Lysosomotropic agents selectively target chronic lymphocytic leukemia cells due to altered sphingolipid metabolism

Abstract

Lysosome membrane permeabilization (LMP) mediates cell death in a variety of cancer cells. However, little is known about lysosomes and LMP in chronic lymphocytic leukemia (CLL). Owing to drug resistance and toxicity in CLL patients, better treatment strategies are required. Our results show that CLL cells were sensitive to the lysosomotropic agent siramesine. Furthermore, this drug was more effective in CLL cells, regardless of prognostic factors, compared with normal B cells. Siramesine caused LMP, lipid peroxidation and transcription factor EB nuclear translocation followed by mitochondrial membrane potential loss and reactive oxygen species release. Siramesine-induced cell death was blocked by lipid antioxidants, but not by soluble antioxidants or protease inhibitors. To determine whether CLL cells had altered lysosomes, we investigated sphingolipid metabolism as the lysosome is a hub for lipid metabolism. We found that CLL cells had more lysosomes, increased sphingosine-1-phosphate phosphatase 1 (SPP1) expression, and increased levels of sphingosine compared with normal B cells. Raising sphingosine levels increased LMP and cell death in CLL cells, but not in normal B cells. Together, these results show that excess sphingosine in CLL cells could contribute to their sensitivity toward LMP. Thus, targeting the lysosome could be a novel therapeutic strategy in CLL.

Lysosomes as Oxidative Targets for Cancer Therapy

“…Cell death can be mediated by the reactive oxygen species (ROS) and/or lysosomal cathepsins [3, 4, 26]. In addition, sphingolipids can contribute to LMP [27]. Sphingosine has been shown to induce LMP when added to cells [27].…”

“…In addition, sphingolipids can contribute to LMP [27]. Sphingosine has been shown to induce LMP when added to cells [27]. Upon TNF α , radiation, and DNA-damaging drug treatments, p53 is phosphorylated and translocates to lysosomes where it induces LMP [5].…”

Typical and Atypical Inducers of Lysosomal Cell Death: A Promising Anticancer Strategy

“…Application of siramesine seems attractive from a therapeutic perspective since it preferentially targets cancer cells [1]. A recent study revealed that siramesine selectively kills leukemic cells as compared to healthy B-cells [17]. Siramesine has also been tested in combination with other drugs, showing synergism in combination with vincristine [25] and lapatinib [41].…”

“…Siramesine has also been tested in combination with other drugs, showing synergism in combination with vincristine [25] and lapatinib [41]. Likewise, LCD has been also observed with other CADs, including antidepressant desipramine, which showed efficacy in CLL [17]. Altogether, it should be noted that CADs hold great potential since most of them are already applied in the clinical setting and have a well-characterized safety and pharmacokinetic profile.…”

“…Another example of altered sphingolipid content in lysosomes has been reported in chronic lymphocytic leukemia (CLL). Compared to healthy B-lymphocytes, elevated levels of sphingosine render CLL cells more prone to lysosome perturbation [17]. Sphingosine can also be converted by two sphingosine-kinase isoforms (SPHK1 and SPHK2) to form sphingosine-1-phosphate, which generally exerts antiapoptotic and prosurvival properties [18].…”