Cationic amphiphilic drugs induce elevation in lysoglycerophospholipid levels and cell death in leukemia cells
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ORIGINAL ARTICLE
Cationic amphiphilic drugs induce elevation in lysoglycerophospholipid levels and cell death in leukemia cells Inger Ødum Nielsen1 · Line Groth‑Pedersen1 · Jano Dicroce‑Giacobini1 · Anna Sofie Holm Jonassen1 · Monika Mortensen1 · Mesut Bilgin1 · Kjeld Schmiegelow3,4 · Marja Jäättelä1,2 · Kenji Maeda1 Received: 12 June 2020 / Accepted: 10 August 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Introduction Repurposing of cationic amphiphilic drugs (CADs) emerges as an attractive therapeutic solution against various cancers, including leukemia. CADs target lysosomal lipid metabolism and preferentially kill cancer cells via induction of lysosomal membrane permeabilization, but the exact effects of CADs on the lysosomal lipid metabolism remain poorly illuminated. Objectives We aimed to systematically monitor CAD-induced alterations in the quantitative lipid profiles of leukemia cell lines in order to chart effects of CADs on the metabolism of various lipid classes present in these cells. Methods We conducted this study on eight cultured cell lines representing two leukemia types, acute lymphoblastic leukemia and acute myeloid leukemia. Mass spectrometry-based quantitative shotgun lipidomics was employed to quantify the levels of around 400 lipid species of 26 lipid classes in the leukemia cell lines treated or untreated with a CAD, siramesine. Results The two leukemia types displayed high, but variable sensitivities to CADs and distinct profiles of cellular lipids. Treatment with siramesine rapidly altered the levels of diverse lipid classes in both leukemia types. These included sphingolipid classes previously reported to play key roles in CAD-induced cell death, but also lipids of other categories. We demonstrated that the treatment with siramesine additionally elevated the levels of numerous cytolytic lysoglycerophospholipids in positive correlation with the sensitivity of individual leukemia cell lines to siramesine. Conclusions Our study shows that CAD treatment alters balance in the metabolism of glycerophospholipids, and proposes elevation in the levels of lysoglycerophospholipids as part of the mechanism leading to CAD-induced cell death of leukemia cells. Keywords Lipidomics · Cancer · Systems biology · Lysosomes · Lysoglycerophospholipids · Sphingolipids Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11306-020-01710-1) contains supplementary material, which is available to authorized users. * Marja Jäättelä [email protected] * Kenji Maeda [email protected] 1
Cell Death and Metabolism Unit, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center (DCRC), 2100 Copenhagen, Denmark
2
Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen, Denmark
3
Department of Paediatrics and Adolescent Medicine, Juliane Marie Centre, Rigshospitalet University Hospital, 2100 Copenhagen, Denmark
4
Institute of Clinical Medicine, Universit
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