Advanced Search
WANG Jiaqi, CHEN Jiao, SUN Xiaoyan, LU Wuguang, YANG Yang, CAI Xueting, WANG Xiao-ning, CAO Peng. A mechanism research of novel inhibitor of PAK1 inducing colorectal cancer DLD-1 apoptosis[J]. Journal of China Pharmaceutical University, 2018, 49(2): 229-237. DOI: 10.11665/j.issn.1000-5048.20180214
Citation: WANG Jiaqi, CHEN Jiao, SUN Xiaoyan, LU Wuguang, YANG Yang, CAI Xueting, WANG Xiao-ning, CAO Peng. A mechanism research of novel inhibitor of PAK1 inducing colorectal cancer DLD-1 apoptosis[J]. Journal of China Pharmaceutical University, 2018, 49(2): 229-237. DOI: 10.11665/j.issn.1000-5048.20180214
shu

A mechanism research of novel inhibitor of PAK1 inducing colorectal cancer DLD-1 apoptosis

More Information
    Graphical Abstract
    • Abstract
  • PAK1 plays an important role in the development of tumors. It is of great significance to screen and develop new PAK1 inhibitors as targeted drugs for cancer treatment. The traditional PAK1 inhibitor screening method has the problems of high cost and low efficiency. Computer virtual screening can reduce the cost of finding active lead compounds and improve the screening efficiency. In this study, a kind of PAK1 candidate compound was screened by computer assisted virtual screening combined with Z′lyteTM high flux kinase screen. In vitro enzyme activity screening showed that compound 18(K788)had good PAK1 inhibitory activity(inhibition rate was 42. 7%). Furtherly by MTT detection, it was found that K788 had significant PAK1 positive tumor killing activity, which was even better than the positive drug IPA-3. Flow cytometry and Western Blot showed that K788 could activate caspase apoptosis pathway and induce apoptosis of colon cancer cell DLD-1 by inhibiting PAK1 expression and activation. K788 has great potential for clinical development and application, and can be used as a PAK1 target for further research.
    • FullText(HTML)
    • References (14)
  • [1]
    Radu M,Semenova G,Kosoff R,et al.PAK signalling during the development and progression of cancer[J].Nat Rev Cancer,2014,14(1):13-25.
    [2]
    Kumar R,Vadlamudi RK.Emerging functions of p21-activated kinases in human cancer cells[J].J Cell Physiol,2002,193(2):133-144.
    [3]
    Sells MA, Knaus UG, Bagrodia S, et al. Human p21-activated kinase(PAK1)regulates actin organization in mammalian cells[J].Curr Biol,1997,7(3):202-210.
    [4]
    Delorme V,Machacek M,Dermardirossian C,et al.Cofilin activity downstream of Pak1 regulates cell protrusion efficiency by organizing lamellipodium and lamella actin networks[J].Dev Cell,2007,13(5):646-662.
    [5]
    Balasenthil S,Sahin AA,Barnes CJ,et al.P21-activated kinase-1 signaling mediates cyclin D1 expression in mammary epithelial and cancer cells[J].J Biol Chem,2004,279(2):1422-1428.
    [6]
    Schraml P,Schwerdtfeger G,Burkhalter F,et al.Combined array comparative genomic hybridization and tissue microarray analysis suggest PAK1 at 11q13.5-q14 as a critical oncogene target in ovarian carcinoma[J].Am J Pathol,2003,163(3):985-992.
    [7]
    Ito M,Nishiyama H,Kawanishi H,et al.P21-activated kinase 1: a new molecular marker for intravesical recurrence after transurethral resection of bladder cancer[J].J Urol,2007,178(3):1073-1079.
    [8]
    Vadlamudi RK,Adam L,Wang RA,et al.Regulatable expression of p21-activated kinase-1 promotes anchorage-independent growth and abnormal organization of mitotic spindles in human epithelial breast cancer cells[J].J Biol Chem,2000,275(46):36238-36244.
    [9]
    Wang RA,Zhang H,Balasenthil S,et al.PAK1 hyperactivation is sufficient for mammary gland tumor formation[J].Oncogene,2006,25(20):2931-2936.
    [10]
    Dummler B,Ohshiro K,Kumar R,et al.Pak protein kinases and their role in cancer[J].Cancer Metast Rev,2009,28(1/2):51-63.
    [11]
    Sala-Vila A,Folkes J,Calder PC.The effect of three lipid emulsions differing in fatty acid composition on growth,apoptosis and cell cycle arrest in the HT-29 colorectal cancer cell line[J].Clin Nutr,2010,29(4):519-524.
    [12]
    Rudolph J,Crawford JJ,Hoeflich KP,et al.Inhibitors of p21-activated kinases(PAKs)[J].J Med Chem,2015,58(1):111.
    [13]
    Ndubaku CO,Crawford JJ,Drobnick,J,et al.Design of selective PAK1 inhibitor G-5555: improving properties by employing an unorthodox low-pKa polar moiety[J].ACS Med Chem Lett,2015,6(12):1241-1246.
    [14]
    Beck JT,Ismail A,Tolomeo C.Targeting the phosphatidylinositol 3-kinase(PI3K)/AKT/mammalian target of rapamycin(mTOR)pathway: an emerging treatment strategy for squamous cell lung carcinoma[J].Cancer Treat Rev,2014,40(8):980-989.
    • Related Articles

