Background:Regulatory proteins involved in human cellular division and proliferation,cyclin-dependent kinases 4 and 6(CDK4/6)are overexpressed in numerous cancers,including triple-negative breast cancer(TNBC).TNBC is ...Background:Regulatory proteins involved in human cellular division and proliferation,cyclin-dependent kinases 4 and 6(CDK4/6)are overexpressed in numerous cancers,including triple-negative breast cancer(TNBC).TNBC is a common pathological subtype of breast cancer that is prone to recurrence and metastasis,and has a single treatment method.As one of the CDK4/6 inhibitors,abemaciclib can effectively inhibit the growth of breast tumors.In this study,we synthesized LA-D-B1,a derivative of Abemaciclib,and investigated its anti-tumor effects in breast cancer.Methods:Cellular viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)assay.Cell cloning and migration abilities were determined by colony formation assay and wound healing assay.Cell invasion abilities and adhesion were determined by cell invasion assay and cell adhesion assay.The impact of compound LA-D-B1 on cell proliferation and the cell cycle was analyzed through Western blotting,which quantified the levels of proteins associated with the cyclin-dependent kinase(CDK)4/6-cyclin D-Rb-E2F pathway.The in vivo anti-tumor activity of compound LA-D-B1 was investigated using a chick chorioallantoic membrane(CAM)model.Results:The study demonstrated that LA-D-B1 effectively suppressed breast cancer cell proliferation,induced apoptosis,and caused cell cycle arrest.Furthermore,LA-D-B1 reduced the expression of key proteins in the CDK4/6-cyclin D-Rb-E2F pathway,including CDK4,CDK6 and E2F1.The results also indicated significant antitumor activity of LA-D-B1 in a transplanted tumor model.Conclusion:In this study,LA-D-B1 demonstrated a potent anti-tumor effect by effectively suppressing cell proliferation and inhibiting cell cycle progression in breast cancer.These findings highlight the potential of LA-D-B1 as a valuable compound for enhancing therapeutic outcomes and controlling the progression of breast cancer.展开更多
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
基金supported by the National Natural Science Foundation of China(82273167,82104174,81602626,12271068,82172558 and 82373112)Jiangsu Province Basic Research Program Natural Science Foundation(Outstanding Youth Fund Project,BK20220063)+7 种基金the Key Program of Basic Science(Natural Science)of Jiangsu Province(22KJA350001)“Huaguo Mountain Talent Plan”of Lianyungang City(Innovative Talents Liu Bin)Qing Lan Project of Jiangsu Universities(Outstanding Young Backbone Teachers,Ji Jing)the Natural Science Foundation of Jiangsu Higher Education Institutions of China(No.20KJB350008)Priority Academic Program Development of Jiangsu Higher Education Institutions,College Students’Innovative Entrepreneurial Training Plan Program(Project Nos.SY202211641640011,SY202311641640002 and SZ202311641640002)Chen Xiao-Ping Foundation for the Development of Science and Technology of Hubei Province(Project No.CXPJJH123003-027)the Distinguished Young Scholars of Nanjing(JQX20008)Scientific Research Foundation for Returned Scholars of Tongji Hospital(Project 2022hgry021).
文摘Background:Regulatory proteins involved in human cellular division and proliferation,cyclin-dependent kinases 4 and 6(CDK4/6)are overexpressed in numerous cancers,including triple-negative breast cancer(TNBC).TNBC is a common pathological subtype of breast cancer that is prone to recurrence and metastasis,and has a single treatment method.As one of the CDK4/6 inhibitors,abemaciclib can effectively inhibit the growth of breast tumors.In this study,we synthesized LA-D-B1,a derivative of Abemaciclib,and investigated its anti-tumor effects in breast cancer.Methods:Cellular viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)assay.Cell cloning and migration abilities were determined by colony formation assay and wound healing assay.Cell invasion abilities and adhesion were determined by cell invasion assay and cell adhesion assay.The impact of compound LA-D-B1 on cell proliferation and the cell cycle was analyzed through Western blotting,which quantified the levels of proteins associated with the cyclin-dependent kinase(CDK)4/6-cyclin D-Rb-E2F pathway.The in vivo anti-tumor activity of compound LA-D-B1 was investigated using a chick chorioallantoic membrane(CAM)model.Results:The study demonstrated that LA-D-B1 effectively suppressed breast cancer cell proliferation,induced apoptosis,and caused cell cycle arrest.Furthermore,LA-D-B1 reduced the expression of key proteins in the CDK4/6-cyclin D-Rb-E2F pathway,including CDK4,CDK6 and E2F1.The results also indicated significant antitumor activity of LA-D-B1 in a transplanted tumor model.Conclusion:In this study,LA-D-B1 demonstrated a potent anti-tumor effect by effectively suppressing cell proliferation and inhibiting cell cycle progression in breast cancer.These findings highlight the potential of LA-D-B1 as a valuable compound for enhancing therapeutic outcomes and controlling the progression of breast cancer.
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.
