• 中国精品科技期刊
  • 中国高校百佳科技期刊
  • 中国中文核心期刊
  • 中国科学引文数据库核心期刊
Advanced Search
ZHAO Limeng, WANG Shuzhen. Therapeutic applications of small molecule kinase inhibitors in liver fibrosis[J]. Journal of China Pharmaceutical University, 2018, 49(2): 147-157. DOI: 10.11665/j.issn.1000-5048.20180203
Citation: ZHAO Limeng, WANG Shuzhen. Therapeutic applications of small molecule kinase inhibitors in liver fibrosis[J]. Journal of China Pharmaceutical University, 2018, 49(2): 147-157. DOI: 10.11665/j.issn.1000-5048.20180203
shu

Therapeutic applications of small molecule kinase inhibitors in liver fibrosis

More Information
    Graphical Abstract
    • Abstract
  • The aberrant activities or overexpression of kinases have been closely linked to the development of many diseases, including liver fibrosis, and kinases have become important therapeutic targets for these diseases. Protein kinases, including tyrosine kinases and serine/threonines protein kinases, and phosphoinositide 3-kinase(PI3K)are involved in the development of liver fibrosis through direct and indirect mechanisms, such as regulating the activation of hepatic stellate cells and intrahepatic angiogenesis. Recent studies have shown that small molecule kinase inhibitors(SMKIs)manifest great potential for treating liver fibrosis by inhibiting cell proliferation and angiogenesis. The present review summarizes the activities of tyrosine kinase, serine/threonine kinase and PI3K in liver fibrosis, as well as the pathway they involved in during the development of liver fibrosis, and the recently reported antifibrotic effects of various SMKIs both on preclinical animal models and on patients with liver fibrosis in clinical trials.
    • FullText(HTML)
    • References (52)
  • [1]
    Higashi T,Friedman SL,Hoshida Y.Hepatic stellate cells as key target in liver fibrosis[J].Adv Drug Deliv Rev,2017,121:27-42.
    [2]
    Nanthakumar CB,Hatley RJD,Lemma S,et al.Dissecting fibrosis:Therapeutic insights from the small-molecule toolbox[J].Nat Rev Drug Discov,2015,14(10):693-720.
    [3]
    Wu P,Nielsen TE,Clausen MH.FDA-approved small-molecule kinase inhibitors[J].Trends Pharmacol Sci,2015,36(7):422-439.
    [4]
    Bansal R,Nagórniewicz B,Prakash J.Clinical advancements in the targeted therapies against liver fibrosis[J].Mediators Inflamm,2016,doi: 10.1155/2016/7629724.
    [5]
    Qu K,Liu T,Lin T,et al.Tyrosine kinase inhibitors:friends or foe in treatment of hepatic fibrosis[J].Oncotarget,2016,7(41):67650-67660.
    [6]
    Berndt N,Karim RM,Schönbrunn E.Advances of small molecule targeting of kinases[J].Curr Opin Chem Biol,2017,39:126-132.
    [7]
    Ying HZ,Chen Q,Zhang WY,et al.PDGF signaling pathway in hepatic fibrosis pathogenesis and therapeutics[J].Mol Med Rep,2017,16(6):7879-7889.
    [8]
    Qu K,Huang Z,Lin T,et al.New insight into the anti-liver fibrosis effect of multitargeted tyrosine kinase inhibitors:from molecular target to clinical trials[J].Front Pharmacol,2016,6:1-8.
    [9]
    Mimche PN, Brady LM, Bray CF, et al. The receptor tyrosine kinase EphB2 promotes hepatic fibrosis in mice[J].Hepatology,2015,62(3):900-914.
    [10]
    Beyer C,Distler JHW.Tyrosine kinase signaling in fibrotic disorders.Translation of basic research to human disease.[J].Biochim Biophys Acta - Mol Basis Dis,2013,1832(7):897-904.
    [11]
    Cannito S,Novo E,Parola M.Therapeutic pro-fibrogenic signaling pathways in fibroblasts[J].Adv Drug Deliv Rev,2017,121:57-84.
    [12]
    Meng X,Nikolic-Paterson DJ,Lan HY.TGF-β:the master regulator of fibrosis[J].Nat Rev Nephrol,2016,12(6):325-338.
    [13]
    Win S,Than TA,Zhang J,et al.New insights into the role and mechanism of c-Jun-N-terminal kinase signaling in the pathobiology of liver diseases[J].Hepatology,2017,doi: 10.1002/hep.29689.
    [14]
    Westra IM,Oosterhuis D,Groothuis GMM,et al.Precision-cut liver slices as amodel for the early onset of liver fibrosis to test antifibrotic drugs[J].Toxicol Appl Pharmacol,2014,274(2):328-338.
