Duan Hongpeng, Lai Qian, Jiang Yuelong, Yang Liuzhen, Deng Manman, Lin Zhijuan, Shan Weihang, Zhong Mengya, Yao Jingwei, Zhang Li, Xu Bing, Zha Jie
Department of Hematology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, China.
Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, No. 55, Zhenhai Road, Xiamen, 361003, Fujian, People's Republic of China.
Exp Hematol Oncol. 2024 Dec 18;13(1):121. doi: 10.1186/s40164-024-00589-1.
A tyrosine kinase inhibitor (TKI) such as Imatinib (IM) is the preferred treatment for Chronic Myeloid Leukemia (CML). However, the emergence of IM resistance presents a significant challenge to disease management. A characteristic of cancer cells, including IM-resistant CMLs, are characterized by heightened uptake of glucose and aberrant glycolysis in the cytosol, which is known as the Warburg effect. In addition to its potential to modulate the Warburg effect, Chiglitazar (Chi), a compound that regulates glucose metabolism, has also been investigated for its implication in cancer treatment. This suggests that combining Chi with IM may be a therapeutic strategy for overcoming IM resistance in CML.
Sensitive and IM-resistance CML cells were treated with Chi in vitro, followed by detecting of extracellular acidification rate (ECAR) using a Seahorse XF Analyzer. CML cell proliferation, cell cycle distribution, and apoptosis were tested by CCK-8 assay and flow cytometry. RNA sequencing was utilized to investigate potential transcriptional changes induced by Chi usage. In vivo studies were conducted on immunodeficient mice implanted with CML cells and given Chi and/or IM later. Tumor growth was monitored, as well as tumor burden and survival rates between groups.
Our metabonomic, transcriptomic, and molecular biology studies demonstrated that Chi, in part, diminished the Warburg effect by reducing glucose and lactate production in imatinib-resistant CML cells through the PPARγ/mTOR/PKM2 pathway. This modulation of glucose metabolism resulted in reduced cell proliferation and enhanced sensitivity to IM in imatinib-resistant CML cells in vitro. Rescue assay by introducing shPPARγ or mTOR activator verified the underlying regulatory pathway. Also, the combination of Chi and IM synergistically increased the sensitivity of IM in vivo and prolonged the survival of imatinib-resistance CML transplanted mice.
Our results demonstrated the potential of Chi to overcome IM resistance in vitro and in vivo. By inhibiting the Warburg effect through the PPARγ/mTOR/PKM2 pathway, Chi resensitizes CML cells towards imatinib treatment. Combining IM with Chi is an alternative therapeutic option for CML management, especially for IM-resistant CML patients.
酪氨酸激酶抑制剂（TKI）如伊马替尼（IM）是慢性髓性白血病（CML）的首选治疗方法。然而，IM耐药的出现给疾病管理带来了重大挑战。癌细胞的一个特征，包括对IM耐药的CML，其特点是葡萄糖摄取增加和胞质中糖酵解异常，这被称为瓦伯格效应。除了其调节瓦伯格效应的潜力外，齐格列他扎（Chi）作为一种调节葡萄糖代谢的化合物，也因其在癌症治疗中的作用而受到研究。这表明将Chi与IM联合使用可能是克服CML中IM耐药的一种治疗策略。
在体外将敏感和对IM耐药的CML细胞用Chi处理，然后使用海马XF分析仪检测细胞外酸化率（ECAR）。通过CCK-8测定法和流式细胞术检测CML细胞增殖、细胞周期分布和凋亡情况。利用RNA测序研究Chi使用诱导的潜在转录变化。在植入CML细胞并随后给予Chi和/或IM的免疫缺陷小鼠上进行体内研究。监测肿瘤生长情况以及各组之间的肿瘤负荷和生存率。
我们的代谢组学、转录组学和分子生物学研究表明，Chi部分地通过PPARγ/mTOR/PKM2途径减少对IM耐药的CML细胞中的葡萄糖和乳酸生成，从而减弱瓦伯格效应。这种对葡萄糖代谢的调节导致体外对IM耐药的CML细胞增殖减少并增强对IM的敏感性。通过引入shPPARγ或mTOR激活剂进行的挽救试验验证了潜在的调节途径。此外，Chi与IM的联合在体内协同增加了对IM的敏感性，并延长了对IM耐药的CML移植小鼠的生存期。
我们的结果证明了Chi在体外和体内克服IM耐药的潜力。通过PPARγ/mTOR/PKM2途径抑制瓦伯格效应，Chi使CML细胞对伊马替尼治疗重新敏感。将IM与Chi联合使用是CML管理的一种替代治疗选择，特别是对于对IM耐药的CML患者。
