Objective:Parthenolide(PTL)induces anti-tumor effects via the nuclear factor kappa B(NF-κB)signaling pathway.MCL3,a PTL derivative,is a sesquiterpene lactone synthesized by the rearrangement and subsequent oxidation ...Objective:Parthenolide(PTL)induces anti-tumor effects via the nuclear factor kappa B(NF-κB)signaling pathway.MCL3,a PTL derivative,is a sesquiterpene lactone synthesized by the rearrangement and subsequent oxidation of PTL.The aim of this study was to elucidate the antitumor activity and mechanism of action of MCL3 in glioblastoma(GBM).Materials and Methods:The effects of MCL3 on G422 cell proliferation,apoptosis,invasion,and angiogenesis in vitro were measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay,flow cytometry,the cell invasion,and tube formation assays.The subcutaneously transplanted G422 xenograft model was used to detect the effect of MCL3 on tumor growth in vivo.Pathological changes were analyzed by immunohistochemical staining.The effects of MCL3 on NF-κB and Stat3 transcriptional activities were examined using a dual-luciferase reporter assay.Protein levels related to the NF-κB/interleukin(IL)-6/Stat3 signaling pathway were determined using western blot analysis.Results:MCL3 inhibited GBM cell proliferation,invasion,and angiogenesis in a concentration-dependent manner.Moreover,MCL3 decreased the transcriptional activities of NF-κB and Stat3.MCL3 suppressed tumor growth in the subcutaneously transplanted G422 xenograft model,while the inhibition rate was 79%in tumor weight at 40.0 mg/kg.MCL3 blocked the NF-κB/IL-6/Stat3 signaling pathway in G422 cells and tumor tissues,resulting in the downregulation of Stat3 target genes related to apoptosis,invasion,etc.,Conclusion:The results show that MCL3 might inhibit G422 GBM growth partly due to the inhibition of the NF-κB/IL-6/Stat3 signaling pathway.展开更多
Objective: To investigate the effects of CAL-101, particularly when combined with bortezomib(BTZ) on mantle cell lymphoma(MCL) cells, and to explore its relative mechanisms.Methods: MTT assay was applied to detect the...Objective: To investigate the effects of CAL-101, particularly when combined with bortezomib(BTZ) on mantle cell lymphoma(MCL) cells, and to explore its relative mechanisms.Methods: MTT assay was applied to detect the inhibitory effects of different concentrations of CAL-101. MCL cells were divided into four groups: control group, CAL-101 group, BTZ group, and CAL-101/BTZ group. The expression of PI3K-p110σ, AKT, ERK, p-AKT and p-ERK were detected by Western blot. The apoptosis rates of CAL-101 group, BTZ group, and combination group were detected by flow cytometry. The location changes of nuclear factor kappa-B(NF-κB) of 4 groups was investigated by NF-κB Kit exploring. Western blot was applied to detect the levels of caspase-3 and the phosphorylation of AKT in different groups. Results: CAL-101 dose- and time-dependently induced reduction in MCL cell viability. CAL-101 combined with BTZ enhanced the reduction in cell viability and apoptosis. Western blot analysis showed that CAL-101 significantly blocked the PI3K/AKT and ERK signaling pathway in MCL cells. The combination therapy contributed to the inactivation of NF-κB and AKT in MCL cell lines. However, cleaved caspase-3 was up-regulated after combined treatment. Conclusion: Our study showed that PI3K/p110σ is a novel therapeutic target in MCL, and the underlying mechanism could be the blocking of the PI3K/AKT and ERK signaling pathways. These findings provided a basis for clinical evaluation of CAL-101 and a rationale for its application in combination therapy, particularly with BTZ.展开更多
基金supported by the Chinese Academy of Medical Sciences(CAMS)Initiation fund for Medical Science(2016-I2M-1-008)the Drug Innovation Major Project(2018ZX09711-001-005)。
文摘Objective:Parthenolide(PTL)induces anti-tumor effects via the nuclear factor kappa B(NF-κB)signaling pathway.MCL3,a PTL derivative,is a sesquiterpene lactone synthesized by the rearrangement and subsequent oxidation of PTL.The aim of this study was to elucidate the antitumor activity and mechanism of action of MCL3 in glioblastoma(GBM).Materials and Methods:The effects of MCL3 on G422 cell proliferation,apoptosis,invasion,and angiogenesis in vitro were measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay,flow cytometry,the cell invasion,and tube formation assays.The subcutaneously transplanted G422 xenograft model was used to detect the effect of MCL3 on tumor growth in vivo.Pathological changes were analyzed by immunohistochemical staining.The effects of MCL3 on NF-κB and Stat3 transcriptional activities were examined using a dual-luciferase reporter assay.Protein levels related to the NF-κB/interleukin(IL)-6/Stat3 signaling pathway were determined using western blot analysis.Results:MCL3 inhibited GBM cell proliferation,invasion,and angiogenesis in a concentration-dependent manner.Moreover,MCL3 decreased the transcriptional activities of NF-κB and Stat3.MCL3 suppressed tumor growth in the subcutaneously transplanted G422 xenograft model,while the inhibition rate was 79%in tumor weight at 40.0 mg/kg.MCL3 blocked the NF-κB/IL-6/Stat3 signaling pathway in G422 cells and tumor tissues,resulting in the downregulation of Stat3 target genes related to apoptosis,invasion,etc.,Conclusion:The results show that MCL3 might inhibit G422 GBM growth partly due to the inhibition of the NF-κB/IL-6/Stat3 signaling pathway.
基金supported by the National Natural Science Foundation of China (Grant No. 30672208, 81270603, and 31301161)Tianjin Natural Science Foundation of China (Grant No. 13JCYBJC22800)
文摘Objective: To investigate the effects of CAL-101, particularly when combined with bortezomib(BTZ) on mantle cell lymphoma(MCL) cells, and to explore its relative mechanisms.Methods: MTT assay was applied to detect the inhibitory effects of different concentrations of CAL-101. MCL cells were divided into four groups: control group, CAL-101 group, BTZ group, and CAL-101/BTZ group. The expression of PI3K-p110σ, AKT, ERK, p-AKT and p-ERK were detected by Western blot. The apoptosis rates of CAL-101 group, BTZ group, and combination group were detected by flow cytometry. The location changes of nuclear factor kappa-B(NF-κB) of 4 groups was investigated by NF-κB Kit exploring. Western blot was applied to detect the levels of caspase-3 and the phosphorylation of AKT in different groups. Results: CAL-101 dose- and time-dependently induced reduction in MCL cell viability. CAL-101 combined with BTZ enhanced the reduction in cell viability and apoptosis. Western blot analysis showed that CAL-101 significantly blocked the PI3K/AKT and ERK signaling pathway in MCL cells. The combination therapy contributed to the inactivation of NF-κB and AKT in MCL cell lines. However, cleaved caspase-3 was up-regulated after combined treatment. Conclusion: Our study showed that PI3K/p110σ is a novel therapeutic target in MCL, and the underlying mechanism could be the blocking of the PI3K/AKT and ERK signaling pathways. These findings provided a basis for clinical evaluation of CAL-101 and a rationale for its application in combination therapy, particularly with BTZ.
