Diffuse large B-cell lymphoma (DLBCL) is the most common category and disease entity of non-Hodgkin lymphoma. Osalmide and pterostilbene are natural products with anticancer activities via different mechanism. In this study, using a new synthetic strategy for the two natural products, we obtained the compound DCZ0801, which was previously found to have anti-multiple myeloma activity. We performed both in vitro and in vivo assays to investigate its bioactivity and explore its underlying mechanism against DLBCL cells. The results showed that DCZ0801 treatment gave rise to a dose- and time-dependent inhibition of cell viability as determined by CCK-8 assay and flow cytometry assay. Western blot analysis results showed that the expression of caspase-3, caspase-8, caspase-9 and Bax was increased, while BCL-2 and BCL-XL levels were decreased, which suggested that DCZ0801 inhibited cell proliferation and promoted intrinsic apoptosis. In addition, DCZ0801 induced G0/G1 phase arrest by downregulating the protein expression levels of CDK4, CDK6 and cyclin D1. Furthermore, DCZ0801 exerted an anti-tumor effect by down-regulating the expressions of p-PI3K and p-AKT. There also existed a trend that the expression of p-JNK and p-P38 was restrained. Intraperitoneal injection of DCZ0801 suppressed tumor development in xenograft mouse models. The preliminary metabolic study showed that DCZ0801 displayed a rapid metabolism within 30 min. These results demonstrated that DCZ0801 may be a new potential anti-DLBCL agent in DLBCL therapy.

中文翻译：

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天然产物osalmide和Pterostilbene的新型环磷酰胺在弥漫性大B细胞淋巴瘤细胞中诱导细胞毒性和细胞周期停滞。

弥漫性大B细胞淋巴瘤（DLBCL）是非霍奇金淋巴瘤的最常见类别和疾病实体。欧沙米特和紫檀皮是通过不同机理具有抗癌活性的天然产物。在这项研究中，我们采用了两种天然产物的新合成策略，获得了化合物DCZ0801，该化合物先前被发现具有抗多发性骨髓瘤的活性。我们进行了体外和体内试验，以研究其生物活性并探索其针对DLBCL细胞的潜在机制。结果表明，DCC0801处理引起细胞活力的剂量和时间依赖性抑制，如通过CCK-8测定和流式细胞术测定所确定的。Western blot分析结果表明，caspase-3，caspase-8，caspase-9和Bax的表达升高，而BCL-2和BCL-XL的表达降低，这提示DCZ0801抑制细胞增殖并促进固有凋亡。此外，DCZ0801通过下调CDK4，CDK6和细胞周期蛋白D1的蛋白表达水平来诱导G0 / G1期停滞。此外，DCZ0801通过下调p-PI3K和p-AKT的表达发挥抗肿瘤作用。还存在抑制p-JNK和p-P38表达的趋势。腹膜内注射DCZ0801抑制异种移植小鼠模型中的肿瘤发展。初步代谢研究表明，DCZ0801在30分钟内显示出快速代谢。这些结果表明DCZ0801可能是DLBCL治疗中潜在的新型抗DLBCL药物。DCZ0801通过下调CDK4，CDK6和细胞周期蛋白D1的蛋白表达水平来诱导G0 / G1期停滞。此外，DCZ0801通过下调p-PI3K和p-AKT的表达发挥抗肿瘤作用。还存在抑制p-JNK和p-P38表达的趋势。腹膜内注射DCZ0801抑制异种移植小鼠模型中的肿瘤发展。初步代谢研究表明，DCZ0801在30分钟内显示出快速代谢。这些结果表明DCZ0801可能是DLBCL治疗中的一种新的潜在抗DLBCL药物。DCZ0801通过下调CDK4，CDK6和细胞周期蛋白D1的蛋白表达水平来诱导G0 / G1期停滞。此外，DCZ0801通过下调p-PI3K和p-AKT的表达发挥抗肿瘤作用。还存在抑制p-JNK和p-P38表达的趋势。腹膜内注射DCZ0801抑制异种移植小鼠模型中的肿瘤发展。初步代谢研究表明，DCZ0801在30分钟内显示出快速代谢。这些结果表明DCZ0801可能是DLBCL治疗中潜在的新型抗DLBCL药物。腹膜内注射DCZ0801抑制异种移植小鼠模型中的肿瘤发展。初步代谢研究表明，DCZ0801在30分钟内显示出快速代谢。这些结果表明DCZ0801可能是DLBCL治疗中潜在的新型抗DLBCL药物。腹膜内注射DCZ0801抑制异种移植小鼠模型中的肿瘤发展。初步代谢研究表明，DCZ0801在30分钟内显示出快速代谢。这些结果表明DCZ0801可能是DLBCL治疗中潜在的新型抗DLBCL药物。