    [15]
    Fraticelli P,Gabrielli B,Pomponio G,et al.Low-dose oral imatinib in the treatment of systemic sclerosis interstitial lung disease unresponsive to cyclophosphamide:a phase II pilot study[J].Arthritis Res Ther,2014,16(4):R144.
    [16]
    Fuchs BC, Hoshida Y, Fujii T, et al. Epidermal growth factor receptor inhibition attenuates liver fibrosis and development of hepatocellular carcinoma[J].Hepatology,2014,59(4):1577-1590.
    [17]
    Ma R,Chen J,Liang Y,et al.Sorafenib:a potential therapeutic drug for hepatic fibrosis and its outcomes[J].Biomed Pharmacother,2017,88:459-468.
    [18]
    Shaker ME,Ghani A,Shiha GE,et al.Nilotinib induces apoptosis and autophagic cell death of activated hepatic stellate cells via inhibition of histone deacetylases[J].Biochim Biophys Acta-Mol Cell Res,2013,1833(8):1992-2003.
    [19]
    Khanjarsim V,Karimi J,Khodadadi I,et al.Ameliorative effects of nilotinib on CCl4 induced liver fibrosis via attenuation of RAGE/HMGB1 gene expression and oxidative stress in rat[J].Chonnam Med J,2017,53(2):118.
    [20]
    Öztürk Akcora B, Storm G, Prakash J, et al. Tyrosine kinase inhibitor BIBF1120 ameliorates inflammation,angiogenesis and fibrosis in CCl4-induced liver fibrogenesis mouse model[J].Sci Rep,2017,7:1-15.
    [21]
    Wang L,Dong J,Xiong L,et al.Gefitinib,an EGFR inhibitor,prevents liver fibrosis development of mice[J].Int J Clin Exp Med,2017,10(2):2890-2896.
    [22]
    Majumder S,Piguet AC,Dufour JF,et al.Study of the cellular mechanism of Sunitinib mediated inactivation of activated hepatic stellate cells and its implications in angiogenesis[J].Eur J Pharmacol,2013,705(1/2/3):86-95.
    [23]
    Mohammadalipour A,Karimi J,Khodadadi I,et al.Dasatinib prevent hepatic fibrosis induced by carbon tetrachloride via anti-inflammatory and antioxidant mechanism[J].Immunopharm Immunot,2017,39(1):19-27.
    [24]
    Elshal M, Abu-Elsaad N, El-Karef A, et al. The multi-kinase inhibitor pazopanib targets hepatic stellate cell activation and apoptosis alleviating progression of liver fibrosis[J].Naunyn Schmiedebergs Arch Pharmacol,2015,388(12):1293-1304.
    [25]
    Nakamura I,Zakharia K,Banini BA,et al.Brivanib attenuates hepatic fibrosis in vivo and stellate cell activation in vitro by inhibition of FGF,VEGF and PDGF signaling[J].PLoS One,2014,9(4):e92273.
    [26]
    Kong LJ,Li H,Du YJ,et al.Vatalanib,a tyrosine kinase inhibitor,decreases hepatic fibrosis and sinusoidal capillarization in CCl4-induced fibrotic mice[J].Mol Med Rep,2017,15(5):2604-2610.
    [27]
    Ganai AA,Husain M.Genistein attenuates D-GalN induced liver fibrosis/chronic liver damage in rats by blocking the TGF-β/Smad signaling pathways[J].Chem Biol Interact,2017,261:80-85.
    [28]
    Piguet AC, Majumder S, Maheshwari U, et al. Everolimus is a potent inhibitor of activated hepatic stellate cell functions in vitro and in vivo,while demonstrating anti-angiogenic activities[J].Clin Sci,2014,126(11):775-791.
    [29]
    Loomba R,Lawitz E,Mantry PS,et al.The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis:A randomized,phase 2 trial[J].Hepatology,2017,67(2):549-559.
    [30]
    Zhou H, Fang CX, Zhang LH, et al. Fasudil hydrochloride hydrate,a Rho-kinase inhibitor,ameliorates hepatic fibrosis in rats with type 2 diabetes[J].Chin Med J(Engl),2014,127(2):225-231.
    [31]
    Nguyen G,Park SY,Le CT,et al.Metformin ameliorates activation of hepatic stellate cells and hepatic fibrosis by succinate and GPR91 inhibition[J].Biochem Biophys Res Commun,2018,495(4):2649-2656.
    [32]
    Kim YJ,Lee ES,Kim SH,et al.Inhibitory effects of rapamycin on the different stages of hepatic fibrosis[J].World J Gastroenterol,2014,20(23):7452-7460.
    [33]
    Hazem SH,Shaker ME,Ashamallah SA,et al.The novel Janus kinase inhibitor ruxolitinib confers protection against carbon tetrachloride-induced hepatotoxicity via multiple mechanisms[J].Chem Biol Interact,2014,220:116-127.
