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Combination therapy of niclosamide with gemcitabine inhibited cell proliferation and apoptosis via Wnt/β-catenin/c-Myc signaling pathway by inducing β-catenin ubiquitination in pancreatic cancer. 氯硝柳胺与吉西他滨联合治疗通过Wnt/β-catenin/c-Myc信号通路诱导β-catenin泛素化抑制癌症细胞增殖和凋亡。
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-12-31 Epub Date: 2023-11-02 DOI: 10.1080/15384047.2023.2272334
Hyeon Woong Kang, Ju Hyun Kim, Da Eun Lee, Yun Sun Lee, Myeong Jin Kim, Hyung Sun Kim, SungSoon Fang, Bo Eun Lee, Kyung Jin Lee, Jongman Yoo, Hyo Jung Kim, Joon Seong Park

Pancreatic ductal adenocarcinoma (PDAC) is a type of cancer with high morbidity and mortality rates worldwide. Owing to a lack of therapeutic options, the overall survival rate of patients with pancreatic cancer is low. Gemcitabine has been mainly used to treat patients with pancreatic cancer, but its efficacy is limited by chemoresistance. Therefore, a novel therapeutic agent for PDAC therapy is urgently needed. An anthelminthic drug, niclosamide, has already been researched in breast, lung, colon, and pancreatic cancer as an anti-cancer purpose by re-positioning its original purpose. However, combination therapy of gemcitabine and niclosamide was not informed yet. Here, we found that niclosamide co-administered with gemcitabine significantly inhibited tumorigenesis of pancreatic cancer compared to gemcitabine alone. Further, combining niclosamide and gemcitabine inhibited cell proliferation and induced apoptosis. Niclosamide induced cell cycle arrest at the G1 phase, and the levels of CDK4/6 and cyclin D1 were lowered after gemcitabine treatment. In addition, the combination of these chemical compounds more effectively increased the binding level of activated β-catenin destruction complex and β-catenin to enable phosphorylation, compared to gemcitabine alone. After phosphorylation, niclosamide - gemcitabine upregulated the ubiquitin level, which caused phosphorylated β-catenin to undergo proteasomal degradation; the combination was more potent than gemcitabine alone. Finally, the combination more effectively suppressed tumor growth in vivo, compared to gemcitabine alone. Altogether, our results indicate that niclosamide synergistically enhances the antitumor effect of gemcitabine in pancreatic cancer, by inducing the degradation of β-catenin with ubiquitination. Therefore, this drug combination can potentially be used in PDAC therapy.

胰腺导管腺癌(PDAC)是一种癌症,在世界范围内发病率和死亡率较高。由于缺乏治疗方案,癌症患者的总生存率较低。吉西他滨主要用于治疗癌症患者,但其疗效受到化疗耐药性的限制。因此,迫切需要一种新型的PDAC治疗剂。一种驱虫药,氯硝柳胺,已经被研究用于乳腺癌、肺癌、结肠癌和胰腺癌癌症,通过重新定位其原始用途来达到抗癌目的。然而,吉西他滨和氯硝柳胺的联合治疗尚未被告知。在此,我们发现与单独使用吉西他滨相比,氯硝柳胺与吉西他宾联合用药显著抑制了胰腺癌症的肿瘤发生。此外,氯硝柳胺和吉西他滨联合使用可抑制细胞增殖并诱导细胞凋亡。氯硝柳胺诱导细胞周期停滞在G1期,吉西他滨治疗后CDK4/6和细胞周期蛋白D1水平降低。此外,与单独使用吉西他滨相比,这些化合物的组合更有效地提高了活化的β-连环蛋白破坏复合物和β-连环素的结合水平,以实现磷酸化。磷酸化后,氯硝柳胺-吉西他滨上调泛素水平,导致磷酸化的β-连环蛋白发生蛋白酶体降解;联合用药比单独使用吉西他滨更有效。最后,与单独使用吉西他滨相比,该组合更有效地抑制了体内肿瘤生长。总之,我们的研究结果表明,氯硝柳胺通过诱导β-连环蛋白的降解和泛素化,协同增强吉西他滨在癌症中的抗肿瘤作用。因此,这种药物组合有可能用于PDAC治疗。
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引用次数: 0
The efficacy of induction chemotherapy or adjuvant chemotherapy added to concurrent chemoradiotherapy in T3-4N0-1M0 nasopharyngeal carcinoma: a propensity score-matched analysis. T3-4N0-1M0鼻咽癌诱导化疗或辅助化疗联合放化疗的疗效:倾向评分匹配分析
