Alkylphospholipids: An update on molecular mechanisms and clinical relevance

Abstract

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.

Erufosine (ErPC3) Cationic Prodrugs as Dual Gene Delivery Reagents for Combined Antitumor Therapy

“…Alkylphospholipids are membrane‐active compounds that can disrupt phospholipid bilayers. They can thus interfere with biological membranes, delimitating the cellular and intracellular compartments, which makes them key players in various membrane signaling pathways involved in carcinogenesis . In the absence of serum, the lytic concentration for different APLs has been shown to reflect their critical micellar concentration (CMC), which are in the low μ m range .…”

“…The intrinsic cytotoxicity of APLs is not strictly related to their ability to permeabilize membranes and lyse cells. It is widely assumed that, at pharmacologically relevant concentration, APLs insert into the cell membrane, provoking a biophysical disturbance through altered cholesterol homeostasis, and perturbing various signal transduction pathways . To estimate the antiproliferative potency of the pro‐erufosine compounds, a dose‐response study was conducted in three human pulmonary cell lines: A549 (alveolar carcinoma epithelial cells), H292 (carcinoma mucoepidermoid cells), and 16HBE (bronchial epithelial cells).…”

Potencial antitumoral da formulação lipossomal DODAC/fosfoetanolamina sintética no modelo de hepatocarcinoma

“…Os AFTs têm surgido como novos agentes antitumorais promissores, os quais apresentam propriedades antiproliferativas e não possuem como alvo o DNA, mas atuam modificando o turnover na membrana celular e induzindo morte por apoptose, com alta seletividade para as células tumorais (Ríos-Marco et al, 2011;Marco et al, 2014 Marco et al, 2014;Ríos-Marco et al, 2017).…”

“…Entre estes análogos sintéticos, o 1-octadecil-2-metilfosforilcolina (ET-18-OCH3; edelfosina) demonstrou ser um composto com ampla atividade antitumoral, tornando-se rapidamente o principal protótipo da classe para a elaboração de novos éteres derivados. A principal aplicação da edelfosina, na prática clínica, é no tratamento de leucemias agudas, tanto mieloides quanto linfoides, nas quais a sua utilização promove apoptose das células leucêmicas (Vogler et al, 1996;Mollinedo et al, 2010;Van Blitterswijk e Verheij, 2013;Ríos-Marco et al, 2017 (Giantonio et al, 2004;Busto et al, 2007;Ríos-Marco et al, 2011;Ríos-Marco et al, 2017 Muñoz-Martínez et al, 2008;Ríos-Marco et al, 2017). Dessa maneira, pelo menos dois mecanismos diferentes são relatados para a internalização dos AFTs; contudo, mais estudos estão sendo conduzidos para elucidar este processo (Ríos-Marco et al, 2017).…”

“…Detmar et al (1994) sugeriram que os efeitos antiproliferativos da miltelfosina estão relacionados com a inibição da biossíntese da fosfatidilcolina (PC), mediada pela inativação da enzima chave neste processo, a CTP (fosfocolina citidiltransferase), levando a translocação desta enzima das membranas para o citosol, onde ela encontra-se inativa. Estudos mais recentes demonstraram que a mitelfosina causa uma redução na biossíntese de PC por alterar a atividade da CTP Ríos-Marco et al, 2011;Marco et al, 2014;Ríos-Marco et al, 2017).…”