Geriatric Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei, China.
Department of General Medicine, Hospital of Huazhong Agricultural University, Wuhan, Hubei, China.
Biochem Biophys Res Commun. 2024 Nov 12;733:150653. doi: 10.1016/j.bbrc.2024.150653. Epub 2024 Sep 3.
Chronic myeloid leukemia (CML) treatment with Bcr-Abl tyrosine kinase inhibitors (TKIs) has significantly improved patient outcomes, yet challenges such as drug resistance and persistence of leukemic stem cells persist. This study explores the potential of naringenin, a natural flavonoid, to enhance the efficacy of Bcr-Abl TKIs in CML therapy. We showed that naringenin reduces viability of a panel of CML cell lines regardless of varying cellular origin and genetic mutations, and acts synergistically with dasatinib and ponatinib. Importantly, naringenin is effective in targeting blast crisis CML CD34 cells by decreasing their colony formation, self-renewal and viability. Compared to CML, naringenin is significantly less effective against normal bone marrow (NBM) counterparts. In addition, naringenin significantly enhances the inhibitory effects of dasatinib in CML but not NBM CD34 cells. Mechanism studies showed that naringenin's inhibitory effects were associated with the induction of oxidative stress and lipid damage, as evidenced by increased reactive oxygen species (ROS) and malondialdehyde (MDA) levels. Notably, naringenin upregulated genes related to mitochondrial biogenesis while downregulating antioxidant defense genes. Pretreatment with α-tocopherol, which inhibits lipid-mediated ROS production, completely abolished the ROS increase and restored cell viability, indicating that lysosomal lipid peroxidation plays a crucial role in naringenin's mechanism of action. In a CML xenograft mouse model, the combination of naringenin and dasatinib resulted in remarkably more tumor growth suppression compared to single drug alone. Importantly, this combination was well-tolerated, with no adverse effects on body weight observed. These findings suggest that naringenin, by inducing oxidative lipid damage, enhances the anti-leukemic effects of Bcr-Abl TKIs, offering a promising therapeutic strategy for CML.
慢性髓性白血病（CML）的 Bcr-Abl 酪氨酸激酶抑制剂（TKI）治疗显著改善了患者的预后，但耐药性和白血病干细胞持续存在等挑战依然存在。本研究探讨了柚皮素（一种天然类黄酮）增强 CML 治疗中 Bcr-Abl TKI 疗效的潜力。我们表明，柚皮素降低了一系列 CML 细胞系的活力，无论其细胞来源和遗传突变如何，并且与达沙替尼和帕纳替尼协同作用。重要的是，柚皮素通过降低其集落形成、自我更新和活力来有效靶向急变期 CML CD34 细胞。与 CML 相比，柚皮素对正常骨髓（NBM）对应物的效果显著降低。此外，柚皮素显著增强了达沙替尼在 CML 但不是 NBM CD34 细胞中的抑制作用。机制研究表明，柚皮素的抑制作用与诱导氧化应激和脂质损伤有关，这表现为活性氧（ROS）和丙二醛（MDA）水平的增加。值得注意的是，柚皮素上调了与线粒体生物发生相关的基因，同时下调了抗氧化防御基因。用α-生育酚预处理，该物质抑制脂质介导的 ROS 产生，完全消除了 ROS 的增加并恢复了细胞活力，表明溶酶体脂质过氧化在柚皮素的作用机制中起关键作用。在 CML 异种移植小鼠模型中，与单独使用药物相比，柚皮素和达沙替尼的联合使用导致肿瘤生长抑制显著增加。重要的是，这种组合耐受性良好，体重没有观察到不良反应。这些发现表明，柚皮素通过诱导氧化脂质损伤，增强了 Bcr-Abl TKI 的抗白血病作用，为 CML 提供了一种有前途的治疗策略。
