New Insights Into Targeting Membrane Lipids for Cancer Therapy

Abstract

Modulation of membrane lipid composition and organization is currently developing as an effective therapeutic strategy against a wide range of diseases, including cancer. This field, known as membrane-lipid therapy, has risen from new discoveries on the complex organization of lipids and between lipids and proteins in the plasma membranes. Membrane microdomains present in the membrane of all eukaryotic cells, known as lipid rafts, have been recognized as an important concentrating platform for protein receptors involved in the regulation of intracellular signaling, apoptosis, redox balance and immune response. The difference in lipid composition between the cellular membranes of healthy cells and tumor cells allows for the development of novel therapies based on targeting membrane lipids in cancer cells to increase sensitivity to chemotherapeutic agents and consequently defeat multidrug resistance. In the current manuscript strategies based on influencing cholesterol/sphingolipids content will be presented together with innovative ones, more focused in changing biophysical properties of the membrane bilayer without affecting the composition of its constituents.

Keywords: amphiphilic molecules; cell signaling; lipid rafts; membrane fluidity; protein receptors.

FIGURE 1

Differences between membrane lipid composition and organization in normal vs MDR cancer cells. In cancer cells PS and PE, mainly confined in the inner leaflet of the membranes, are present in high concentrations in the outer leaflet. Cancer cells have also higher concentrations of cholesterol and consequently an increase in membrane thickness and rigidity is observed. Increased levels of saturated fatty acyl chains in membrane lipids have been associated to the presence of more lipid rafts while low amount of ceramide in MDR cells is a consequence of the low activity of SMase or of the increased SM levels. Changes in lipid composition of the outer membrane of cancer cells are also correlated to a more acidic extracellular pH.

FIGURE 2

Different rationales behind the use of statins in cancer therapy for modulation of membrane lipids. The beneficial effects of statins in cancer therapy are achieved by a combination of classical and pleiotropic effects. The classical cholesterol lowering activity decreases the cholesterol concentration in the plasma membrane influencing membrane fluidity and thickness. Pleiotropic effects include lipid rafts clustering and displacement of receptors in non-raft domains. All these effects contribute to an increase in apoptosis and in decrease in resistance of cancer cells to chemotherapeutic agents.