Background:The primary cause of treatment failure in patients with refractory or relapsed B-cell non-Hodgkin lymphoma(r/r B-NHL)is resistance to current therapies,and therapy-induced senescence(TIS)stands out as a cru...Background:The primary cause of treatment failure in patients with refractory or relapsed B-cell non-Hodgkin lymphoma(r/r B-NHL)is resistance to current therapies,and therapy-induced senescence(TIS)stands out as a crucial mechanism contributing to tumor drug resistance.Here,we analyzed SENEX/Rho GTPase Activating Protein 18(ARHGAP18)expression and prognostic significance in doxorubicin-induced B-NHL-TIS model and r/r B-NHL patients,investigating its target in B-NHL cell senescence and the effect of combining specific inhibitors on apoptosis resistance in B-NHL-TIS cells.Methods:Raji cells were transfected with the human SENEX shRNA recombinant lentiviral vector(Sh-SENEX)and the empty vector negative(NC)to construct a stable transfection cell line with knockdown of SENEX.Effect of SENEX-silencing on B-NHL-TIS formation,cell function and cell cycle-related pathways was analyzed.Using doxorubicin(DOX)-inducible senescent B-NHL cells combined with the specific cyclin dependent kinase 4/6(CDK4/6)inhibitor Palbociclib to observe that blocking CDK4/6 effects on TIS formation.SENEX expression of 21 B-NHL patients and 8 healthy controls were analyzed by qRT-PCR,and the correlation between its expression and clinical indicators were evaluated.Results:The downregulation of SENEX expression promotes G1-S phase transition and apoptosis while inhibiting cell proliferation,collectively suppressing the formation of TIS in B-NHL.Blockade of CDK4/6 promotes the DOX-induced G1 phase arrest to enhance TIS formation in B-NHL cells which can reverse the regulatory effect of silencing SENEX on B-NHL cell cycle regulation and senescence.The expression levels of SENEX were notably elevated in B-NHL patients compared to healthy controls,and Elevated expression levels of SENEX were associated with poor prognosis of B-NHL patients.Conclusions:SENEX enhances apoptosis resistance in B-NHL by inhibiting CDK4/6,thereby preventing G1-S phase transition and promoting TIS formation.展开更多
目的分析CDK4/6抑制剂在临床应用中所致不良反应(ADR)的特点,为临床安全用药提供参考。方法检索维普、中国知网、万方、Web of Science、PubMed等数据库中关于CDK4/6抑制剂致ADRs的文献并进行分析。结果CDK4/6抑制剂致ADRs的个案报道共3...目的分析CDK4/6抑制剂在临床应用中所致不良反应(ADR)的特点,为临床安全用药提供参考。方法检索维普、中国知网、万方、Web of Science、PubMed等数据库中关于CDK4/6抑制剂致ADRs的文献并进行分析。结果CDK4/6抑制剂致ADRs的个案报道共34例;患者平均年龄约63.5岁,ADRs多发生在用药4个月内(29例,85.29%);CDK4/6抑制剂致ADRs主要以皮肤及其附件损害(14例,41.18%)、呼吸系统损害(6例,17.65%)、肝胆系统损害(4例,11.76%)为主;经停药和/或对症治疗后达到症状好转或治愈的有31例;3例最终死亡。结论临床使用CDK4/6抑制剂时应加强用药监测,开展多学科患者管理,而CDK4/6抑制剂的ADR发生机制尚需进一步研究。展开更多
基金This work was supported by the Major Subject of Science and Technology of Anhui Province(Grant Number:201903a07020030).
文摘Background:The primary cause of treatment failure in patients with refractory or relapsed B-cell non-Hodgkin lymphoma(r/r B-NHL)is resistance to current therapies,and therapy-induced senescence(TIS)stands out as a crucial mechanism contributing to tumor drug resistance.Here,we analyzed SENEX/Rho GTPase Activating Protein 18(ARHGAP18)expression and prognostic significance in doxorubicin-induced B-NHL-TIS model and r/r B-NHL patients,investigating its target in B-NHL cell senescence and the effect of combining specific inhibitors on apoptosis resistance in B-NHL-TIS cells.Methods:Raji cells were transfected with the human SENEX shRNA recombinant lentiviral vector(Sh-SENEX)and the empty vector negative(NC)to construct a stable transfection cell line with knockdown of SENEX.Effect of SENEX-silencing on B-NHL-TIS formation,cell function and cell cycle-related pathways was analyzed.Using doxorubicin(DOX)-inducible senescent B-NHL cells combined with the specific cyclin dependent kinase 4/6(CDK4/6)inhibitor Palbociclib to observe that blocking CDK4/6 effects on TIS formation.SENEX expression of 21 B-NHL patients and 8 healthy controls were analyzed by qRT-PCR,and the correlation between its expression and clinical indicators were evaluated.Results:The downregulation of SENEX expression promotes G1-S phase transition and apoptosis while inhibiting cell proliferation,collectively suppressing the formation of TIS in B-NHL.Blockade of CDK4/6 promotes the DOX-induced G1 phase arrest to enhance TIS formation in B-NHL cells which can reverse the regulatory effect of silencing SENEX on B-NHL cell cycle regulation and senescence.The expression levels of SENEX were notably elevated in B-NHL patients compared to healthy controls,and Elevated expression levels of SENEX were associated with poor prognosis of B-NHL patients.Conclusions:SENEX enhances apoptosis resistance in B-NHL by inhibiting CDK4/6,thereby preventing G1-S phase transition and promoting TIS formation.
文摘目的分析CDK4/6抑制剂在临床应用中所致不良反应(ADR)的特点,为临床安全用药提供参考。方法检索维普、中国知网、万方、Web of Science、PubMed等数据库中关于CDK4/6抑制剂致ADRs的文献并进行分析。结果CDK4/6抑制剂致ADRs的个案报道共34例;患者平均年龄约63.5岁,ADRs多发生在用药4个月内(29例,85.29%);CDK4/6抑制剂致ADRs主要以皮肤及其附件损害(14例,41.18%)、呼吸系统损害(6例,17.65%)、肝胆系统损害(4例,11.76%)为主;经停药和/或对症治疗后达到症状好转或治愈的有31例;3例最终死亡。结论临床使用CDK4/6抑制剂时应加强用药监测,开展多学科患者管理,而CDK4/6抑制剂的ADR发生机制尚需进一步研究。
