Yao Si, Yin Jie, Liu Wen, Li Yang, Huang Jianzheng, Qi Changxing, Hu Zhengxi, Tong Qingyi, Gu Lianghu, Zhang Yonghui
Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji-Rongcheng Center for Biomedicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji-Rongcheng Center for Biomedicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
Bioorg Chem. 2022 Oct;127:106019. doi: 10.1016/j.bioorg.2022.106019. Epub 2022 Jul 11.
Diffuse large B-cell lymphoma (DLBCL) is an aggressive B-cell non-Hodgkin's lymphoma. Currently, moderate efficacy and limitations of approved drugs still exist, and it is necessary to develop newer and more effective drugs. Gboxin is a promising inhibitor of OXPHOS, which specifically inhibits the growth of many kinds of cancer cell lines. In the present study, 21 Gboxin analogs incorporating amide and ester moieties were designed and synthesized. Preliminary screening results show that 5d also has specific selectivity for cancer cells, particularly on the DLBCL cells, which is weaker than that of Gboxin but still good. Thus, the effect and underlying mechanism of 5d on DLBCL cells were further studied. The results showed that 5d exhibits potent proliferation inhibition and cell cycle arrest effects, and its IC to DLBCL cells is below 1 µM. In addition, 5d induces apoptosis of DLBCL cells in a time- and dose-dependent manner, and this effect is stronger than that of Gboxin and VP16. Mechanistically, 5d plays its role mainly through the stimulation of metabolic stress in DLBCL cell lines, which induces OXPHOS inhibition, inflammation, DNA damage and mitochondrial dysfunction. These data suggest that 5d has potential as a candidate agent for DLBCL alternative drug development.
弥漫性大B细胞淋巴瘤（DLBCL）是一种侵袭性B细胞非霍奇金淋巴瘤。目前，已获批药物仍存在疗效一般和局限性的问题，因此有必要研发更新、更有效的药物。Gboxin是一种有前景的氧化磷酸化抑制剂，可特异性抑制多种癌细胞系的生长。在本研究中，设计并合成了21种含有酰胺和酯基的Gboxin类似物。初步筛选结果表明，5d对癌细胞也具有特异性选择性，尤其是对DLBCL细胞，其选择性虽弱于Gboxin，但仍较好。因此，进一步研究了5d对DLBCL细胞的作用及其潜在机制。结果表明，5d具有强大的增殖抑制和细胞周期阻滞作用，其对DLBCL细胞的IC50低于1µM。此外，5d以时间和剂量依赖性方式诱导DLBCL细胞凋亡，且这种作用强于Gboxin和VP16。从机制上讲，5d主要通过刺激DLBCL细胞系中的代谢应激发挥作用，进而诱导氧化磷酸化抑制、炎症、DNA损伤和线粒体功能障碍。这些数据表明，5d有潜力作为DLBCL替代药物开发的候选药物。
