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Quercetin pretreatment enhances the radiosensitivity of colon cancer cells by targeting Notch-1 pathway.

槲皮素预处理通过靶向 Notch-1 通路增强结肠癌细胞的放射敏感性。

  • 影响因子:2.69
  • DOI:10.1016/j.bbrc.2020.01.048
  • 作者列表:"Li Y","Wang Z","Jin J","Zhu SX","He GQ","Li SH","Wang J","Cai Y
  • 发表时间:2020-01-18
Abstract

:Cancer stem-like cells are rare immortal cells within tumor, which are thought to play important roles in ionizing radiation (IR) therapy-resistance. Quercetin is a natural flavonoid with potential anti-cancer properties without significant cytotoxicity in normal tissues. In this study, we demonstrated that quercetin-IR combination treatment exhibited more dramatic anti-cancer effect than either quercetin or IR treatment alone via targeting colon cancer stem cells (CSCs) and inhibiting the Notch-1 signaling. These effects were further verified by in vivo studies which showed remarkable decrease of the CSCs markers and the expression of Notch-1 signaling proteins in human colon cancer xenografts in nude mice. Co-treatment with quercetin and low dose of radiation significantly reduced the expressions of all five proteins of γ-secretase complex in HT-29 and DLD-1 cells. In addition, ectopic expression of the Notch intracellular domain (NICD) partly reversed the inhibition effects by the combination therapy. In conclusion, our results indicated that the combination of quercetin (20 μM) and IR (5Gy) might be a promising therapeutic strategy for colon cancer treatment by targeting colon cancer stem-like cells and inhibiting the Notch-1 signaling. In future studies, we intend to further explore the potential therapeutic efficacy of the quercetin-radiation combination treatment in clinical trials.

摘要

肿瘤干细胞样细胞是肿瘤内罕见的永生细胞,被认为在电离辐射 (IR) 治疗抵抗中发挥重要作用。槲皮素是一种天然黄酮类化合物,具有潜在的抗癌特性,在正常组织中没有显着的细胞毒性。在这项研究中,我们证明了槲皮素-IR 联合治疗比单独槲皮素或 IR 治疗通过靶向结肠癌干细胞 (CSCs) 表现出更显著的抗癌效果抑制 Notch-1 信号。这些作用进一步被体内研究证实,体内研究显示 CSCs 标志物和 Notch-1 信号蛋白在人结肠癌裸鼠移植瘤中的表达显著降低。槲皮素和低剂量辐射共同处理显著降低了 HT-29 和 DLD-1 细胞中 γ-分泌酶复合物所有 5 种蛋白的表达。此外,Notch 细胞内结构域 (NICD) 的异位表达部分逆转了联合治疗的抑制作用。总之,我们的结果表明槲皮素 (20 μ m) 和 IR (5Gy) 的组合通过靶向结肠癌干细胞样细胞和抑制 Notch-1 信号传导,可能是结肠癌治疗的一个有前途的治疗策略。在未来的研究中,我们打算在临床试验中进一步探索槲皮素-辐射联合治疗的潜在治疗效果。

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影响因子:2.03
发表时间:2020-01-27
DOI:10.1080/09553002.2020.1721609
作者列表:["Anuja K","Kar M","Chowdhury AR","Shankar G","Padhi S","Roy S","Akhter Y","Rath AK","Banerjee B"]

METHODS::Aims: Radiotherapy is predominantly used as one of the treatment modalities to treat local tumor in colorectal cancer (CRC). Hindrance in disease treatment can be attributed to radio-tolerance of cancer stem cells (CSCs) subsistence in the tumor. Understanding the radio-resistant property of CSCs might help in the accomplishment of targeted radiotherapy treatment and increased disease-free survival. Telomeric RAP1 contributes in modulation of various transcription factors leading to aberrant cell proliferation and tumor cell migration. Therefore, we investigated the role of RAP1 in maintaining resistance phenotype and acquired stemness in radio-resistant cells.Main Methods: Characterization of HCT116 derived radio-resistant cell (HCT116RR) was performed by cell survival and DNA damage profiling. RAP1 silenced cells were investigated for DNA damage and expression of CSC markers through western blotting and Real-time PCR post-irradiation. Molecular docking and co-immunoprecipitation study were performed to investigate RAP1 and KLF4 interaction followed by RAP1 protein status profiling in CRC patient.Key findings: We established radio-resistant cells, which showed tolerance to radiotherapy and elevated expression of CSC markers along with RAP1. RAP1 silencing showed enhanced DNA damage and reduced expression of CSC markers post-irradiation. We observed strong physical interaction between RAP1 and KLF4 protein. Furthermore, higher RAP1 expression was observed in the tumor of CRC patients. Dataset analysis also revealed that high expression of RAP1 expression is associated with poor prognosis.Significance: We conclude that higher expression ofRAP1 implicates its possible role in promoting radio-resistance in CRC cells by modulating DNA damage and CSC phenotype.

