A proteomic approach to investigate the mechanism of action of anticancer peptides

Many efforts to improve survival of patients affected by Ovarian Cancer (OC) have focused on more effective systemic therapies and on the search for new therapeutic targets. One of the molecular targets for OC is human Thymidylate Synthase (hTS), a homodimeric enzyme essential for DNA biosynthesis. The main goal of our research is to identify compounds able to inhibit hTS by interfering with its dimerization, without causing its over-expression and the onset of cellular drug resistance against the traditional hTStargeted compounds. We have recently discovered some peptides which specifically target the hTS dimer interface and inhibit the enzyme by stabilizing its di-inactive form [1]. These molecules have been recently investigated for their SAR profile. LR, our lead compound, inhibits the intracellular enzyme in both cisplatin (cDDP)-sensitive and -resistant ovarian cancer cells without causing protein overexpression, thus showing a potential for overcoming the limits of OC chemotherapy. This work aims at setting up a proteomic approach able to provide information on the changes in the protein expression profile induced in OC cells by treatment with LR with respect to a well-known folate antimetabolite, Pemetrexed (PTX) and identify key proteins that are involved in its mechanism of action.