摘要
Diffuse large B-cell lymphoma(DLBCL)is a highly heterogeneous malignant tumor characterized by diffuse growth.DCZ0858 is a novel small molecule with excellent antitumor effects in DLBCL.This study explored in depth the inhibitory effect of DCZ0858 on DLBCL cell lines.Cell Counting Kit-8(CCK-8)and plate colony formation assays were used to evaluate cell proliferation levels.Flow cytometry was employed to analyze apoptosis and the cell cycle,and western blotting was used to quantify the expression of cell cycle regulators.The results indicated that DCZ0858 inhibited cell growth in a concentration-dependent and time-dependent manner while inducing no significant toxicity in normal cells.Moreover,DCZ0858 initiated cell apoptosis via both internal and external apoptotic pathways.DCZ0858 also induced cell cycle arrest in the G0/G1 phase,thereby controlling cell proliferation.Further investigation of the molecular mechanism showed that the JAK2/STAT3 pathway was involved in the DCZ0858-mediated antitumor effects and that JAK2 was the key target for DCZ0858 treatment.Knockdown of JAK2 partly weakened the DCZ0858-mediated antitumor effect in DLBCL cells,while JAK2 overexpression strengthened the effect of DCZ0858 in DLBCL cells.Moreover,a similar antitumor effect was observed for DCZ0858 and the JAK2 inhibitor ruxolitinib,and combining the two could significantly enhance cancer-suppressive signaling.Tumor xenograft models showed that DCZ0858 inhibited tumor growth in vivo and had low toxicity in important organs,findings that were consistent with the in vitro data.In summary,DCZ0858 is a promising drug for the treatment of DLBCL.
基金
supported by the National Natural Science Foundation of China(Nos.81529001,81570190,81670194,and 81870158)
National Science&Technology Major Project“Key New Drug Creation and Manufacturing Program”,China(Number:2018ZX09711002).
