Antitumor alkylphospholipid analogs: A promising and growing family of synthetic cell membrane-targeting molecules for cancer treatment

Editorial.F.M.’s team is supported by grants from Ministerio de Economia y Competitividad of Spain (SAF2011-30518), Red Temática de Investigación Cooperativa en Cáncer, Instituto de Salud Carlos III, cofunded by the Fondo Europeo de Desarrollo Regional of the European Union (RD12/0036/0065), European Community’s Seventh Framework Programme FP7-2007-2013 (Grant HEALTHF2-2011-256986, PANACREAS), and Junta de Castilla y León (CSI221A12-2).Peer Reviewe

Biological activities, mechanisms of action and biomedical prospect of the antitumor ether phospholipid ET-18-OCH3 (edelfosine), a proapoptotic agent in tumor cells

The antitumor ether lipid ET-18-OCH3 (edelfosine) is the type of a new class of antineoplastic agents, synthetic analogues of lysophosphatidylcholine, that shows a high metabolic stability, does not interact with DNA and shows a selective apoptotic response in tumor cells, sparing normal cells. Unlike currently used antitumor drugs, ET-18-OCH3 does not act directly on the formation and function of the replication machinery, and thereby its effects are independent of the proliferative state of target cells. Because of its capacity to modulate cellular regulatory and signaling events, including those failing in cancer cells, like defective apoptosis, ET-18-OCH3, beyond its putative clinical importance, is an interesting model compound for the development of more selective drugs for cancer therapy. Although ET-18-OCḢ 3 enhances host defense mechanisms against tumors, its major antitumor action lies in a direct effect on cancer cells, inhibiting phosphatiḋylcholine bioṡynthesis and inducing apoptosis in tumor cells. Recent progress has allowed unravelinġ the molecular mechanism underlying the apoptotic action of ET-18-OCH3, leading to the notion that ET-18-OCH3 is selectively incorporated into tumor cells and induces cell death by intracellular activation of the cell death receptor Fas/CD95. This intracellular Fas/CD95 activation is a novel mechanism of action for an antitumor drug and represents a new way to target tumor cells in cancer chemotherapy that can be of interest as a new framework in designing novel antitumor drugs. ET-18-OCH3 and some analogues are pleiotropic agents that affect additional biomedical important diseases, including parasitic and autoimmune diseases, suggesting new therapeutic indications for these compounds.The work of the authors was supported by grant CDTI 97-0355 from INKEYSA and Ministerio de Industria y Energía of Spain, and grants 1FD97-2018-C02-01 and 1FD97-0622 from the European Commission and Comisión Interministerial de Ciencia y Tecnología of Spain.Peer Reviewe

Apoptosis en el desarrollo y terapia del Cáncer

Máster Universitario en Biología y Clínica del Cáncer: Programa, Objetivos y Metodología.Peer Reviewe

Organización y función de las subunidades de ATPasa Translocadora de protones (F1 - ATPasa) de micrococcus lysodeikticus : estudio inmunológico y bioquímico

Tesis-Universidad Complutense, 1.984.Depto. de Bioquímica y Biología MolecularFac. de Ciencias QuímicasTRUEProQuestpu

Involvement of raft aggregates enriched in Fas/CD95 death-inducing signaling complex in the antileukemic action of edelfosine in Jurkat cells

[Background]: Recent evidence suggests that co-clustering of Fas/CD95 death receptor and lipid rafts plays a major role in death receptor-mediated apoptosis. [Methodology/Principal Findings]: By a combination of genetic, biochemical, and ultrastructural approaches, we provide here compelling evidence for the involvement of lipid raft aggregates containing recruited Fas/CD95 death receptor, Fas-associated death domain-containing protein (FADD), and procaspase-8 in the induction of apoptosis in human T-cell leukemia Jurkat cells by the antitumor drug edelfosine, the prototype compound of a promising family of synthetic antitumor lipids named as synthetic alkyl-lysophospholipid analogues. Co-immunoprecipitation assays revealed that edelfosine induced the generation of the so-called death-inducing signaling complex (DISC), made up of Fas/CD95, FADD, and procaspase-8, in lipid rafts. Electron microscopy analyses allowed to visualize the formation of raft clusters and their co-localization with DISC components Fas/CD95, FADD, and procaspase-8 following edelfosine treatment of Jurkat cells. Silencing of Fas/CD95 by RNA interference, transfection with a FADD dominant-negative mutant that blocks Fas/CD95 signaling, and specific inhibition of caspase-8 prevented the apoptotic response triggered by edelfosine, hence demonstrating the functional role of DISC in drug-induced apoptosis. By using radioactive labeled edelfosine and a fluorescent analogue, we found that edelfosine accumulated in lipid rafts, forming edelfosine-rich membrane raft clusters in Jurkat leukemic T-cells. Disruption of these membrane raft domains abrogated drug uptake and drug-induced DISC assembly and apoptosis. Thus, edelfosine uptake into lipid rafts was critical for the onset of both co-aggregation of DISC in membrane rafts and subsequent apoptotic cell death. [Conclusions/Significance]: This work shows the involvement of DISC clusters in lipid raft aggregates as a supramolecular and physical entity responsible for the induction of apoptosis in leukemic cells by the antitumor drug edelfosine. Our data set a novel framework and paradigm in leukemia therapy, as well as in death receptor-mediated apoptosis.This work was supported by grants from Fondo de Investigacion Sanitaria and European Commission (FIS-FEDER 06/0813), Ministerio de Ciencia e Innovacion of Spain (SAF2008-02251 and RD06/0020/1037 - Red Tematica de Investigacion Cooperativa en Cancer, Instituto de Salud Carlos III), Junta de Castilla y Leon (CSI01A08, SAN673/SA32/08, and GR15 - Experimental Therapeutics and Translational Oncology Program), Fundacion “la Caixa” (BM05-30-0), and Fundacion de Investigacion Medica Mutua Madrilena (FMM). CG is supported by the Ramon y Cajal Program from the Ministerio de Ciencia e Innovacion of Spain.Peer Reviewe

