Department of Immunology, Institute for Biological Research "SinišaStanković", Belgrade University, 11060 Belgrade, Serbia.
Institute of Inorganic Chemistry, Faculty of Chemistry and Mineralogy, Leipzig University, 04103 Leipzig, Germany.
Molecules. 2022 Jul 14;27(14):4503. doi: 10.3390/molecules27144503.
Lipoxygenases convert polyunsaturated fatty acids into biologically active metabolites such as inflammatory mediators-prostaglandins and leukotrienes. The inhibition of lipoxygenases is increasingly employed in the treatment of cancer. We evaluated the anticancer potential of two novel 5-lipoxygenase inhibitors, named CarbZDNaph and CarbZDChin, which are analogues of the commercially available inhibitor Rev-5901. The in vitro segment of this study was conducted on a mouse colorectal carcinoma cell line-CT26CL25. For an in vivo model, we induced tumors in BALB/c mice by the implantation of CT26CL25 cells, and we treated the animals with potential inhibitors. A 48 h treatment resulted in diminished cell viability. Calculated IC values (half-maximal inhibitory concentrations) were 25 μM, 15 μM and 30 μM for CarbZDNaph, CarbZDChin and Rev-5901, respectively. The detailed analysis of mechanism revealed an induction of caspase-dependent apoptosis and autophagy. In the presence of chloroquine, an autophagy inhibitor, we observed an increased mortality of cells, implying a cytoprotective role of autophagy. Our in vivo experiment reports tumor growth attenuation in animals treated with CarbZDChin. Compounds CarbZDNaph and Rev-5901 lacked an in vivo efficacy. The results presented in this study display a strong effect of compound CarbZDChin on malignant cell growth. Having in mind the important role of inflammation in cancer development, these results have a significant impact and are worthy of further evaluation.
脂氧合酶将多不饱和脂肪酸转化为生物活性代谢物，如炎症介质——前列腺素和白三烯。脂氧合酶的抑制作用越来越多地应用于癌症的治疗。我们评估了两种新型 5-脂氧合酶抑制剂的抗癌潜力，它们分别被命名为 CarbZDNaph 和 CarbZDChin，是市售抑制剂 Rev-5901 的类似物。本研究的体外部分在一种小鼠结直肠癌细胞系 CT26CL25 上进行。对于体内模型，我们通过植入 CT26CL25 细胞在 BALB/c 小鼠中诱导肿瘤，并使用潜在的抑制剂治疗动物。48 小时的治疗导致细胞活力降低。计算得出的 IC 值（半最大抑制浓度）分别为 25 μM、15 μM 和 30 μM，用于 CarbZDNaph、CarbZDChin 和 Rev-5901。对机制的详细分析表明诱导了 caspase 依赖性细胞凋亡和自噬。在用氯喹（一种自噬抑制剂）处理时，我们观察到细胞死亡率增加，这表明自噬具有细胞保护作用。我们的体内实验报告称，在用 CarbZDChin 治疗的动物中肿瘤生长受到抑制。化合物 CarbZDNaph 和 Rev-5901 在体内没有疗效。本研究的结果显示化合物 CarbZDChin 对恶性细胞生长有很强的作用。考虑到炎症在癌症发展中的重要作用，这些结果具有重要意义，值得进一步评估。
