Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.
Sci Rep. 2024 Feb 29;14(1):4975. doi: 10.1038/s41598-024-55286-0.
Venetoclax has been approved recently for treatment of Acute myeloid leukemia (AML). Venetoclax is a BH3-mimetic and induces apoptosis via Bcl-2 inhibition. However, venetoclax's effect is still restrictive and a novel strategy is needed. In the present study, we demonstrate that sodium butyrate (NaB) facilitates the venetoclax's efficacy of cell death in AML cells. As a single agent, NaB or venetoclax exerted just a weak effect on cell death induction for AML cell line KG-1. The combination with NaB and venetoclax drastically induced cell death. NaB upregulated pro-apoptotic factors, Bax and Bak, indicating the synergistic effect by the collaboration with Bcl-2 inhibition by venetoclax. The combined treatment with NaB and venetoclax strongly cleaved a caspase substrate poly (ADP-ribose) polymerase (PARP) and a potent pan-caspase inhibitor Q-VD-OPh almost completely blocked the cell death induced by the combination, meaning that the combination mainly induced apoptosis. The combination with NaB and venetoclax also strongly induced cell death in another AML cell line SKNO-1 but did not affect chronic myeloid leukemia (CML) cell line K562, indicating that the effect was specific for AML cells. Our results provide a novel strategy to strengthen the effect of venetoclax for AML treatment.
维奈托克最近已被批准用于治疗急性髓系白血病 (AML)。维奈托克是一种 BH3 模拟物，通过抑制 Bcl-2 诱导细胞凋亡。然而，维奈托克的作用仍然有限，需要一种新的策略。在本研究中，我们证明丁酸钠 (NaB) 可增强维奈托克在 AML 细胞中的细胞死亡效果。作为单一药物，丁酸钠或维奈托克对 AML 细胞系 KG-1 的细胞死亡诱导作用较弱。丁酸钠与维奈托克联合使用可显著诱导细胞死亡。丁酸钠上调促凋亡因子 Bax 和 Bak，表明与维奈托克抑制 Bcl-2 协同作用。联合使用丁酸钠和维奈托克可强烈切割半胱天冬酶底物多聚（ADP-核糖）聚合酶 (PARP)，并且强效的 pan-caspase 抑制剂 Q-VD-OPh 几乎完全阻断了联合诱导的细胞死亡，这意味着联合治疗主要诱导了细胞凋亡。联合使用丁酸钠和维奈托克也可强烈诱导另一种 AML 细胞系 SKNO-1 的细胞死亡，但不影响慢性髓系白血病 (CML) 细胞系 K562，表明该作用对 AML 细胞具有特异性。我们的研究结果为增强维奈托克治疗 AML 的效果提供了一种新的策略。