  • Related Articles

    [1]LAI Xingzhao, FAN Lingling, HUANG Suqing, HUANG Congcong, LI Jian, TAN Ninghua. Effects and mechanism of Mailuoning oral liquid on arteriosclerosis occlusion in vitro[J]. Journal of China Pharmaceutical University, 2025, 56(1): 91-98. DOI: 10.11665/j.issn.1000-5048.2024070201
    [2]SU Boya, XU Yuansheng, WANG Hua, TANG Yuqing, ZHANG Shiqun, SONG Yan. Progress of research on disease-modifying osteoarthritis drugs[J]. Journal of China Pharmaceutical University, 2021, 52(2): 253-260. DOI: 10.11665/j.issn.1000-5048.20210215
    [3]FAN Wenxiang. Research progress on the mechanism of ischemic stroke[J]. Journal of China Pharmaceutical University, 2018, 49(6): 751-759. DOI: 10.11665/j.issn.1000-5048.20180618
    [4]SHAO Hua, SONG Yifan, HE Jie, HU Linlin. Pharmacokinetics and drug concentration monitoring of high-dose tigecycline in patients with septic shock[J]. Journal of China Pharmaceutical University, 2017, 48(6): 721-726. DOI: 10.11665/j.issn.1000-5048.20170614
    [5]ZHA Zhengqi, CHEN Qiuli, WANG Yufeng, ZHU Hui, WANG Ying, YIN Hongping, YUE Long. Protective effects of Cordyceps sinensis polysaccharide CPS-A on angiotensin II-induced injury of liver L02 cells[J]. Journal of China Pharmaceutical University, 2017, 48(4): 490-495. DOI: 10.11665/j.issn.1000-5048.20170415
    [6]YANG Ruocong, DUAN Feipeng, CHAO Jiahong, TIAN Pengpeng, YAN Zhiyong, LI Shaojing. Advances of microRNA activity in innate immunity[J]. Journal of China Pharmaceutical University, 2017, 48(4): 396-406. DOI: 10.11665/j.issn.1000-5048.20170403
    [7]LIU Hui, JI Xu. P2X7 receptor and renal diseases[J]. Journal of China Pharmaceutical University, 2015, 46(5): 629-634. DOI: 10.11665/j.issn.1000-5048.20150519
    [8]WANG Tao, ZHOU Zhixing, LIU Wei, JIANG Zhenzhou, ZHAO Guolin, SHANG Jing, ZHANG Luyong. Effects of colchicine on cholestatic liver injury in rats induced by bile duct ligation[J]. Journal of China Pharmaceutical University, 2014, 45(6): 715-719. DOI: 10.11665/j.issn.1000-5048.20140618
    [9]Non-traditional antiarrhythmic medicines for atrial fibrillation[J]. Journal of China Pharmaceutical University, 2010, 41(1): 86-90.
    [10]Effects of Herbs-Electrothermic Pad on Experimental Ankle Joint Inflammation of Rats[J]. Journal of China Pharmaceutical University, 1991, (6): 381-382.

Catalog

    Get Citation
    PDF
    XML
    Article views PDF downloads 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：436315

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return