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

Abstract

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 σ1 antagonist and σ2 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 PC3 prostate cancer cells. Preliminary binding studies of (±)-MRJF4 for σ1, σ2, D2 and D3 receptors and inhibition HDAC activity were reported. MTT cell viability assays highlighted a notable increase of antiproliferative activity of (±)-MRJF4 (IC50 = 11 and 13 μM 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 σ1 agonist (+)-pentazocine and σ2 antagonist AC927 in order to evaluate the role of σ receptor subtypes in prostate cancer cell death.