Alkylphospholipids: An update on molecular mechanisms and clinical relevance
| Autor: | María P. Carrasco, Pablo Ríos-Marco, Xiomara Galvez, Carmen Marco, José M. Jiménez-López |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cell Biophysics Phospholipid Antineoplastic Agents Biology Biochemistry Cell membrane 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Biosynthesis immune system diseases Autophagy medicine Humans neoplasms Phospholipids Phosphocholine Leishmania Cholesterol Cell Membrane Lipid metabolism Cell Biology Cell biology 030104 developmental biology medicine.anatomical_structure chemistry 030220 oncology & carcinogenesis lipids (amino acids peptides and proteins) Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Biomembranes. 1859:1657-1667 |
| ISSN: | 0005-2736 |
| Popis: | Alkylphospholipids (APLs) represent a new class of drugs which do not interact directly with DNA but act on the cell membrane where they accumulate and interfere with lipid metabolism and signalling pathways. This review summarizes the mode of action at the molecular level of these compounds. In this sense, a diversity of mechanisms has been suggested to explain the actions of clinically-relevant APLs, in particular, in cancer treatment. One consistently reported finding is that APLs reduce the biosynthesis of phosphatidylcholine (PC) by inhibiting the rate-limiting enzyme CTP:phosphocholine cytidylyltransferase (CT). APLs also alter intracellular cholesterol traffic and metabolism in human tumour-cell lines, leading to an accumulation of cholesterol inside the cell. An increase in cholesterol biosynthesis associated with a decrease in the synthesis of choline-containing phospholipids and cholesterol esterification leads to a change in the free-cholesterol:PC ratio in cells exposed to APLs. Akt phosphorylation status after APL exposure shows that this critical regulator for cell survival is modulated by changes in cholesterol levels induced in the plasma membrane by these lipid analogues. Furthermore, APLs produce cell ultrastructural alterations with an abundant autophagic vesicles and autolysosomes in treated cells, indicating an interference of autophagy process after APL exposure. Thus, antitumoural APLs interfere with the proliferation of tumour cells via a complex mechanism involving phospholipid and cholesterol metabolism, interfere with lipid-dependent survival-signalling pathways and autophagy. Although APLs also exert antiparasitic, antibacterial, and antifungal effects, in this review we provide a summary of the antileishmanial activity of these lipid analogues. This article is part of a Special Issue entitled: Membrane Lipid Therapy: Drugs Targeting Biomembranes edited by Pablo V. Escribá. |
| Databáze: | OpenAIRE |
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