Mahbub Amani, Le Maitre Christine, Haywood-Small Sarah, Cross Neil, Jordan-Mahy Nicola
Laboratory Medicine College, Pathology Department, Umm Al Qura University, Makkah, Saudi Arabia.
Biomolecular Sciences Research Center, Sheffield Hallam University, Sheffield, UK.
Oncotarget. 2017 Aug 24;8(62):104877-104893. doi: 10.18632/oncotarget.20501. eCollection 2017 Dec 1.
Polyphenols have been previously shown to sensitize leukemia cell lines to topoisomerase inhibitors. Here, we assess the effects of five polyphenols when used alone and in combination with antimetabolites: methotrexate, 6-mercaptopurine and 5-fluorouracil; in lymphoid and myeloid leukemia cells lines, and non-tumor control cells. The effects of combined treatments were investigated on ATP and glutathione levels, cell-cycle progression, DNA damage and apoptosis. Polyphenols antagonized methotrexate and 6-mercaptopurine induced cell-cycle arrest and apoptosis in most leukemia cell lines. This was associated with reduced DNA damage and increased glutathione levels, greater than that seen following individual treatments alone. In contrast, 5-fluorouracil when combined with quercetin, apigenin and rhein caused synergistic decrease in ATP levels, induction of cell-cycle arrest and apoptosis in some leukemia cell lines. However, antagonistic effects were observed when 5-fluorouracil was combined with rhein and -stilbene in myeloid cell lines. The effects were dependant on polyphenol type and chemotherapy agent investigated, and cell type treated. Interestingly treatment of non-tumor control cells with polyphenols protected cells from antimetabolite treatments. This suggests that polyphenols modulate the action of antimetabolite agents; more importantly they antagonized methotrexate and 6-mercaptopurine actions, thus suggesting the requirement of polyphenol-exclusion during their use.
先前已证明多酚可使白血病细胞系对拓扑异构酶抑制剂敏感。在此，我们评估了五种多酚单独使用以及与抗代谢物（甲氨蝶呤、6-巯基嘌呤和5-氟尿嘧啶）联合使用时，在淋巴样和髓样白血病细胞系以及非肿瘤对照细胞中的作用。研究了联合治疗对ATP和谷胱甘肽水平、细胞周期进程、DNA损伤和细胞凋亡的影响。在大多数白血病细胞系中，多酚拮抗甲氨蝶呤和6-巯基嘌呤诱导的细胞周期停滞和细胞凋亡。这与DNA损伤减少和谷胱甘肽水平升高有关，且高于单独进行个体治疗时的水平。相比之下，5-氟尿嘧啶与槲皮素、芹菜素和大黄酸联合使用时，在某些白血病细胞系中导致ATP水平协同降低、诱导细胞周期停滞和细胞凋亡。然而，在髓样细胞系中，当5-氟尿嘧啶与大黄酸和白藜芦醇联合使用时观察到拮抗作用。这些作用取决于所研究的多酚类型、化疗药物以及所处理的细胞类型。有趣的是，用多酚处理非肿瘤对照细胞可保护细胞免受抗代谢物治疗的影响。这表明多酚可调节抗代谢物药物的作用；更重要的是，它们拮抗甲氨蝶呤和6-巯基嘌呤的作用，因此提示在使用这些药物时需要排除多酚。
