Centre Hospitalier Universitaire (CHU) de Québec Research Center, Faculty of Pharmacy and Université Laval Cancer Research Center, Université Laval, R4701.5, 2705 Blvd Laurier, Quebec, QC, G1V 4G2, Canada.
Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
Clin Exp Med. 2024 Jul 30;24(1):174. doi: 10.1007/s10238-024-01440-x.
Elevated levels of circulating C16:0 glucosylceramides (GluCer) and increased mRNA expression of UDP-glucose ceramide glycosyltransferase (UGCG), the enzyme responsible for converting ceramides (Cer) to GluCer, represent unfavorable prognostic markers in chronic lymphocytic leukemia (CLL) patients. To evaluate the therapeutic potential of inhibiting GluCer synthesis, we genetically repressed the UGCG pathway using in vitro models of leukemic B cells, in addition to UGCG pharmacological inhibition with approved drugs such as eliglustat and ibiglustat, both individually and in combination with ibrutinib, assessed in cell models and primary CLL patient cells. Cell viability, apoptosis, and proliferation were evaluated in vitro, and survival and apoptosis were examined ex vivo. UGCG inhibition efficacy was confirmed by quantifying intracellular sphingolipid levels through targeted lipidomics using mass spectrometry. Other inhibitors of sphingolipid biosynthesis pathways were similarly assessed. Blocking UGCG significantly decreased cell viability and proliferation, highlighting the oncogenic role of UGCG in CLL. The efficient inhibition of UGCG was confirmed by a significant reduction in GluCer intracellular levels. The combination of UGCG inhibitors with ibrutinib demonstrated synergistic effect. Inhibitors that target alternative pathways within sphingolipid metabolism, like sphingosine kinases inhibitor SKI-II, also demonstrated promising therapeutic effects both alone and when used in combination with ibrutinib, reinforcing the oncogenic impact of sphingolipids in CLL cells. Targeting sphingolipid metabolism, especially the UGCG pathway, represents a promising therapeutic strategy and as a combination therapy for potential treatment of CLL patients, warranting further investigation.
循环 C16:0 葡萄糖神经酰胺（GluCer）水平升高和 UDP-葡萄糖神经酰胺糖基转移酶（UGCG）的 mRNA 表达增加，UGCG 是将神经酰胺（Cer）转化为 GluCer 的酶，这代表慢性淋巴细胞白血病（CLL）患者预后不良的标志物。为了评估抑制 GluCer 合成的治疗潜力，我们使用白血病 B 细胞的体外模型遗传抑制 UGCG 途径，此外还使用已批准的药物（如 eliglustat 和 ibiglustat）抑制 UGCG ，单独和与伊布替尼联合使用，在细胞模型和原发性 CLL 患者细胞中进行评估。在体外评估细胞活力、凋亡和增殖，在体外评估存活和凋亡。通过使用靶向脂质组学和质谱法定量细胞内鞘脂水平来确认 UGCG 抑制效果。还评估了其他鞘脂生物合成途径的抑制剂。阻断 UGCG 可显著降低细胞活力和增殖，突出了 UGCG 在 CLL 中的致癌作用。通过 GluCer 细胞内水平的显著降低证实了 UGCG 的有效抑制。UGCG 抑制剂与伊布替尼的联合使用显示出协同作用。靶向鞘脂代谢替代途径的抑制剂，如鞘氨醇激酶抑制剂 SKI-II，单独使用和与伊布替尼联合使用时也显示出有希望的治疗效果，这进一步证实了鞘脂在 CLL 细胞中的致癌作用。靶向鞘脂代谢，特别是 UGCG 途径，代表了一种有前途的治疗策略，并且作为联合治疗方案可能适用于 CLL 患者，值得进一步研究。
