Pharmacology

Biography

Biography: Gisele Monteiro

Abstract

Carboplatin is a derivative of cisplatin, characterized by its ability to generate DNA lesions through the formation of adducts with platinum. Carboplatin was approved by the FDA in the 1980s and since then it has been widely used in the treatment of several types of tumors. In 2008, Hillenmeyeret al. published a wide toxicogenomic study of the yeast Saccharomyces cerevisiae, characterizing the fitness defect of this model cell when challenged against a large library of different chemical agents, including carboplatin. Using the results of this study as a preliminary guide, 53 yeast mutant strains from the Yeast Knockout (YKO) collection were selected and analyzed individually regarding their cell viability and growth ratio when carboplatin was present in the culture media. Thirty-four mutant strains were responsive to carboplatin treatment; among them 21 possess 88 human homolog genes. Focusing on the function of these human homologs, results showed an enrichment of proteins undertaking a physical interaction with cullins 1, 2 and 3 or regulated by HuR (ELAV1). Cullins are proteins that need to undertake a post-translation modification called NEDDylation to be active. Recent works have demonstrated that NEDDylation of HuR leads to its stabilization.HuR is a predictive marker of gemcitabine response and it has recently been demonstrated that cells treated with carboplatin possess an accumulation of cytoplasmic HuR. Additionally, inhibition of this pathway overcomes cisplatin resistance.The results suggest that HuR and cullins are involved in the cell response to carboplatinthrough theNEDDylation pathway. Upcoming experimentation with a NEDDylation inhibitor will be carried out on a human ovarian cancer cell line to further test this hypothesis.