Institute of Hematology and Blood Transfusion, Prague, Czech Republic; Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic.
Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
Mol Metab. 2024 Oct;88:102016. doi: 10.1016/j.molmet.2024.102016. Epub 2024 Aug 23.
A prominent, safe and efficient therapy for patients with chronic myeloid leukemia (CML) is inhibiting oncogenic protein BCR::ABL1 in a targeted manner with imatinib, a tyrosine kinase inhibitor. A substantial part of patients treated with imatinib report skeletomuscular adverse events affecting their quality of life. OCTN2 membrane transporter is involved in imatinib transportation into the cells. At the same time, the crucial physiological role of OCTN2 is cellular uptake of carnitine which is an essential co-factor for the mitochondrial β-oxidation pathway. This work investigates the impact of imatinib treatment on carnitine intake and energy metabolism of muscle cells.
HTB-153 (human rhabdomyosarcoma) cell line and KCL-22 (CML cell line) were used to study the impact of imatinib treatment on intracellular levels of carnitine and vice versa. The energy metabolism changes in cells treated by imatinib were quantified and compared to changes in cells exposed to highly specific OCTN2 inhibitor vinorelbine. Mouse models were used to test whether in vitro observations are also achieved in vivo in thigh muscle tissue. The analytes of interest were quantified using a Prominence HPLC system coupled with a tandem mass spectrometer.
This work showed that through the carnitine-specific transporter OCTN2, imatinib and carnitine intake competed unequally and intracellular carnitine concentrations were significantly reduced. In contrast, carnitine preincubation did not influence imatinib cell intake or interfere with leukemia cell targeting. Blocking the intracellular supply of carnitine with imatinib significantly reduced the production of most Krebs cycle metabolites and ATP. However, subsequent carnitine supplementation rescued mitochondrial energy production. Due to specific inhibition of OCTN2 activity, the influx of carnitine was blocked and mitochondrial energy metabolism was impaired in muscle cells in vitro and in thigh muscle tissue in a mouse model.
This preclinical experimental study revealed detrimental effect of imatinib on carnitine-mediated energy metabolism of muscle cells providing a possible molecular background of the frequently occurred side effects during imatinib therapy such as fatigue, muscle pain and cramps.
对于慢性髓性白血病（CML）患者，一种突出的、安全且有效的治疗方法是通过靶向抑制致癌蛋白 BCR::ABL1 来实现，其使用的药物是酪氨酸激酶抑制剂伊马替尼。大量接受伊马替尼治疗的患者报告称，骨骼肌肉不良反应会影响其生活质量。OCTN2 膜转运蛋白参与伊马替尼向细胞内的转运。与此同时，OCTN2 的关键生理作用是摄取肉碱，肉碱是线粒体β-氧化途径的必需辅助因子。本研究旨在探讨伊马替尼治疗对肌肉细胞肉碱摄取和能量代谢的影响。
使用 HTB-153（人横纹肌肉瘤）细胞系和 KCL-22（CML 细胞系）来研究伊马替尼治疗对细胞内肉碱水平的影响，反之亦然。使用伊马替尼处理的细胞的能量代谢变化被量化，并与暴露于高度特异性 OCTN2 抑制剂长春瑞滨的细胞的变化进行比较。使用小鼠模型来测试体外观察是否也能在体内的大腿肌肉组织中实现。使用 Prominence HPLC 系统与串联质谱仪联用定量分析感兴趣的分析物。
本研究表明，通过肉碱特异性转运体 OCTN2，伊马替尼和肉碱的摄取存在竞争关系，且细胞内肉碱浓度显著降低。相反，肉碱预孵育并不影响伊马替尼的细胞摄取，也不会干扰白血病细胞的靶向性。用伊马替尼阻断细胞内肉碱供应会显著降低大多数三羧酸循环代谢物和 ATP 的产生。然而，随后的肉碱补充挽救了线粒体能量产生。由于 OCTN2 活性的特异性抑制，肉碱内流在体外的肌肉细胞和小鼠模型的大腿肌肉组织中被阻断，线粒体能量代谢受损。
这项临床前实验研究揭示了伊马替尼对肌肉细胞肉碱介导的能量代谢的有害影响，为伊马替尼治疗过程中经常发生的副作用（如疲劳、肌肉疼痛和痉挛）提供了可能的分子背景。
