Modulators of cellular cholesterol homeostasis as antiproliferative and model membranes perturbing agents

Cholesterol is an important component of mammalian cell membranes affecting their fluidity and permeability. Together with sphingomyelin, cholesterol forms microdomains, called lipid rafts. They play important role in signal transduction forming platforms for interaction of signal proteins. Altered levels of cholesterol are known to be strongly associated with the development of various pathologies (e.g., cancer, atherosclerosis and cardio-vascular diseases). In the present work, the group of compounds that share the property of affecting cellular homeostasis of cholesterol was studied. It contained antipsychotic and antidepressant drugs, as well as the in-hibitors of cholesterol biosynthesis, simvastatin, betulin, and its derivatives. All compounds were demonstrated to be cytotoxic to colon cancer cells but not to non-cancerous cells. Moreover, the most active compounds decreased the level of free cellular cholesterol. The interaction of drugs with raft-mimicking model membranes was visualized. All compounds reduced the size of lipid domains, however, only some affected their number and shape. Membrane interactions of betulin and its novel derivatives were characterized in detail. Molecular modeling indicated that high dipole moment and significant lipophilicity were characteristic for the most potent antiproliferative agents. The importance of membrane interactions of cholesterol homeostasis-affecting com-pounds, especially betulin derivatives, for their anticancer potency was suggested.

Automated summary

Cholesterol is an important component of mammalian cell membranes, and together with sphingomyelin, it forms lipid rafts, which play a role in signal transduction. Altered cholesterol levels are associated with various diseases. This study investigated compounds that affect cellular cholesterol homeostasis. These compounds were found to be cytotoxic to colon cancer cells and decreased cellular cholesterol levels. The interaction of these compounds with model membranes was visualized, and certain compounds were found to affect the size and shape of lipid domains. The importance of membrane interactions for the anticancer potency of these compounds, especially betulin derivatives, was suggested.