title: Caenorhabditis elegans as a platform to study the mechanism of action of synthetic antitumor lipids.
abstract: Drugs capable of specifically recognizing and killing cancer cells while sparing healthy cells are of great interest in anti-cancer therapy. An example of such a drug is edelfosine, the prototype molecule of a family of synthetic lipids collectively known as antitumor lipids (ATLs). A better understanding of the selectivity and the mechanism of action of these compounds would lead to better anticancer treatments. Using Caenorhabditis elegans, we modeled key features of the ATL selectivity against cancer cells. Edelfosine induced a selective and direct killing action on C. elegans embryos, which was dependent on cholesterol, without affecting adult worms and larvae. Distinct ATLs ranked differently in their embryonic lethal effect with edelfosine > perifosine > erucylphosphocholine >> miltefosine. Following a biased screening of 57 C. elegans mutants we found that inactivation of components of the insulin/IGF-1 signaling pathway led to resistance against the ATL edelfosine in both C. elegans and human tumor cells. This paper shows that C. elegans can be used as a rapid platform to facilitate ATL research and to further understand the mechanism of action of edelfosine and other synthetic ATLs.
authors.affiliation: a Instituto de Biología Molecular y Celular del Cáncer ; Centro de Investigación del Cáncer ; CSIC-Universidad de Salamanca ; Campus Miguel de Unamuno ; Salamanca , Spain.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Sánchez-Blanco
authors.forename: Alberto G
authors.initials: AG
authors.lastname: Rodríguez-Matellán
authors.forename: Mariana
authors.initials: M
authors.lastname: Reis-Sobreiro
authors.forename: Beatriz
authors.initials: B
authors.lastname: Sáenz-Narciso
authors.forename: Juan
authors.initials: J
authors.lastname: Cabello
authors.forename: William A
authors.initials: WA
authors.lastname: Mohler
authors.forename: Faustino
authors.initials: F
authors.lastname: Mollinedo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D017173:Caenorhabditis elegans / Q000254:growth & development / Q000378:metabolism; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism; D004351:Drug Resistance; D004625:Embryo, Nonmammalian / Q000187:drug effects*; D047108:Embryonic Development / Q000187:drug effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007814:Larva / Q000187:drug effects; D021962:Membrane Microdomains / Q000378:metabolism; D010742:Phospholipid Ethers / Q000494:pharmacology; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D010742:Phospholipid Ethers; D010767:Phosphorylcholine; C075010:erucylphosphocholine; C026659:edelfosine; C105905:perifosine; C039128:miltefosine; D007334:Insulin-Like Growth Factor I; D002784:Cholesterol
keywords: APL, alkylphospholipid analog; ATL, antitumor lipid; DIC, differential interference contrast; IIS, insulin/IGF-1-like signaling; MCD, methyl-β-cyclodextrin; NGM, nematode growth medium; Caenorhabditis elegans; alkylphospholipid analogs; antitumor lipids; cholesterol; edelfosine; embryo; insulin/IGF-1 signaling; mechanism of action; miltefosine; tumor cell