Key Laboratory of Bio-resources and Eco-environment of the Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, China.
Center of Science and Research, Chengdu Medical College, Chengdu 610513, China.
Molecules. 2020 Feb 21;25(4):971. doi: 10.3390/molecules25040971.
Benzoxazole derivative K313 has previously been reported to possess anti-inflammatory effects in lipopolysaccharide-induced RAW264.7 macrophages. To date, there have been no related reports on the anticancer effects of K313. In this study, we found that K313 reduced the viability of human B-cell leukemia (Nalm-6) and lymphoma (Daudi) cells in a dose-dependent manner without affecting healthy peripheral blood mononuclear cells (PBMCs) and induced moderate cell cycle arrest at the G0/G1 phase. Meanwhile, K313 mediated cell apoptosis, which was accompanied by the activation of caspase-9, caspase-3, and poly ADP-ribose polymerase (PARP). Furthermore, cells treated with K313 showed a significant decrease in mitochondrial membrane potential (MMP), which may have been caused by the caspase-8-mediated cleavage of Bid, as detected by Western blot analysis. We also found that K313 led to the downregulation of p-p70S6K protein, which plays an important role in cell survival and cell cycle progression. In addition, treatment of these cells with K313 blocked autophagic flux, as reflected in the accumulation of LC3-II and p62 protein levels in a dose- and time-dependent manner. In conclusion, K313 decreases cell viability without affecting normal healthy PBMCs, induces cell cycle arrest and apoptosis, reduces p-p70S6K protein levels, and mediates strong autophagy inhibition. Therefore, K313 and its derivatives could be developed as potential anticancer drugs or autophagy blockers in the future.
苯并恶唑衍生物 K313 先前已被报道具有脂多糖诱导的 RAW264.7 巨噬细胞中的抗炎作用。迄今为止，尚无关于 K313 的抗癌作用的相关报道。在这项研究中，我们发现 K313 以剂量依赖性方式降低人 B 细胞白血病（Nalm-6）和淋巴瘤（Daudi）细胞的活力，而不影响健康的外周血单核细胞（PBMC），并诱导适度的细胞周期停滞在 G0/G1 期。同时，K313 介导细胞凋亡，伴随着半胱天冬酶-9、半胱天冬酶-3 和多聚 ADP-核糖聚合酶（PARP）的激活。此外，用 K313 处理的细胞表现出线粒体膜电位（MMP）显著下降，这可能是由于 caspase-8 介导的 Bid 裂解，通过 Western blot 分析检测到。我们还发现 K313 导致 p-p70S6K 蛋白水平下调，该蛋白在细胞存活和细胞周期进展中起重要作用。此外，用 K313 处理这些细胞会阻断自噬流，这反映在 LC3-II 和 p62 蛋白水平的剂量和时间依赖性积聚。总之，K313 在不影响正常健康 PBMC 的情况下降低细胞活力，诱导细胞周期停滞和凋亡，降低 p-p70S6K 蛋白水平，并介导强烈的自噬抑制。因此，K313 及其衍生物将来可能被开发为潜在的抗癌药物或自噬抑制剂。
