor-b signaling was examined by western blot analysis. Results: Prostate cancer incidence was significantly lower in men who received naftopidil for 3 months or longer compared with tamsulosin (P = 0.035). Multivariate analysis confirmed a decreased hazard ratio, 0.46, for naftopidil use (P = 0.013), which was more evident with longer treatment. Immunohistochemical positivity for Bcl2, a marker for resistance to apoptosis, was less frequently detected in prostate cancer cells of men who received naftopidil compared with tamsulosin (P < 0.05). Naftopidil inhibited cancer cell growth, induced apoptosis and blocked Smad2 phosphorylation activated by transforming growth factor-b in cell lines, with a half maximal inhibitory concentration of 1.1 mmol/L. Conclusions: Naftopidil seems to reduce prostate cancer incidence, possibly by inducing apoptosis, preferentially in cancer cells, and blocking transforming growth factor-b signaling.