Apoptotic effects of (±) MRJF4 in prostate cancer cells

Prostate cancer is a heterogeneous disease, whose etiology appears to be related to a complex range of risk factors. Particularly, aberrant epigenetic gene regulation by histone deacetylases (HDAC) plays a dominant role in its patho:physiology. Indeed, HDACs are part of a transcriptional co:repressor complex that represses tumor suppressor genes, such as those involved in the control of cell growth, apoptosis, migration, and invasion. For these reason, HDACs inhibitors are emerging as a new class of chemotherapeutic agents and, among them, 4:phenylbutyric acid, has reached phase I/II clinical trials for the treatment of refractory solid tumor malignancies. The new therapeutic cancer strategies suggest the use of the combination of drugs or single molecules able to interact with more crucial targets. Particularly, σ compounds were used as markers for prostate cancer because of the high expression of σ receptor in hormone sensitive: (LNCaP) and hormone refractory: (DU:145 and PC3) prostate cell lines; moreover, σ ligands have been studied for the treatment of drug:resistant tumors (1). With this aim, we studied the antiproliferative activity of (±):MRJF4, an ester of 4:phenylbutyric acid and haloperidol metabolite II (σ1 antagonist/σ2agonist) in prostate cancer cell lines, LNCaP and PC3, comparing its effect to 4:phenylbutyric acid, haloperidol metabolite II and an equimolar mixture of both compounds (2). We evaluated also the apoptotic process induced by (±):MRJF4 in prostate cancer cells through nuclear staining of cells, caspase assay and Western blot analysis of protein pro: and anti:apoptotic. The encouraging results obtained suggest a deepening of studies designed to characterize in more detail the molecular targets as a novel tool for treatment of prostate cancer.