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Fandong Meng Yan LiXin Tian Liye FuYuanqin Yin Chengguang SuiPing Ma Youhong Jiang 《Biochemical and biophysical research communications》2014
Renal cell carcinoma (RCC) is common renal malignancy within poor prognosis. TGF-β-activated kinase 1 (TAK1) plays vital roles in cell survival, apoptosis-resistance and carcinogenesis through regulating nuclear factor-κB (NF-κB) and other cancer-related pathways. Here we found that TAK1 inhibitors (LYTAK1, 5Z-7-oxozeanol (5Z) and NG-25) suppressed NF-κB activation and RCC cell (786-O and A489 lines) survival. TAK1 inhibitors induced apoptotic cytotoxicity against RCC cells, which was largely inhibited by the broad or specific caspase inhibitors. Further, shRNA-mediated partial depletion of TAK1 reduced 786-O cell viability whiling activating apoptosis. Significantly, TAK1 was over-expressed in human RCC tissues, and its level was correlated with phosphorylated NF-κB. Finally, kinase inhibition or genetic depletion of TAK1 enhanced the activity of vinblastine sulfate (VLB) in RCC cells. Together, these results suggest that TAK1 may be an important oncogene or an effective target for RCC intervention. 相似文献
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Lang JM Kaikobad MR Wallace M Staab MJ Horvath DL Wilding G Liu G Eickhoff JC McNeel DG Malkovsky M 《Cancer immunology, immunotherapy : CII》2011,60(10):1447-1460
Prior to the advent of VEGF-targeted therapies, renal cell carcinoma (RCC) was among the few solid tumors shown to respond
to cytokine-based therapies such as interleukin-2 (IL-2) and interferon alpha. Previous work has shown that aminobisphosphonates,
including zoledronic acid (ZA), are capable of activating human Vγ9 Vδ2 T cells in vitro, and these cells can be further expanded
with IL-2. Moreover, these Vγ9 Vδ2 T cells have cytolytic activity in vitro to multiple human tumor cell lines. In the current
report, we have conducted a pilot trial in patients with metastatic RCC, evaluating different doses of ZA in combination with
low-dose IL-2 to determine whether combining these agents can promote in vivo proliferation of Vγ9 Vδ2 T cells and elicit
an antitumor response. In 12 patients evaluated, no objective clinical responses were observed by RECIST criteria; however,
two patients experienced prolonged stable disease. A modest increase in Vγ9 Vδ2 T-cell frequency could be detected by Day
8 of therapy in four of the nine patients who received at least one cycle of therapy, but not to the magnitude anticipated
from preclinical models. Repeated administration of IL-2 and ZA resulted in both a diminished in vivo percentage of Vγ9 Vδ2
T cells as well as impaired expansion in vitro after the first cycle of therapy. These results suggest that repeated administration
of IL-2 and ZA, at the doses and schedules used in this trial, may actually inhibit the proliferative capacity of Vγ9 Vδ2
T cell in patients with metastatic RCC. 相似文献