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-12-31 Epub Date: 2023-11-15 DOI: 10.1080/15384047.2023.2274121
Qiulu Zhong, Danjing Luo, Xiangde Li, Qinghua Du, Qianfu Liang, Wenqi Liu, Jian Li, Xiaodong Zhu
ABSTRACT This research aimed to assess the effectiveness of combining induction chemotherapy (IC) or adjuvant chemotherapy (AC) with concurrent chemoradiotherapy (CCRT) in patients with T3-4N0-1M0 nasopharyngeal carcinoma (NPC). Before propensity score matching(PSM),we retrospectively collected 457 patients with T3-4N0-1M0 NPC treated with CCRT with or without IC/AC. PSM method selected 285 patients from two cohort(148 in CCRT±IC/AC group,137 in CCRT group). The 3-year overall survival(OS), locoregional relapse-free survival (LRFS) and distant metastasis-free survival (DMFS) were estimated. The median follow-up was 41.03 months(range 2.13–94.67 months). No significant differences in 3 year-OS,LRFS and DMFS between CCRT±IC/AC group and CCRT group.Univariate analysis have shown that induction chemotherapy was significantly associated with 3 year LRFS(hazard ratio[HR] 0.214, 95%confidence interval[CI] 0.053–0.861,P = .030).Overall stage(HR 0.260, CI 0.078–0.870, P = .029) and T classification (HR 0.260, CI 0.078–0.870, P = .029)were significantly associated with OS.Multivariate analysis demonstrated no independent factors were related to 3-year OS,LRFS and DMFS. Subgroup analyses revealed that no significant survival differences in the two groups in patients with T3N1.In terms of T4N1 disease, patients received CCRT±IC/AC had lower 3-year DMFS than those treated with CCRT(90.4% vs 98.7%, P = .015). Adding IC or AC to CCRT did not significantly improve the prognosis of T3-4N0-1M0 NPC patients. Patients with T4N1M0 treated with CCRT had better DMFS than those received CCRT±IC/AC.However,more investigations should be confirmed the results.
本研究旨在评估诱导化疗(IC)或辅助化疗(AC)联合同步放化疗(CCRT)治疗T3-4N0-1M0鼻咽癌(NPC)患者的有效性。在倾向评分匹配(PSM)之前,我们回顾性收集了457例接受CCRT治疗的T3-4N0-1M0鼻咽癌患者,有或没有IC/AC。PSM方法选择两组285例患者(CCRT±IC/AC组148例,CCRT组137例)。估计3年总生存期(OS)、局部无复发生存期(LRFS)和远处无转移生存期(DMFS)。中位随访时间为41.03个月(2.13-94.67个月)。CCRT±IC/AC组与CCRT组3年os、LRFS、DMFS无显著差异。单因素分析显示,诱导化疗与3年LRFS显著相关(风险比[HR] 0.214, 95%可信区间[CI] 0.053-0.861,P = 0.030)。总分期(HR 0.260, CI 0.078 ~ 0.870, P = 0.029)和T分期(HR 0.260, CI 0.078 ~ 0.870, P = 0.029)与OS显著相关。多因素分析显示,3年OS、LRFS和DMFS无独立影响因素。亚组分析显示,两组T3N1患者的生存率无显著差异。在T4N1疾病方面,接受CCRT±IC/AC治疗的患者3年DMFS低于接受CCRT治疗的患者(90.4% vs 98.7%, P = 0.015)。在CCRT中加入IC或AC对T3-4N0-1M0鼻咽癌患者的预后没有显著改善。CCRT治疗T4N1M0患者的DMFS优于CCRT±IC/AC治疗。然而,这一结果还需要更多的调查来证实。
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引用次数: 0
Chaperonin containing TCP1 subunit 6A may activate Notch and Wnt pathways to facilitate the malignant behaviors and cancer stemness in oral squamous cell carcinoma 含 TCP1 亚基 6A 的伴侣素可能会激活 Notch 和 Wnt 通路,从而促进口腔鳞状细胞癌的恶性行为和癌症干细胞的形成
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-12-12 DOI: 10.1080/15384047.2023.2287122
Yangyi Chen, Yongge Chen, Weixian Liu
Chaperonin containing TCP1 subunit 6A (CCT6A) was recently discovered to be involved in cancer pathogenesis and stemness; however, its role in oral squamous cell carcinoma (OSCC) has not been repor...
