Analytical Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden.
Translational Drug Development and Discovery, Department of Pharmaceutical Biosciences, Uppsala University, 751 23 Uppsala, Sweden.
Cells. 2021 May 11;10(5):1163. doi: 10.3390/cells10051163.
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.
代谢和个性化干预癌症治疗需要更好地理解细胞死亡和代谢之间的关系。因此，我们用两种蒽环类抗生素（阿霉素和伊达比星）处理三种原发性肝癌细胞系，并研究了脂质组的变化。我们发现两种蒽环类抗生素在三种细胞系中均增加了多不饱和脂肪酸（PUFA）和烷基酰基甘油磷酸乙醇胺（醚 PE）的水平，其中 PUFAs 存在于烷基酰基甘油磷酸乙醇胺中。由于 PUFAs 和烷基酰基甘油磷脂中的 PUFAs 在铁死亡过程中脂质过氧化中是基本的，我们的结果表明补充 PUFAs 和/或含有 PUFAs 的醚 PE 作为蒽环类抗生素的潜在一般佐剂。相比之下，在所有细胞系和处理中，新生脂质合成的标记物和胆固醇脂质都没有呈现出相同的趋势。与之前的研究一致，这表明胆固醇代谢的调节可以被认为是蒽环类抗生素的特定佐剂，具体取决于肿瘤类型和个体。最后，与之前的研究一致，我们在不同细胞类型之间发现了内质网（ER）应激的变化与 PUFAs 与胆固醇和饱和脂质之间的不平衡之间的关系。根据之前的研究，这种不平衡部分解释了不同细胞对蒽环类抗生素的敏感性。总之，我们的结果表明，不同脂质代谢途径的调节可以被考虑用于广义和个性化的代谢化疗。