Organización y función de las subunidades de ATPasa Translocadora de protones (F1 - ATPasa) de micrococcus lysodeikticus : estudio inmunológico y bioquímico

Tesis-Universidad Complutense, 1.984.Depto. de Bioquímica y Biología MolecularFac. de Ciencias QuímicasTRUEProQuestpu

Necroptosis is associated with low procaspase-8 and active RIPK1 and −3 in human glioma cells

This is an open-access article distributed under the terms of the Creative Commons Attribution License.Necroptosis is a regulated necrotic cell death that involves receptor-interacting protein kinases RIPK1 and RIPK3. Here, we report that edelfosine triggers a rapid and massive cell death in human glioblastoma cells with characteristics of necrosis. Only a minor proportion of edelfosine-treated cells underwent caspase-dependent apoptosis. Autophagy and a rapid influx of extracellular calcium into the cells had little impact on cell death. Levels of procaspase-8 were very low in necroptosis-prone glioma cells compared with the levels in other cancer cell types that underwent apoptosis upon edelfosine treatment. The RIPK1-dependent necroptosis inhibitors necrostatin-1 (Nec-1) and Nec-1s as well as siRNA-mediated silencing of RIPK3 inhibited edelfosine-induced necroptosis, resulting in increased caspase-dependent apoptosis in edelfosine-treated glioblastoma U118 cells. Inhibition of the RIPK3 substrate MLKL with necrosulfonamide also increased apoptosis in edelfosine-treated cells. These data support a major role for RIPK1 and RIPK3 in the induction of necrotic cell death and in the switch from necrosis to apoptosis following edelfosine treatment. These results indicate that the ether lipid edelfosine exerts a rapid necroptotic cell death in apoptosis-reluctant glioblastoma cells, suggesting that induction of necroptosis could constitute a new approach for glioblastoma therapy.This work was supported by grants from the Spanish Ministerio de Ciencia e Innovación (SAF2011-30518), Spanish Ministerio de Economía y Competitividad (RD12/0036/0065 from Red Temática de Investigación Cooperativa en Cáncer, Instituto de Salud Carlos III, cofunded by the Fondo Europeo de Desarrollo Regional of the European Union), Fundação para a Ciência e Tecnologia (SFRH/BD/46330/2008, Portuguese Ministério da Ciencia, Tecnología e Ensino Superior), European Community's Seventh Framework Programme FP7-2007-2013 (grant HEALTH-F2-2011-256986, PANACREAS), and Junta de Castilla y León (CSI052A11-2). S.M.-L. was recipient of a predoctoral fellowship from the Fundação para a Ciência e Tecnologia (Ministério da Ciencia, Tecnología e Ensino Superior of Portugal).Peer reviewe

Arginase activity and CD3ζ expression after major surgery

Letter.-- et al.The studies from our laboratory were supported by grants from Spanish Ministerio de Economia y Competitividad (SAF2011-30518; and RD12/0036/0065 from Red Temática de Investigación Cooperativa en Cáncer, Instituto de Salud Carlos III, cofunded by the Fondo Europeo de Desarrollo Regional of the European Union), the European Community’s Seventh Framework Programme FP7-2007-2013 (grant HEALTH-F2-2011-256986, PANACREAS), and Junta de Castilla y León (CSI052A11-2 and CSI221A12-2).Peer Reviewe

New indolesulfonamide derivatives targeting the colchicine site of tubulin: synthesis, anti-tumour activity, structure–activity relationships, and molecular modelling

Searching for improved indolesulfonamides with higher polarities, 45 new analogues with modifications on the sulfonamide nitrogen, the methoxyaniline, and/or the indole 3-position were synthesised. They show submicromolar to nanomolar antiproliferative IC50 values against four human tumour cell lines and they are not P-glycoprotein substrates as their potencies against HeLa cells did not improve upon cotreatment with multidrug resistance (MDR) inhibitors. The compounds inhibit tubulin polymerisation in vitro and in cells, thus causing a mitotic arrest followed by apoptosis as shown by cell cycle distribution studies. Molecular modelling studies indicate binding at the colchicine site. Methylated sulfonamides were more potent than those with large and polar substitutions. Amide, formyl, or nitrile groups at the indole 3-position provided drug-like properties for reduced toxicity, with Polar Surface Areas (PSA) above a desirable 75 Å2. Nitriles 15 and 16 are potent polar analogues and represent an interesting class of new antimitotics.This work was financially supported by the Consejería de Educación de la Junta de Castilla y León [SA262P18 and SA116P20], co-funded by the EU’s European Regional Development Fund-FEDER, and the Spanish Ministry of Science, Innovation, and Universities [RTI2018-099474-B-I00]