Abstract

Cytotoxic nucleoside analogs (NAs) hold great promise in cancer therapeutics by mimicking endogenous nucleosides and interfering with crucial cellular processes. Here, we investigate the potential of the novel cytidine analog, 4′-azido-2′-deoxy-2′-fluoro(arbino)cytidine (FNC), as a therapeutic agent for Non-Hodgkin lymphoma (NHL) using Dalton’s lymphoma (DL) as a T-cell lymphoma model. FNC demonstrated dose- and time-dependent inhibition of DL cell growth and proliferation. IC-50 values of FNC were measured at 1 µM, 0.5 µM, and 0.1 µM after 24, 48, and 72 h, respectively. Further elucidation of FNC’s mechanism of action uncovers its role in inducing apoptosis in DL cells. Notable DNA fragmentation and nuclear condensation point to activated apoptotic pathways. FNC-induced apoptosis was concomitant with changes in cellular membranes, characterized by membrane rupture and altered morphology. The robust anticancer effects of FNC are linked to its capacity to induce reactive oxygen species (ROS) production, prompting oxidative stress-mediated apoptosis. Additionally, FNC disrupted mitochondrial membrane potential (MMP), leading to mitochondrial dysfunction, further promoting apoptosis. Dysregulation of apoptotic genes, with upregulation of Bax and downregulation of Bcl-2 and Bcl-xl, implicates the mitochondrial-mediated apoptosis pathway. Furthermore, FNC-induced G2/M phase cell cycle arrest was mediated through modulation of the cell cycle inhibitor p21. Overall, this study highlights the potential of FNC as a promising therapeutic agent for NHL.

中文翻译：

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FNC（4′-叠氮基-2′-脱氧-2′-氟（阿二）胞苷）作为 NHL 的有效治疗剂：ROS 生成、细胞周期停滞和线粒体介导的细胞凋亡

摘要

细胞毒性核苷类似物 (NA) 通过模仿内源性核苷并干扰关键的细胞过程，在癌症治疗中具有广阔的前景。在这里，我们研究了新型胞苷类似物 4'-叠氮基-2'-脱氧-2'-氟（阿二）胞苷 (FNC) 作为道尔顿淋巴瘤 (NHL) 治疗剂的潜力。 DL）作为T细胞淋巴瘤模型。FNC 表现出对 DL 细胞生长和增殖的剂量和时间依赖性抑制。分别在 24、48 和 72 小时后测量 1 µM、0.5 µM 和 0.1 µM 的 FNC 的 IC-50 值。进一步阐明 FNC 的作用机制揭示了其在诱导 DL 细胞凋亡中的作用。显着的 DNA 碎片和核浓缩表明细胞凋亡途径被激活。FNC 诱导的细胞凋亡伴随着细胞膜的变化，其特征是膜破裂和形态改变。FNC 强大的抗癌作用与其诱导活性氧 (ROS) 产生、促进氧化应激介导的细胞凋亡的能力有关。此外，FNC 破坏线粒体膜电位 (MMP)，导致线粒体功能障碍，进一步促进细胞凋亡。凋亡基因的失调，伴随着 Bax 的上调以及 Bcl-2 和 Bcl-xl 的下调，暗示着线粒体介导的细胞凋亡途径。此外，FNC 诱导的 G2/M 期细胞周期停滞是通过细胞周期抑制剂 p21 的调节介导的。总体而言，这项研究凸显了 FNC 作为 NHL 治疗药物的潜力。