Cationic amphiphilic drugs induce elevation in lysoglycerophospholipid levels and cell death in leukemia cells
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Standard
Cationic amphiphilic drugs induce elevation in lysoglycerophospholipid levels and cell death in leukemia cells. / Nielsen, Inger Ødum; Groth-Pedersen, Line; Dicroce-Giacobini, Jano; Jonassen, Anna Sofie Holm; Mortensen, Monika; Bilgin, Mesut; Schmiegelow, Kjeld; Jäättelä, Marja; Maeda, Kenji.
I: Metabolomics, Bind 16, Nr. 9, 91, 2020.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Cationic amphiphilic drugs induce elevation in lysoglycerophospholipid levels and cell death in leukemia cells
AU - Nielsen, Inger Ødum
AU - Groth-Pedersen, Line
AU - Dicroce-Giacobini, Jano
AU - Jonassen, Anna Sofie Holm
AU - Mortensen, Monika
AU - Bilgin, Mesut
AU - Schmiegelow, Kjeld
AU - Jäättelä, Marja
AU - Maeda, Kenji
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - Cancer
KW - Lipidomics
KW - Lysoglycerophospholipids
KW - Lysosomes
KW - Sphingolipids
KW - Systems biology
U2 - 10.1007/s11306-020-01710-1
DO - 10.1007/s11306-020-01710-1
M3 - Journal article
C2 - 32851548
AN - SCOPUS:85089853209
VL - 16
JO - Metabolomics
JF - Metabolomics
SN - 1573-3882
IS - 9
M1 - 91
ER -
ID: 249106275