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

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.