Multi-Acting Mitochondria-Targeted Platinum(IV) Prodrugs of Kiteplatin with α-Lipoic Acid in the Axial Positions.

Salvatore Savino,Giovanni Natile,Valentina Gandin,James Hoeschele,Nicola Margiotta,Cristina Marzano

doi:10.3390/ijms19072050

Abstract

Platinum(II) drugs are activated intracellularly by aquation of the leaving groups and then bind to DNA, forming DNA adducts capable to activate various signal-transduction pathways. Mostly explored in recent years are Pt(IV) complexes which allow the presence of two additional ligands in the axial positions suitable for the attachment of other cancer-targeting ligands. Here we have extended this strategy by coordinating in the axial positions of kiteplatin ([PtCl2(cis-1,4-DACH)], DACH = Diaminocyclohexane) and its CBDCA (1,1-cyclobutanedicarboxylate) analogue the antioxidant α-Lipoic acid (ALA), an inhibitor of the mitochondrial pyruvate dehydrogenase kinase (PDK). The new compounds (cis,trans,cis-[Pt(CBDCA)(ALA)2(cis-1,4-DACH)], 2, and cis,trans,cis-[PtCl2(ALA)2(cis-1,4-DACH)], 3), after intracellular reduction, release the precursor Pt(II) species and two molecules of ALA. The Pt residue is able to target DNA, while ALA could act on mitochondria as activator of the pyruvate dehydrogenase complex, thus suppressing anaerobic glycolysis. Compounds 2 and 3 were tested in vitro on a panel of five human cancer cell lines and compared to cisplatin, oxaliplatin, and kiteplatin. They proved to be much more effective than the reference compounds, with complex 3 most effective in 3D spheroid tumor cultures. Notably, treatment of human A431 carcinoma cells with 2 and 3 did not determine increase of cellular ROS (usually correlated to inhibition of mitochondrial PDK) and did not induce a significant depolarization of the mitochondrial membrane or alteration of other morphological mitochondrial parameters.

Highlights

IntroductionIt is well known that numerous cancer cells preferentially convert glucose to lactate, even in the presence of oxygen (aerobic glycolysis), for the generation of ATP
It is well known that numerous cancer cells preferentially convert glucose to lactate, even in the presence of oxygen, for the generation of ATP
The Pt residue is able to target DNA, while antioxidant α-Lipoic acid (ALA) could act on mitochondria as activator of the pyruvate dehydrogenase complex, suppressing anaerobic glycolysis

Summary

Introduction

It is well known that numerous cancer cells preferentially convert glucose to lactate, even in the presence of oxygen (aerobic glycolysis), for the generation of ATP. Aerobic glycolysis is not very efficient from an energetical point of view since it leads to the production of only two molecules of ATP per molecule of glucose while the complete oxidation of glucose to carbon dioxide and water produces 32 molecules of ATP. For this reason, cancer cells need huge amounts of glucose to satisfy their high demand of energy, but, at the same time, they are able to adapt to hypoxic conditions. DCA works to counteract the increased production of lactate exhibited by tumor cells (anaerobic respiration) by activating the pathway to pull the intermediates into the citric acid cycle and finish off with oxidative phosphorylation (aerobic respiration) [3]

Methods

Results

Conclusion