目的 制备Ⅰ型葡萄糖转运蛋白(glucose transporter-1,GLUT-1)抑制剂BAY-876的微晶制剂,测定其药剂学特性,并利用裸鼠肝脏原位肿瘤模型确定BAY-876微晶制剂的长效-缓释特性与抗肝细胞癌(Hepatocellular carcinoma,HCC)的活性。方法 建立HCC细胞在裸鼠肝脏原位的肿瘤模型,对动物行灌胃给药,连续3 d给予BAY-876后解剖肝脏拍照并进行PET/CT检测。制备BAY-876的微晶制剂与增溶制剂,在HCC皮下肿瘤中注射BAY-876微晶与增溶制剂,在不同时间留取实验动物血液与肿瘤组织标本,通过检测标本中BAY-876含量确定BAY-876微晶制剂的缓释特性。在此基础上,在HCC肝脏原位肿瘤组织中注射BAY-876微晶与增溶制剂,在不同时间点进行PET/CT检测。结果 BAY-876具有显著的抑制HCC细胞生长作用。BAY-876微晶制剂能在组织局部起长效与缓释作用,在HCC肝脏原位单次给药即能实现对HCC肿瘤的抑制作用。结论 本实验制备的BAY-876微晶制剂对裸鼠肝脏原位的肿瘤抑制具有长效-缓释作用。
Abstract
OBJECTIVE To prepare the microcrystalline glucose transporter-1(GLUT-1)inhibitor BAY-876 and determine its pharmacological properties and examine the slow-release characteristics and in vivo anti-tumor efficiency of BAY-876-microcrystal on mice liver tumor model. METHODS The tumor model of HCC cells in liver of nude mice was established. The model mice were administrated BAY-876 by means of intragastric administration for three days, and then the liver of mice were photographed and examined by PET / CT. The solubilizing solution or microcrystalline BAY-876 was prepared. BAY-876-solution or microcrystal was injected into subcutaneous tumors. Blood and tumor tissue were taken from mice at different times, and the content of BAY-876 was detected. On this basis, BAY-876-solution or microcrystal was injected into the tumor in liver of nude mice, and the livers were tested by PET / CT at different times. RESULTS BAY-876-microcrystal can inhibit the cell growth of HCC cells. BAY-876-microcrystal can take long-term effect and slow-release in tissue. A single administration of BAY-876 in HCC liver can achieve the inhibition of HCC tumors CONCLUSION The microcrystal BAY-876 is prepared, which can long-term inhibit the tumor growth in liver of nude mice.
关键词
肝细胞癌 /
葡萄糖转运蛋白 /
BAY-876 /
微晶制剂
{{custom_keyword}} /
Key words
Hepatocellular carcinoma /
glucose transporter /
BAY-876 /
microcrystal agent
{{custom_keyword}} /
中图分类号：
R817.1
R735.7
{{custom_clc.code}}
({{custom_clc.text}})
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
[1] WANG F S, FAN J G, ZHANG Z, et al. The global burden of liver disease: the major impact of China. Hepatology,2014, 60(6):2099-2108.
[2] MA Y, CHEN Y, AN L J, et al. Clinical features of HBsAg-negative HBV-related hepatocellular carcinoma. J Clin Hepatol(临床肝胆病杂志), 2017, 33(4):674-678.
[3] FENG F, JIANG Q, JIA H, et al. Which is the best combination of TACE and sorafenib for advanced hepatocellular carcinoma treatment? A systematic review and network meta-analysis. Pharmacol Res, 2018, 135:89-101.
[4] JIA H, YANG Q, WANG T, et al. Rhamnetin induces sensitization of hepatocellular carcinoma cells to a small molecular kinase inhibitor or chemotherapeutic agents. Biochim Biophys Acta,2016, 1860(7):1417-1430.
[5] KIM D W,TALATI C,KIM R. Hepatocellular carcinoma (HCC): beyond sorafenib-chemotherapy. J Gastrointest Oncol,2017,8(2):256-265.
[6] MUECKLER M, THORENS B. The SLC2 (GLUT) family of membrane transporters. Mol Aspec Med, 2013, 34(2): 121-138.
[7] CHAN D A, SUTPHIN P D, NGUYEN P, et al. Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality. Sci Transl Med, 2011,3(94):94ra70.
[8] ADAMS D J, ITO D, REES M G, et al. NAMPT is the cellular target of STF-31-like small-molecule probes. ACS Chem Biol, 2014,9(10):2247-2254.
[9] LIU Y L, CAO Y, ZHANG W, et al. A small-molecule inhibitor of glucose transporter 1 downregulates glycolysis, induces cell-cycle arrest, and inhibits cancer cell growth in vitro and in vivo. Mol Cancer Ther, 2012, 11(8):1672-1682.
[10] LIU Y L, ZHANG W, CAO Y, et al. Small compound inhibitors of basal glucose transport inhibit cell proliferation and induce apoptosis in cancer cells via glucose-deprivation-like mechanisms. Cancer Lett, 2010, 298(2):176-185.
[11] ZHANG W, LIU Y, CHEN X, et al. Novel inhibitors of basal glucose transport as potential anticancer agents. Bioorg Med Chem Lett, 2010, 20(7):2191-2194.
[12] SIEBENEICHER H, CLEVE A, REHWINKEL H, et al. Identification and optimization of the first highly selective GLUT1 inhibitor BAY-876. Chem Med Chem, 2016, 11(20):2261-2271.
[13] AN L, LI D D, CHU H X, et al. Terfenadine combined with epirubicin impedes the chemo-resistant human non-small cell lung cancer both in vitro and in vivo through EMT and Notch reversal. Pharmacol Res, 2017, 124:105-115.
[14] SHAO Z, LI Y, DAI W, et al. ETS-1 induces sorafenib-resistance in hepatocellular carcinoma cells via regulating transcription factor activity of PXR. Pharmacol Res, 2018, 135:188-200.
[15] FENG F, JIANG Q, CAO S, et al. Pregnane X receptor mediates sorafenib resistance in advanced hepatocellular carcinoma. Biochim Biophys Acta Gen Subj, 2018, 1862(4):1017-1030.
[16] DENG D, XU C, SUN P, et al. Crystal structure of the human glucose transporter GLUT1. Nature, 2014, 510(7503): 121-125.
[17] XIE H, TIAN S, YU H, et al. A new apatinib microcrystal formulation enhances the effect of radiofrequency ablation treatment on hepatocellular carcinoma. Onco Targets Ther, 2018, 11:3257-3265.
[18] LUKÁOVÁ-CHOMISTEKOVÁ Z,CULKOVÁ E, BELLOVÁ R, et al. Voltammetric detection of antimony in natural water on cathodically pretreated microcrystalline boron doped diamond electrode: a possibility how to eliminate interference of arsenic without surface modification. Talanta,2018,178:943-948.
[19] XU X, FAN Z, KANG L, et al. Hepatitis B virus X protein represses miRNA-148a to enhance tumorigenesis. J Clin Invest, 2013, 123(2): 630.
[20] XU X,FAN Z,LIANG C, et al. A signature motif in LIM proteins mediates binding to checkpoint proteins and increases tumour radiosensitivity. Nat Commun,2017,8:14059.
{{custom_fnGroup.title_cn}}
脚注
{{custom_fn.content}}
PDF(2869 KB)