    [34]
    Luangmonkong T, Suriguga S, Bigaeva E, et al. Evaluating the antifibrotic potency of galunisertib in a human ex vivo model of liver fibrosis[J].Br J Pharmacol,2017,174(18):3107-3117.
    [35]
    Geng Y,Sun Q,Li W,et al.The common dietary flavonoid myricetin attenuates liver fibrosis in carbon tetrachloride treated mice[J].Mol Nutr Food Res,2017,61(4):1-9.
    [36]
    Abd-elgawad H, Abu-elsaad N, El-karef A, et al. Piceatannol increases the expression of hepatocyte growth factor and IL-10 thereby protecting hepatocytes in thioacetamide-induced liver fibrosis[J].Can J Physiol Pharmacol,2016,94(7):779-787.
    [37]
    Lu C,Zou Y,Liu Y,et al.Rosmarinic acid counteracts activation of hepatic stellate cells via inhibiting the ROS-dependent MMP-2 activity:involvement of Nrf2 antioxidant system[J].Toxicol Appl Pharmacol,2017,318:69-78.
    [38]
    Kim MJ,Park SA,Kim CH,et al.TGF-β type I receptor kinase inhibitor EW-7197 suppresses cholestatic liver fibrosis by inhibiting HIF1α-induced epithelial mesenchymal transition[J].Cell Physiol Biochem,2016,38(2):571-588.
    [39]
    Kagan P,Sultan M,Tachlytski I,et al.Both MAPK and STAT3 signal transduction pathways are necessary for IL-6-dependent hepatic stellate cells activation[J].PLoS One,2017,12(5):1-11.
    [40]
    Davies MR,Liu X,Lee L,et al.TGF-β small molecule inhibitor sb431542 reduces rotator cuff muscle fibrosis and fatty infiltration by promoting fibro/ adipogenic progenitor apoptosis[J].PLoS One,2016,11(5):e0155486.
    [41]
    Kao YH,Chen PH,Wu TY,et al.Lipopolysaccharides induce Smad2 phosphorylation through PI3K/Akt and MAPK cascades in HSC-T6 hepatic stellate cells[J].Life Sci,2017,184:37-46.
    [42]
    Zhang C-G,Zhang B,Deng W-S,et al.Role of estrogen receptor β selective agonist in ameliorating portal hypertension in rats with CCl 4 -induced liver cirrhosis[J].World J Gastroenterol,2016,22(18):4484.
    [43]
    Son MK,Ryu YL,Jung KH,et al.HS-173,a novel PI3K inhibitor,attenuates the activation of hepatic stellate cells in liver fibrosis[J].Sci Rep,2013,3(1):3470.
    [44]
    Yu D,Zhang C,Zhao S,et al.The anti-fibrotic effects of epigallocatechin-3-gallate in bile duct-ligated cholestatic rats and human hepatic stellate LX-2 cells are mediated by the PI3K/Akt/Smad pathway[J].ACTA Pharmacol Sin,2015,36(4):473-482.
    [45]
    Wang B,Yang H,Fan Y,et al.3-Methyladenine ameliorates liver fibrosis through autophagy regulated by the NF-κB signaling pathways on hepatic stellate cell[J].2017,8(64):107603-107611.
    [46]
    Karczmarek-Borowska B,Saek-Zań A.Hepatotoxicity of molecular targeted therapy[J].Contemp Oncol(Poznań,Poland),2015,19(2):87-92.
    [47]
    Teo YL,Ho HK,Chan A.Formation of reactive metabolites and management of tyrosine kinase inhibitor-induced hepatotoxicity:a literature review[J].Expert Opin Drug Metab Toxicol,2015,11(2):231-242.
    [48]
    Shah RR, Morganroth J, Shah DR. Hepatotoxicity of tyrosine kinase inhibitors:clinical and regulatory perspectives[J].Drug Saf,2013,36(7):491-503.
    [49]
    Takeda M,Okamoto I,Fukuoka M,et al.Successful treatment with erlotinib after gefitinib-related severe hepatotoxicity[J].J Clin Oncol,2010,28(17):e273-e274.
    [50]
    El-Mezayen NS,El-Hadidy WF,El-Refaie WM,et al.Hepatic stellate cell-targeted imatinib nanomedicine versus conventional imatinib:a novel strategy with potent efficacy in experimental liver fibrosis[J].J Control Release,2017,266:226-237.
    [51]
    Dai L,Zhang L,Ji H,et al.Therapeutic effects of ZK14,a novel nitric oxide donating biphenyldicarboxylate derivative,on hepatic fibrosis in rats[J].J China Pharm Univ(中国药科大学学报),2009,40(3):254-257.
    [52]
    Wan AN,Xu DS,Cai YF,et al.Anti-liver fibrosis activities of human insulin-like growth factor-1 in vitro[J].J China Pharm Univ(中国药科大学学报),2017,48(4):476-482.
    • Related Articles

