Anthracyclins Increase PUFAs: Potential Implications in ER Stress and Cell Death.

David Balgoma,Maria Kopsida,Femke Heindryckx,Hans Lennernäs,Mikael Hedeland,Fredrik Kullenberg,Carlemi Calitz

doi:10.3390/cells10051163

Abstract

Metabolic and personalized interventions in cancer treatment require a better understanding of the relationship between the induction of cell death and metabolism. Consequently, we treated three primary liver cancer cell lines with two anthracyclins (doxorubicin and idarubin) and studied the changes in the lipidome. We found that both anthracyclins in the three cell lines increased the levels of polyunsaturated fatty acids (PUFAs) and alkylacylglycerophosphoethanolamines (etherPEs) with PUFAs. As PUFAs and alkylacylglycerophospholipids with PUFAs are fundamental in lipid peroxidation during ferroptotic cell death, our results suggest supplementation with PUFAs and/or etherPEs with PUFAs as a potential general adjuvant of anthracyclins. In contrast, neither the markers of de novo lipogenesis nor cholesterol lipids presented the same trend in all cell lines and treatments. In agreement with previous research, this suggests that modulation of the metabolism of cholesterol could be considered a specific adjuvant of anthracyclins depending on the type of tumor and the individual. Finally, in agreement with previous research, we found a relationship across the different cell types between: (i) the change in endoplasmic reticulum (ER) stress, and (ii) the imbalance between PUFAs and cholesterol and saturated lipids. In the light of previous research, this imbalance partially explains the sensitivity to anthracyclins of the different cells. In conclusion, our results suggest that the modulation of different lipid metabolic pathways may be considered for generalized and personalized metabochemotherapies.

Highlights

All cancers are characterized by an inherent metabolic reprograming that promotes tumorigenesis by facilitating and enabling proliferation, metastasis, and resistance to therapies [1,2]
Anthracyclins induced a reduction in cell number higher than 50%, when compared with the vehicle
To the best of our knowledge, here, we showed, for the first time, that the upregulation of free polyunsaturated fatty acids (PUFAs) and etherPEs with PUFAs is a general trait of anthracyclins

Summary

Introduction

All cancers are characterized by an inherent metabolic reprograming that promotes tumorigenesis by facilitating and enabling proliferation, metastasis, and resistance to therapies [1,2]. The changes in the lipidome may affect the further internalization of the drug and the mechanism of action of the drug to induce cell death, in which endoplasmic reticulum (ER) stress plays a key role This interplay among anthracyclin uptake, the lipidome, and ER stress may partially explain the different sensitivity to anthracyclins in both cancerous and non-transformed cells (e.g., cardiomyocytes). The sensitivity is conditioned by the mechanism of cell death induced by anthracyclins, which depends on the cell type and drug concentration [10] Understanding this interplay in anthracyclin/lipidome/cell death might open the possibility to: (i) improve diagnosis by biomarkers of the tumor resistance to anthracyclins [11,12], and (ii) propose novel treatments that may potentiate and/or complement the metabolic transformations caused by anthracyclins to induce cell-death

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