Interacción de compuestos antitumorales con membranas lipídicassu impacto en la terapia del cáncer

Abstract

Cancer is one of the main causes of death worldwide, and the global number of cancer patients will increase significantly in the coming years. Chemotherapy, one of the most important cancer treatments, uses chemical compounds to decrease the number of cancer cells or destroy them, but unfortunately it also affects normal tissues causing harmful side effects. Antitumor drugs, although they have different mechanisms of action, must cross cell membranes to produce their effects. The interactions of antitumor drugs with the membrane can affect its composition and function, hence understanding the mechanism of these interactions represents a research field of basic interest as it is directly related to pharmacological activity. There is evidence of the participation of lipids in the regulation of the activity of membrane proteins and cell function, and therapies based on the regulation of the structure of membrane lipids have been proposed in order to control the molecular events that are produced during the cancerous process. From this perspective, the interaction of antitumor agents with the membrane acquires fundamental importance. Docetaxel (DTX) is an anticarcinogenic taxane that is used in the treatment of a wide spectrum of cancer types and causes serious side effects. Tea catechins have shown various beneficial effects on cancer in humans. Trimethoxybenzoate of catechin (TMBC) is a semisynthetic analog that has shown high antiproliferative activity against melanoma and breast cancer cells. Objectives and methodology In this doctoral thesis, the interaction of the antitumor agents DTX and TMBC with lipid bilayers formed by important membrane phospholipids (phosphatidylcholine, phosphatidylserine, phosphatidylglycerol and phosphatidylethanolamine) is studied at the molecular level. The general objective is to determine the alteration that these antitumor agents produce in the structural properties of the membrane, in order to understand the relationship between these interactions and their mechanisms of action. Biomimetic membranes were used, and biophysical techniques like differential scanning calorimetry, X-ray diffraction, infrared spectroscopy, and fluorescence polarization were applied, along with molecular dynamics simulations. Results and conclusions DTX is poorly miscible in phosphatidylcholine membranes, this antitumor agent increases bilayer thickness, dehydrates the aqueous interface, and aggregates in the middle of the lipid palisade approaching the interfacial zone. TMBC readily incorporates into phosphatidylserine, phosphatidylglycerol, and phosphatidylethanolamine membranes, it produces a decrease in bilayer thickness and an increase in the number of hydrogen bonds at the aqueous interface. TMBC induces interdigitation in gel-phase phosphatidylserine membranes and localizes mostly in the phospholipid palisade as monomers. In phosphatidylglycerol membranes, TMBC is immiscible both in the gel phase and in the fluid phase, and it is preferentially organized in aggregates. In phosphatidylethanolamine membranes, TMBC promotes the formation of gel phase immiscibility, and stabilizes the liquid crystalline phase by blocking the formation of non-lamellar structures. TMBC localizes at the top of the lipid palisade forming small clusters that affect the lateral pressure profile of the phosphatidylethanolamine membrane. The two antitumor agents perturb the physical properties of the membrane and cause important disturbances that could alter its function. These results support the hypothesis that antitumor drugs, in addition to having specific effects on specific cellular targets, may also have nonspecific effects caused by their interaction with the membrane, the consequences of which will depend on the composition and organization of the lipids and the proteins present in the membrane of individual cells. These results help to understand the interrelationship between the antitumor agents-membrane interaction and their anticarcinogenic actions and other biological activities, both toxic and beneficial.