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.

中文翻译：

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阳离子两亲性药物可引起溶血甘油磷脂水平升高和白血病细胞死亡。

介绍

阳离子两亲药物（CAD）的重新利用作为一种有吸引力的治疗方法，针对各种癌症（包括白血病）出现。CADs靶向溶酶体脂质代谢，并通过诱导溶酶体膜通透性优先杀伤癌细胞，但CADs对溶酶体脂质代谢的确切作用仍知之甚少。

目标

我们旨在系统地监测CAD诱导的白血病细胞系定量脂质谱中的变化，以便绘制CAD对这些细胞中存在的各种脂质类别的代谢的影响。

方法

我们对代表两种白血病（急性淋巴细胞白血病和急性髓细胞白血病）的八种培养细胞系进行了这项研究。基于质谱的定量shot弹枪脂质组学被用于量化在用CAD，西拉美辛治疗或未治疗的白血病细胞系中约26种脂质类别的约400种脂质种类的水平。

结果

两种白血病类型显示出对CAD的高但敏感的可变性和细胞脂质的不同特征。在两种白血病类型中，西拉美新治疗迅速改变了不同脂质类别的水平。这些包括以前据报道在CAD诱导的细胞死亡中起关键作用的鞘脂类，还有其他类别的脂质。我们证明了用西拉美新的治疗还提高了许多细胞溶解的溶血甘油糖脂的水平，与单个白血病细胞系对西拉美新的敏感性呈正相关。

结论

我们的研究表明，CAD治疗可改变甘油磷脂代谢的平衡，并提出溶血甘油磷脂水平的升高是导致CAD诱导白血病细胞死亡的机制的一部分。