Cisplatin-Membrane Interactions and Their Influence on Platinum Complexes Activity and Toxicity

Abstract

Cisplatin and other platinum(II) analogs are widely used in clinical practice as anti-cancer drugs for a wide range of tumors. The primary mechanism by which they exert their action is through the formation of adducts with genomic DNA. However, multiple cellular targets by platinum(II) complexes have been described. In particular, the early events occurring at the plasma membrane (PM), i.e., platinum-membrane interactions seem to be involved in the uptake, cytotoxicity and cell-resistance to cisplatin. In fact, PM influences signaling events, and cisplatin-induced changes on membrane organization and fluidity were shown to activate apoptotic pathways. This review critically discusses the sequence of events caused by lipid membrane-platinum interactions, with emphasis on the mechanisms that lead to changes in the biophysical properties of the membranes (e.g., fluidity and permeability), and how these correlate with sensitivity and resistance phenotypes of cells to platinum(II) complexes.

Keywords: chemotherapeutic; cisplatin mechanism of action; membrane biophysical properties; membrane fluidity; membrane interactions; membrane permeability; sphingolipids.

FIGURE 1

General mechanisms of interaction between platinum(II) complexes with cells. Different forms of platinum(II) complexes interact at different depths of the lipid membrane, which also influences their ability to permeate the cell membrane. Once inside the cell, platinum(II) complexes promote a cascade of events that lead to cell death or resistance mechanisms to platinum(II) complexes. These mechanisms are described in detail in the text.

FIGURE 2

Molecular chemical structure of several platinum(II) compounds studied for interaction with lipid membranes.

FIGURE 3

Cisplatin equilibrium in aqueous medium where it exchanges chloride with hydroxyls and water to form the so called aquated species. [Scheme was redrawn based on reference (Boot et al., 2018)].

FIGURE 4

Interaction of cisplatin with DOPS and with two DPPC lipids. In the DPPC interaction it was observed further changes in the glycerol group that altered the common gauche configurations to a trans configuration. [Scheme was redrawn based on references (Suwalsky et al., 2000; Beretta et al., 2002)].