  • Related Articles

    [1]HUANG Zhicheng, YE Liu, DU Yu, GU Hongfeng, GAO Fanyun, ZHU Qihua, XU Yungen. Design, synthesis and biological evaluation of PARP-1/PI3K dual-target inhibitors[J]. Journal of China Pharmaceutical University, 2023, 54(4): 450-460. DOI: 10.11665/j.issn.1000-5048.2023050301
    [2]LI Xiaoshi, WU Xunxun, ZHENG Zuguo, YANG Hua, LI Ping. Advances of long noncoding RNAs in myocardial fibrosis[J]. Journal of China Pharmaceutical University, 2020, 51(6): 646-654. DOI: 10.11665/j.issn.1000-5048.20200602
    [3]KE Ke, JIANG Wenli, WANG Yu, ZHU Jingyu, JIN Jian. Study on the bioactivity against hematologic malignancies and theoretical binding mechanism of a novel PI3K inhibitor JN-65[J]. Journal of China Pharmaceutical University, 2019, 50(4): 410-416. DOI: 10.11665/j.issn.1000-5048.20190405
    [4]CAI Yanfei, WAN Aini, CHEN Yun, JIN Jian. Anti-liver fibrosis activities of the extracellular domain of transforming growth factor beta type II receptor fusion protein in vivo[J]. Journal of China Pharmaceutical University, 2019, 50(2): 246-252. DOI: 10.11665/j.issn.1000-5048.20190217
    [5]XIE Weina, DING Qi, SUN Jing, ZHANG Chaofeng, ZHANG Mian, XU Xianghong. Protective effects of Baibu Tang on bleomycin-induced pulmonary fibrosis in mice[J]. Journal of China Pharmaceutical University, 2018, 49(4): 483-489. DOI: 10.11665/j.issn.1000-5048.20180415
    [6]FAN Qianqian, XING Lei, QIAO Jianbin, ZHANG Chenglu, JIANG Hulin. Advances in drug delivery systems for the treatment of liver fibrosis[J]. Journal of China Pharmaceutical University, 2018, 49(3): 263-271. DOI: 10.11665/j.issn.1000-5048.20180302
    [7]JIA Chengshu, WANG Junwei, LI Hui, ZHU Qihua, GE Yiran, XU Yungen. Advances of phosphoinositide-3 kinase inhibitors in combination with other drugs to overcome drug resistance[J]. Journal of China Pharmaceutical University, 2017, 48(5): 523-528. DOI: 10.11665/j.issn.1000-5048.20170503
    [8]WAN Aini, XU Dongsheng, CAI Yanfei, CHEN Yun, JIN Jian, LI Huazhong. Anti-liver fibrosis activities of human insulin-like growth factor-1 in vitro[J]. Journal of China Pharmaceutical University, 2017, 48(4): 476-482. DOI: 10.11665/j.issn.1000-5048.20170413
    [9]XIANG Juan, YU Ping, LI Mingdan, ZHANG Chaofeng, XU Xianghong, ZHANG Mian. Protective effects of stemona alkaloids on mice with bleomycin-induced pulmonary fibrosis[J]. Journal of China Pharmaceutical University, 2017, 48(1): 76-81. DOI: 10.11665/j.issn.1000-5048.20170112
    [10]DAI Li, ZHANG Lu, JI Hui, KONG Xiang-wen. Therapeutic effects of ZK14，a novel nitric oxide donating biphenyldicarboxylate derivative，on hepatic fibrosis in rats[J]. Journal of China Pharmaceutical University, 2009, 40(3): 254-257.

Catalog

    Get Citation
    PDF
    XML
    Article views (1011) PDF downloads (2004) Cited by()
    Turn off MathJax
    Article Contents
    Abstract
    References
    Related Articles

    Copyright © Journal of China Pharmaceutical University苏ICP备12050101号-2

    Address：24 Tongjia Lane, Nanjing City, Jiangsu Province （210009）Tel: 025-83271566E-mail: xuebao@cpu.edu.cn

    Supported by: Beijing Renhe Information Technology Co., Ltd.  Baidu Analytics

    Total visits：302638

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return