最近发现,含TCP1亚基的伴侣素6A(CCT6A)参与了癌症发病机制和干细胞的形成;然而,它在口腔鳞状细胞癌(OSCC)中的作用尚未被报道。
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引用次数: 0
Elucidating structural variability in p53 conformers using combinatorial refinement strategies and molecular dynamics 利用组合细化策略和分子动力学阐明 p53 构象的结构可变性
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-12-10 DOI: 10.1080/15384047.2023.2290732
Md Rimon Parves, Maria J. Solares, William J. Dearnaley, Deborah F. Kelly
Low molecular weight proteins and protein assemblies can now be investigated using cryo-electron microscopy (EM) as a complement to traditional structural biology techniques. It is important, howev...
作为传统结构生物学技术的补充,现在可以使用冷冻电镜(EM)来研究低分子量蛋白质和蛋白质组装体。然而,重要的是...
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引用次数: 0
The amino acid transporter SLC7A11 expression in breast cancer 乳腺癌中氨基酸转运体 SLC7A11 的表达
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-12-10 DOI: 10.1080/15384047.2023.2291855
Preyanka Nath, Lutfi H. Alfarsi, Rokaya El-Ansari, Brendah K. Masisi, Busra Erkan, Ali Fakroun, Ian O. Ellis, Emad A. Rakha, Andrew R. Green
Breast cancer (BC), characterized by its diverse molecular profiles and clinical outcomes, presents a significant challenge in the development of effective therapeutic strategies. Metabolic reprogr...
乳腺癌(BC)的分子特征和临床结果多种多样,这给有效治疗策略的开发带来了巨大挑战。新陈代谢重塑是乳腺癌治疗的关键。
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引用次数: 0
Tumor-derived exosomal miR-1247-3p promotes angiogenesis in bladder cancer by targeting FOXO1 源于肿瘤的外泌体 miR-1247-3p 通过靶向 FOXO1 促进膀胱癌的血管生成
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-12-10 DOI: 10.1080/15384047.2023.2290033
Zonglai Liu, Dan Du, Shizhong Zhang
Tumor-derived exosomes are highly correlated with tumor progression and angiogenesis. This study was designed to probe the role of tumor-derived exosomal miR-1247-3p in mediating the angiogenesis i...
肿瘤衍生的外泌体与肿瘤进展和血管生成高度相关。本研究旨在探究肿瘤源性外泌体 miR-1247-3p 在介导肿瘤血管生成中的作用。
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引用次数: 0
Molecular profiles of different PD-L1 expression in patients with esophageal squamous cell carcinoma 食管鳞状细胞癌患者PD-L1不同表达的分子图谱
4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-09-21 DOI: 10.1080/15384047.2023.2256927
Songchen Zhao, Xintong Hu, Peiwen Zhou, Ang Li, Liguo Chen, Duo Wang, Jiaxue He, Yanfang Jiang
Background PD-1/PD-L1 inhibitors are approved treatments for patients with esophageal squamous cell carcinoma (ESCC). The present investigation aspired to explore the interrelation between molecular phenotype and PD-L1 expression in ESCC.
背景PD-1/PD-L1抑制剂已被批准用于食管鳞状细胞癌(ESCC)患者的治疗。本研究旨在探讨ESCC中分子表型与PD-L1表达之间的相互关系。
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引用次数: 0
NEDD4L inhibits glycolysis and proliferation of cancer cells in oral squamous cell carcinoma by inducing ENO1 ubiquitination and degradation. NEDD4L通过诱导ENO1泛素化和降解抑制口腔鳞状细胞癌糖酵解和癌细胞增殖。
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-12-31 DOI: 10.1080/15384047.2022.2054244
Guangping Zhang, Xin Zhao, Weixian Liu

Glycolysis contributes to cell metabolism and facilitates cell proliferation of oral squamous cell carcinoma (OSCC), the most common type of oral cancer. Understanding the regulatory mechanisms involved in the glycolysis of OSCC cells may provide important therapeutic inspirations. Immunohistochemistry was used to examine protein localization patterns in human OSCC tissues and Western blot was conducted to gauge protein level. Lentivirus transduction was used to overexpress or silence genes of interest. Cell proliferation was assessed by Cell Counting Kit (CCK)-8 assay while glycolysis was examined via measurement of extracellular acidification rate, oxygen consumption rate, and lactate and ATP production. In vivo cancer development was evaluated with a mouse tumor growth model. OSCC tissues displayed reduced expression of NEDD4L compared with normal tissues. NEDD4L expression positively correlated with 5-year patient survival rate, indicating that NEDD4L may be a prognosis marker for OSCC. NEDD4L overexpression suppressed proliferation, cell cycle transition, and glycolysis in OSCC cells, and inhibited in vivo tumor growth. UbiBrowser identified ENO1, an enzyme that catalyzes glycolysis, as a substrate of NEDD4L. Overexpression of NEDD4L resulted in the ubiquitination and subsequent degradation of ENO1 whereas overexpression of ENO1 reversed the functional effects of NEDD4L overexpression, restoring proliferation, cell cycle transition, and glycolysis in OSCC cells. NEDD4L elicits tumor-suppressive functions via inhibition of OSCC cell proliferation, cell cycle transition, and glycolysis by stimulating ENO1 ubiquitination and degradation. Our results unraveled a signaling axis important for OSCC cell survival and metabolism, which can serve as a potential therapeutic target.

