Study on the Mechanism of Action of the Pt(IV) Complex with Lonidamine Ligands by Ultrafast Chemical Proteomics

Abstract

Platinum(II) complexes such as cisplatin, among a few others, are well-known anticancer metal-based drugs approved for clinical use. In spite of their wide acceptance, the respective chemotherapy is associated with severe side effects and the ability of tumors to quickly develop resistance. To overcome these drawbacks, the novel strategy is considered, which is based on the use of platinum complexes with bioactive ligands attached to act in synergy with platinum and to further improve its pharmacological properties. Among the recently introduced multiaction prodrugs is the Pt(IV) complex with two lonidamine ligands, the latter selectively inhibiting hexokinase and, thus, glycolysis in cancer cells. While platinum-based multiaction prodrugs exhibit increased levels of activity toward cancer cells and, thus, are considered potent to overcome the resistance to cisplatin, there is a crucial need to uncover their mechanism of action by revealing all possibly affected processes and targets across the whole cellular proteome. These are challenging tasks in proteomics requiring high-throughput analysis of hundreds of samples for just a single drug-to-proteome system. In this work, we performed these analyses for 8-azaguanine and the experimental Pt(IV)-lonidamine complex applied to ovarian cancer cell line A2780 employing both mechanism- and compound-centric ultrafast chemical proteomics approaches. These approaches were based on protein expression analysis and thermal proteome profiling, respectively. Data obtained for the Pt(IV)-lonidamine complex revealed regulation of proteins involved in the glucose metabolic process associated with lonidamine, further supporting the multiaction mechanism of this prodrug action.