Department of Hematology, The Affiliated People's Hospital of Ningbo University, Ningbo, China; Department of Pathology and Pathogenic Biology, and Zhejiang Key Laboratory of Pathophysiology, School of Basic Medical Sciences, Health Science Center, Ningbo University, Ningbo, China; Institute of Hematology, Ningbo University, Ningbo, China.
Department of Pathology and Pathogenic Biology, and Zhejiang Key Laboratory of Pathophysiology, School of Basic Medical Sciences, Health Science Center, Ningbo University, Ningbo, China.
Eur J Pharmacol. 2023 Oct 5;956:175957. doi: 10.1016/j.ejphar.2023.175957. Epub 2023 Aug 3.
Acute myeloid leukemia (AML) is a highly heterogeneous and rapidly progressive hematopoietic neoplasm characterized by frequent relapses and variable prognoses. The development of new treatment options, therefore, is of crucial importance. Platycodin D (PD) is a triterpenoid saponin, extracted from the roots of the traditional Chinese herbal medicine Platycodon grandiflorum (Jacq.) A. DC., which has been reported to exhibit therapeutic potential against a broad range of cancers. Although the effects of PD on AML remain unclear, in the present study, we observed a concentration-dependent reduction in the viability of multiple human AML cell lines in response to treatment with PD. In addition to triggering mitochondria-dependent apoptosis via the upregulation of BAK and BIM, treatment with PD also induced cell cycle arrest at the G0/G1 phase. Western blot analyses revealed marked suppression of the phosphorylation of protein kinase B (AKT), glycogen synthase kinase-3β, ribosomal protein S6, and extracellular signal-regulated kinase (ERK) by PD, in turn implying the participation of the phosphoinositide 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK)/ERK pathways. Pre-incubation with LY294002, MK2206, AR-A014418, or U0126 was consistently found to significantly aggravate PD-induced inhibition of viability. Additionally, PD combined with the B-cell lymphoma 2 (BCL2) inhibitor venetoclax elicited synergistically enhanced cytotoxic effects. The anti-leukemic activity of PD was further validated using primary samples from de novo AML patients. Given the results of the present study, PD may be a potent therapeutic candidate for the treatment of AML.
急性髓细胞白血病（AML）是一种高度异质性和快速进展的造血肿瘤，其特点是频繁复发和预后可变。因此，开发新的治疗方案至关重要。远志酸（PD）是一种从传统中药桔梗（Platycodon grandiflorum（Jacq.）A. DC.）的根中提取的三萜皂苷，已被报道对多种癌症具有治疗潜力。尽管 PD 对 AML 的作用尚不清楚，但在本研究中，我们观察到 PD 处理可浓度依赖性地降低多种人 AML 细胞系的活力。除了通过上调 BAK 和 BIM 触发线粒体依赖性细胞凋亡外，PD 还诱导细胞周期停滞在 G0/G1 期。Western blot 分析显示，PD 显著抑制蛋白激酶 B（AKT）、糖原合成酶激酶-3β、核糖体蛋白 S6 和细胞外信号调节激酶（ERK）的磷酸化，这暗示了磷酸肌醇 3-激酶（PI3K）/AKT 和丝裂原激活蛋白激酶（MAPK）/ERK 途径的参与。LY294002、MK2206、AR-A014418 或 U0126 的预孵育始终发现可显著加重 PD 诱导的活力抑制。此外，PD 与 B 细胞淋巴瘤 2（BCL2）抑制剂 venetoclax 联合使用可产生协同增强的细胞毒性作用。使用来自初发 AML 患者的原始样本进一步验证了 PD 的抗白血病活性。鉴于本研究的结果，PD 可能是治疗 AML 的有效治疗候选物。
