title: Defined lipid analogues induce transient channels to facilitate drug-membrane traversal and circumvent cancer therapy resistance.
abstract: Design and efficacy of bioactive drugs is restricted by their (in)ability to traverse cellular membranes. Therapy resistance, a major cause of ineffective cancer treatment, is frequently due to suboptimal intracellular accumulation of the drug. We report a molecular mechanism that promotes trans-membrane movement of a stereotypical, widely used anti-cancer agent to counteract resistance. Well-defined lipid analogues adapt to the amphiphilic drug doxorubicin, when co-inserted into the cell membrane, and assemble a transient channel that rapidly facilitates the translocation of the drug onto the intracellular membrane leaflet. Molecular dynamic simulations unveiled the structure and dynamics of membrane channel assembly. We demonstrate that this principle successfully addresses multi-drug resistance of genetically engineered mouse breast cancer models. Our results illuminate the role of the plasma membrane in restricting the efficacy of established therapies and drug resistance - and provide a mechanism to overcome ineffectiveness of existing and candidate drugs.
authors.affiliation: The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Divisions of Biological Stress Responses, Amsterdam, The Netherlands.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: van Hell
authors.forename: Manuel N
authors.initials: MN
authors.lastname: Melo
authors.forename: Wim J
authors.initials: WJ
authors.lastname: van Blitterswijk
authors.forename: Dayana M
authors.initials: DM
authors.lastname: Gueth
authors.forename: Tanya M
authors.initials: TM
authors.lastname: Braumuller
authors.forename: Lilia R C
authors.initials: LR
authors.lastname: Pedrosa
authors.forename: Ji-Ying
authors.initials: JY
authors.lastname: Song
authors.forename: Siewert J
authors.initials: SJ
authors.lastname: Marrink
authors.forename: Gerben A
authors.initials: GA
authors.lastname: Koning
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
authors.forename: Marcel
authors.initials: M
authors.lastname: Verheij
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001692:Biological Transport; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics; D019008:Drug Resistance, Neoplasm; D005260:Female; D020404:Glycerophospholipids / Q000737:chemistry / Q000378:metabolism; D006028:Glycosphingolipids / Q000737:chemistry / Q000378:metabolism*; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008081:Liposomes; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D047368:Tumor Burden
chemical_list: D000970:Antineoplastic Agents; D020404:Glycerophospholipids; D006028:Glycosphingolipids; D008051:Lipid Bilayers; D008081:Liposomes; D004317:Doxorubicin