糖酵解有助于细胞代谢,促进口腔鳞状细胞癌(OSCC)细胞增殖,口腔鳞状细胞癌是最常见的口腔癌类型。了解参与OSCC细胞糖酵解的调节机制可能提供重要的治疗灵感。采用免疫组化技术检测人OSCC组织中蛋白定位模式,Western blot检测蛋白水平。慢病毒转导用于过表达或沉默感兴趣的基因。通过细胞计数试剂盒(CCK)-8检测细胞增殖,通过测量细胞外酸化率、耗氧量、乳酸和ATP产量检测糖酵解。用小鼠肿瘤生长模型评估体内肿瘤的发展。与正常组织相比,OSCC组织NEDD4L表达降低。NEDD4L表达与患者5年生存率呈正相关,提示NEDD4L可能是OSCC的预后指标。NEDD4L过表达抑制OSCC细胞增殖、细胞周期转变和糖酵解,抑制体内肿瘤生长。UbiBrowser发现ene1,一种催化糖酵解的酶,是NEDD4L的底物。NEDD4L的过表达导致ENO1的泛素化和随后的降解,而ENO1的过表达逆转了NEDD4L过表达的功能作用,恢复了OSCC细胞的增殖、细胞周期转变和糖酵解。NEDD4L通过刺激ENO1泛素化和降解,抑制OSCC细胞增殖、细胞周期转变和糖酵解,从而引发肿瘤抑制功能。我们的研究结果揭示了一个对OSCC细胞存活和代谢很重要的信号轴,它可以作为潜在的治疗靶点。
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引用次数: 14
CAFs-derived small extracellular vesicles circN4BP2L2 promotes proliferation and metastasis of colorectal cancer via miR-664b-3p/HMGB3 pathway. cafs来源的细胞外小泡circN4BP2L2通过miR-664b-3p/HMGB3途径促进结直肠癌的增殖和转移。
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-12-31 DOI: 10.1080/15384047.2022.2072164
Keda Yang, Fan Zhang, Baihua Luo, Zhan Qu

Our previous research has demonstrated that colorectal cancer (CRC) progression was promoted by circN4BP2L2. This study aimed to further explore the mechanism of circN4BP2L2 in the development of CRC from the perspective of small extracellular vesicles (sEVs). Cancer-associated fibroblasts cell (CAFs) and normal fibroblasts cell (NFs) were isolated from CRC tissues and adjacent tissues, respectively. The ultra-centrifugation was used for extraction of their related sEVs. Cell proliferation and apoptosis were analyzed using CCK-8 and flow cytometry, respectively. Transwell assay was conducted to measure cell migration. The tube formation ability was assessed by tube formation assay. The target relationships between circN4BP2L2 and miR-664b-3p, and miR-664b-3p and HMGB3 were validated by dual-luciferase reporter detection. The effect of CAFs-derived sEV (CAFs-sEVs) circN4BP2L2 on CRC was further studied in nude mice. CAFs-exo promoted cell proliferation, migration, tube formation ability, and inhibited apoptosis of CRC cells. CAFs-sEV circN4BP2L2 knockdown reversed the above results. CircN4BP2L2 directly targeted miR-664b-3p, and HMGB3 was targeted by miR-664b-3p. Moreover, subcutaneous tumorigenesis and liver metastasis of nude mice with CRC were repressed by CAFs-sEV circN4BP2L2 knockdown. CAFs-sEV circN4BP2L2 knockdown restrained CRC cell proliferation and migration by regulating miR-664b-3p/HMGB3 pathway.