翻译标题与摘要 下载文献
影响因子:2.69
发表时间:2020-01-18
DOI:10.1016/j.bbrc.2020.01.048
作者列表:["Li Y","Wang Z","Jin J","Zhu SX","He GQ","Li SH","Wang J","Cai Y"]

METHODS::Cancer stem-like cells are rare immortal cells within tumor, which are thought to play important roles in ionizing radiation (IR) therapy-resistance. Quercetin is a natural flavonoid with potential anti-cancer properties without significant cytotoxicity in normal tissues. In this study, we demonstrated that quercetin-IR combination treatment exhibited more dramatic anti-cancer effect than either quercetin or IR treatment alone via targeting colon cancer stem cells (CSCs) and inhibiting the Notch-1 signaling. These effects were further verified by in vivo studies which showed remarkable decrease of the CSCs markers and the expression of Notch-1 signaling proteins in human colon cancer xenografts in nude mice. Co-treatment with quercetin and low dose of radiation significantly reduced the expressions of all five proteins of γ-secretase complex in HT-29 and DLD-1 cells. In addition, ectopic expression of the Notch intracellular domain (NICD) partly reversed the inhibition effects by the combination therapy. In conclusion, our results indicated that the combination of quercetin (20 μM) and IR (5Gy) might be a promising therapeutic strategy for colon cancer treatment by targeting colon cancer stem-like cells and inhibiting the Notch-1 signaling. In future studies, we intend to further explore the potential therapeutic efficacy of the quercetin-radiation combination treatment in clinical trials.

翻译标题与摘要 下载文献
影响因子:2.46
发表时间:2020-01-01
DOI:10.1097/COC.0000000000000609
作者列表:["Appelt AL","Andersen RF","Lindebjerg J","Jakobsen A"]

METHODS:OBJECTIVES:Long-term prevention of metastatic disease remains a challenge in locally advanced rectal cancer, and robust pretreatment prognostic factors for metastatic progression are lacking. We hypothesized that detecting circulating tumor-specific DNA (ctDNA) based on hypermethylation of the neuropeptide Y gene (meth-ctDNA) could be a prognostic marker in the neoadjuvant setting; we examined this in a secondary, explorative analysis of a prospective trial. MATERIALS AND METHODS:Serum samples were prospectively collected in a phase III trial for locally advanced rectal cancer. Positivity for and fractional abundance of meth-ctDNA in baseline samples were estimated. Overall survival (OS) and the rate of distant metastases were compared between meth-ctDNA positive and negative patients; other prognostic factors were controlled for in multivariate Cox regression. Importance of quantitative load was examined by considering the fractional abundance of meth-ctDNA relative to total circulating DNA. RESULTS:Baseline serum samples were available for 146 patients. In total, 30 patients had presence of meth-ctDNA, with no correlation with cT (P=0.8) or cN (P=0.6) stages. Median follow-up was 10.6 years for OS and 5.1 years for freedom from distant metastases. Patients with meth-ctDNA had significantly worse 5-year OS (47% vs. 69%), even when controlling for other prognostic factors (hazard ratio=2.08; 95% confidence interval, 1.23-1.51). This seemed mainly driven by disparity in the rate of distant metastases (55% vs. 72% at 5 y, P=0.01); hazard ratio=2.20 (95% confidence interval, 1.19-4.07, P=0.01) in multivariate analysis. Increased quantitative load was highly significant for worse outcomes. CONCLUSIONS:Meth-ctDNA could be a potential prognostic marker in the neoadjuvant setting and may, if validated, identify patients at increased risk of distant metastases.

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