Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Division of Hematology, Faculty of Medicine, Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran.
Mol Biol Rep. 2022 Jan;49(1):19-29. doi: 10.1007/s11033-021-06778-z. Epub 2021 Nov 24.
The tumor necrosis factor (TNF)-related apoptosis-inducing ligand, TRAIL, an apoptosis-inducing cytokine, has attracted much attention in the treatment of cancer for its selective toxicity to malignant rather than normal cells. However, the apoptosis-inducing ability of TRAIL is weaker than expected primarily due to cancer cell resistance. As one of the dietary flavonoids, kaempferol, has been shown to be antiproliferative and might have a protective effect against TRAIL resistance, particularly for hematologic malignancies.
Here, we studied the potential of kaempferol to enhance the TRAIL-induced cytotoxicity and apoptosis in human chronic myelogenous leukemia (CML) cell line K-562, as well as the expression of specific genes with impact on TRAIL signal regulation. Analysis of flowcytometry data showed that treatment with kaempferol did enhance sensitivity of CML cells to pro-apoptotic effects of anti-TRAIL antibody. Although the gene expression levels were heterogeneous, cFLIP, cIAP1 and cIAP2 expression were generally downregulated where co-treatment of kaempferol and TRAIL was employed and these effects appeared to be dose-dependent. We further demonstrated that the expression of death receptors 4 and 5 tended to increase subsequent to the combination treatment.
Consequently, it is reasonable to conclude that sensitization of chronic leukemia cells to TRAIL by kaempferol in vitro should be considered as a way of focusing clinical attention on leukemia therapy.
肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）是一种凋亡诱导细胞因子，因其对恶性细胞而非正常细胞的选择性毒性而在癌症治疗中受到广泛关注。然而，TRAIL 的凋亡诱导能力低于预期，主要是由于癌细胞耐药。作为一种膳食类黄酮，山奈酚已被证明具有抗增殖作用，并且可能对 TRAIL 耐药具有保护作用，特别是对于血液恶性肿瘤。
在这里，我们研究了山奈酚增强人慢性髓系白血病（CML）细胞系 K-562 中 TRAIL 诱导的细胞毒性和细胞凋亡的潜力，以及对 TRAIL 信号调节有影响的特定基因的表达。流式细胞术数据分析表明，山奈酚处理可增强 CML 细胞对促凋亡抗 TRAIL 抗体的敏感性。尽管基因表达水平存在异质性，但当联合使用山奈酚和 TRAIL 时，cFLIP、cIAP1 和 cIAP2 的表达通常下调，并且这些作用似乎呈剂量依赖性。我们进一步证明，联合治疗后死亡受体 4 和 5 的表达趋于增加。
因此，有理由认为，山奈酚在体外使慢性白血病细胞对 TRAIL 敏感，这应被视为关注白血病治疗的一种临床方法。
