Antiproliferative activity of phenylbutyrate ester of haloperidol metabolite II [(+/-)-MRJF4] in prostate cancer cells

作者：Marrazzo Agostino^*; Fiorito Jole; Zappala Laura; Prezzavento Orazio; Ronsisvalle Simone; Pasquinucci Lorella; Scoto Giovanna M; Bernardini Renato; Ronsisvalle Giuseppe

来源：European Journal of Medicinal Chemistry, 2011, 46(1): 433-438.

DOI：10.1016/j.ejmech.2010.10.012

• Histone deacetylase
• Inhibitors
• LNCaP
• PC3
• Sigma receptors

Complex mechanisms of prostate cancer progression prompt to novel therapeutic strategies concerning a combination of drugs or of single molecules able to interact with more crucial targets. Histone deacetylase inhibitors and sigma ligands with mixed sigma(1) antagonist and sigma(2) agonist properties were proposed as new potential tools for treatment of prostate cancer. (+/-)-MRJF4 was synthesized as phenylbutyrate ester of haloperidol metabolite II, which is a molecule consisting of a histone deacetilase inhibitor (4-phenylbutyric acid) and a sigma ligand (haloperidol metabolite II). Antiproliferatives activities of 4-phenylbutyric acid, haloperidol metabolite II, equimolar mixture of both compounds and (+/-)-MRJF4 were evaluated in vitro on LNCaP and PO prostate cancer cells. Preliminary binding studies of (+/-)-MRJF4 for sigma(1), sigma(2), D-2 and D-3 receptors and inhibition HDAC activity were reported. KIT cell viability assays highlighted a notable increase of antiproliferative activity of (+/-)-MRJF4 (IC50 = 11 and 13 mu M for LNCaP and PC3, respectively) compared to 4-phenylbutyric acid, haloperidol metabolite II and the respective equimolar pharmacological association. (+/-)-MRJF4 was also used in combination with sigma(1) agonist (+)-pentazocine and sigma(2) antagonist AC927 in order to evaluate the role of sigma receptor subtypes in prostate cancer cell death.

• 出版日期2011-1