我们之前的研究表明,circN4BP2L2促进了结直肠癌(CRC)的进展。本研究旨在从细胞外小泡(sEVs)的角度进一步探讨circN4BP2L2在结直肠癌发生发展中的机制。分别从结直肠癌组织和癌旁组织中分离出癌相关成纤维细胞(CAFs)和正常成纤维细胞(NFs)。采用超离心法提取其相关sev。CCK-8和流式细胞术分别检测细胞增殖和凋亡。Transwell法测定细胞迁移量。通过成管试验评价其成管能力。通过双荧光素酶报告基因检测验证circN4BP2L2与miR-664b-3p、miR-664b-3p与HMGB3之间的靶标关系。在裸鼠实验中进一步研究了cafs衍生sEV (cafs -sEV) circN4BP2L2对结直肠癌的影响。CAFs-exo促进细胞增殖、迁移、成管能力,抑制结直肠癌细胞凋亡。CAFs-sEV circN4BP2L2敲低逆转了上述结果。CircN4BP2L2直接靶向miR-664b-3p, HMGB3被miR-664b-3p靶向。此外,CAFs-sEV敲低circN4BP2L2可抑制结直肠癌裸鼠皮下肿瘤发生和肝转移。CAFs-sEV circN4BP2L2敲低通过调控miR-664b-3p/HMGB3通路抑制结直肠癌细胞增殖和迁移。
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引用次数: 6
PSMD12 promotes the activation of the MEK-ERK pathway by upregulating KIF15 to promote the malignant progression of liver cancer. PSMD12通过上调KIF15促进MEK-ERK通路的激活,从而促进肝癌的恶性进展。
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-12-31 DOI: 10.1080/15384047.2022.2125260
Hanpu Zhang, Chenyuan Li, Shichong Liao, Yi Tu, Shengrong Sun, Feng Yao, Zhiyu Li, Zhong Wang

The tumor recurrence and drug resistance of hepatocellular carcinoma (HCC) threatened patients a lot. The mechanism should be further explored. The information of expression status and survival were available in public databases. The Western blot and immunohistochemistry staining displayed the level of related proteins. CCK-8, colony-formation assays, transwell assay and wound healing assay were performed to illustrate the ability of tumor growth, invasion and migration. In vivo model was established to verify our cell experiments. In our study, we revealed that proteasome 26S subunit, non-ATPase 12 (PSMD12) was high expressed in HCC tissues and positive related to the survival. In vitro experiments suggested that PSMD12 knockdown attenuated tumor cell growth, invasion and migration. Moreover, PSMD12 interference blocked the activation of MEK-ERK pathway. The ERK inhibitor could alleviate the tumor-promoting effect in PSMD12-overexpression cells. In addition, kinesin family member 15 (KIF15) was also observed to be highly expressed in HCC and be harmful to the survival. The public database, the images of immunohistochemistry and the western blot illustrated that PSMD12 and KIF15 was positive correlated. KIF15 knockdown impaired tumor progression and tumor-promoting effect of PSMD12. The xenograft models supported the results of cell experiments. In conclusion, PSMD12 could activated MEK-ERK pathway via KIF15 upregulation, thereby promoting tumor progression.

肝细胞癌(HCC)的肿瘤复发和耐药给患者带来了很大的威胁。这一机制有待进一步探索。表达状态和存活信息可在公共数据库中查询。Western blot和免疫组化染色显示相关蛋白水平。通过CCK-8、菌落形成实验、transwell实验和伤口愈合实验来说明肿瘤的生长、侵袭和迁移能力。建立了体内模型来验证我们的细胞实验。在我们的研究中,我们发现蛋白酶体26S亚基,非atp酶12 (PSMD12)在HCC组织中高表达,并且与生存呈正相关。体外实验表明,PSMD12基因敲低可减弱肿瘤细胞的生长、侵袭和迁移。此外,PSMD12干扰阻断了MEK-ERK通路的激活。ERK抑制剂可减轻psmd12过表达细胞的促瘤作用。此外,在HCC中也观察到激酶家族成员15 (KIF15)的高表达,并对生存有害。公共数据库、免疫组化图像和western blot显示PSMD12与KIF15呈正相关。KIF15敲除抑制肿瘤进展和PSMD12的促瘤作用。异种移植模型支持细胞实验结果。综上所述,PSMD12可以通过上调KIF15激活MEK-ERK通路,从而促进肿瘤进展。
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引用次数: 2
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Cancer Biology & Therapy
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