Abstract 6375: Development of novel Pt-based drugs using Deferasirox as ligand to diminish systemic toxicity and resistance induced by CisPt

Today, CisPt is one of the most successful chemotherapeutic metallodrugs. Unfortunately, the use of CisPt is restricted by the dose-limiting toxic effects and the acquired resistance, especially in lung cancer. As an alternatively, FDA-approved drugs for different diseases which target cancer metabolic pathways, are considered an attractive strategy to diminish systemic toxic effects. In the same way, the mechanistic pathways activated/inactivated by this drug could potentially overcome the acquired resistance induced by CisPt. For this reason in our approach, we incorporated deferasirox (Def), a clinical drug for iron (Fe) overload, as the ligand in the development of novel Pt complexes. In cancer progression, Fe plays a key role as a nutrient for cell growth and energy production. In consequence, we have synthesized and characterized our first library of three Pt-Def complexes: Pt(Def-COOH), Pt(Def-CONH2), Pt(Def-COOCH3). In this strategy, we have modified the OH of the carboxylic group of the Def to see the effects in the metabolic pathways. Viability assay results showed that Pt(Def-CONH2) induced a dramatic decrease in the IC50 in non-small lung adenocarcinoma cells after 24 h of incubation compared to CisPt, Def and Def-CONH2. Gene expression studies were conducted for cell growth, resistance and metastases related genes, where Pt(Def-CONH2) showed a significant downregulation of all of them. In addition, insight into target sites and metabolic pathways (apoptosis, caspase 3, ROS, cell cycle) inhibited or activated was garnered. This study will afford the optimization of the rationale to fine tune the structure of novel potential drugs. Citation Format: Yamixa Delgado, Mallesh Pandrala, Daraishka Perez, Eddian Velazquez, Jaisy Vega, Melissa Milian, Anamaris Torres. Development of novel Pt-based drugs using Deferasirox as ligand to diminish systemic toxicity and resistance induced by CisPt [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6375.