HALOPERIDOL METABOLITE II VALPROATE ESTER: ANTIANGIOGENIC ACTIVITY IN HUMAN MICROVASCULAR RETINAL ENDOTHELIAL CELLS

Aberrant angiogenic processes play a critical role in the development of cancer, heart diseases, atherosclerosis, and are a key component of several ophthalmic diseases, such as proliferative diabetic retinopathy,age-related macular degeneration, choroidal sub-retinal neovascularization and retinopathy of prematurity, retinoblastoma, all causes of irreversible visual loss. Vascular endothelial growth factor (VEGF) is the main regulator of angiogenesis, including retinal and choroidal angiogenesis. Cancers require VEGF for their survival and, so far, anti-angiogenic therapies rely on neutralizing angiogenic factors such as VEGF or on blocking the receptor tyrosine kinase intracellularly. The monoclonal antibody Bevacizumab is the first approved inhibitor of VEGF clinically available in the USA for the treatment of cancers in metastatic phase, such as colorectal cancer. Sigma (σ) receptors have been involved in many of cellular functions, biological processes, and diseases. Two σ receptor subtypes are recognized and termed sigma-1 (σ1)and sigma-2 (σ2). Recently, the σ1 receptor has been found to dynamically control the membrane expression of the human voltage dependent K+ channel hERG in different cancer cell lines. As consequence, the presence of σ1 receptor in cancer cells increases VEGF secretion. Valproic Acid (VPA) has been involved in anti-angiogenic processes, indeed it significantly inhibit the in vitro angiogenic potential and VEGF expression in human cervical cancer HeLa and SiHa cells. Considering these new data, we have developed compound (±)-MRJF22, a novel prodrug of haloperidol metabolite II obtained by conjugation to VPA via an ester bond. In vitro binding assays (±)-MRJF22 showed binding affinities towards σ1 and σ2 receptors in nanomolar range (Ki 13 and 124 nM, respectively) and exhibited antiangiogenic activity being able to reduce Human Retinal Endothelial Cells (HREC) viability and proliferation (IC50 = 10 μM). Moreover, (±)-MRJF22 was able to reduce significantly endothelial cell proliferation, migration and tube formation on Matrigel in VEGF-A- stimulated HREC, in a comparable manner to Bevacizumab. Based on our results, the prodrug (±)-MRJF22 could be a promising candidate for the development of a therapeutic strategy for the treatment of angiogenesis related diseases.