The Effect of Biotinylated PAMAM G3 Dendrimers Conjugated with COX-2 Inhibitor (celecoxib) and PPARγ Agonist (Fmoc-L-Leucine) on Human Normal Fibroblasts, Immortalized Keratinocytes and Glioma Cells in Vitro

被引:23
作者
Uram, Lukasz [1 ]
Misiorek, Maria [1 ]
Pichla, Monika [1 ]
Filipowicz-Rachwal, Aleksandra [2 ]
Markowicz, Joanna [1 ]
Wolowiec, Stanislaw [3 ]
Walajtys-Rode, Elibieta [4 ]
机构
[1] Rzeszow Univ Technol, Fac Chem, 6 Powstancow Warszawy Ave, PL-35959 Rzeszow, Poland
[2] Rzeszow Univ Informat Technol & Management, Dept Cosmet & Pharmaceut Prod Technol, 2 Sucharskiego Str, PL-35225 Rzeszow, Poland
[3] Univ Rzeszow, Fac Med, Warzywna 1a, PL-35310 Rzeszow, Poland
[4] Warsaw Univ Technol, Fac Chem, Dept Drug Technol & Biotechnol, 75 Koszykowa Str, PL-00664 Warsaw, Poland
来源
MOLECULES | 2019年 / 24卷 / 20期
关键词
biotinylated PAMAM G3 dendrimer; COX-2; inhibitor-celecoxib; PPAR gamma agonist-Fmoc-L-Leucine; human fibroblast; glioblastoma and immortalized keratinocytes; ACTIVATED-RECEPTOR-GAMMA; CELLULAR UPTAKE; DRUG-DELIVERY; APOPTOSIS; CYCLOOXYGENASE-2; PROLIFERATION; MIGRATION; INVASION; GROWTH; HACAT;
D O I
10.3390/molecules24203801
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Glioblastoma multiforme (GBM) is the most malignant type of central nervous system tumor that is resistant to all currently used forms of therapy. Thus, more effective GBM treatment strategies are being investigated, including combined therapies with drugs that may cross the blood brain barrier (BBB). Another important issue considers the decrease of deleterious side effects of therapy. It has been shown that nanocarrier conjugates with biotin can penetrate BBB. In this study, biotinylated PAMAM G3 dendrimers substituted with the recognized anticancer agents cyclooxygenase-2 (COX-2) inhibitor celecoxib and peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist Fmoc-L-Leucine (G3-BCL) were tested in vitro on human cell lines with different p53 status: glioblastoma (U-118 MG), normal fibroblasts (BJ) and immortalized keratinocytes (HaCaT). G3-BCL penetrated efficiently into the lysosomal and mitochondrial compartments of U-118 MG cells and induced death of U-118 MG cells via apoptosis and inhibited proliferation and migration at low IC50 = 1.25 mu M concentration, considerably lower than either drug applied alone. Comparison of the effects of G3-BCL on expression of COX-2 and PPAR gamma protein and PGE(2) production of three different investigated cell line phenotypes revealed that the anti-glioma effect of the conjugate was realized by other mechanisms other than influencing PPAR-gamma expression and regardless of p53 cell status, it was dependent on COX-2 protein level and high PGE(2) production. Similar G3-BCL cytotoxicity was seen in normal fibroblasts (IC50 = 1.29 mu M) and higher resistance in HaCaT cells (IC50 = 4.49 mu M). Thus, G3-BCL might be a good candidate for the targeted, local glioma therapy with limited site effects.
引用
收藏
页数:20
相关论文
共 100 条
  • [1] Dendrimer Internalization and Intracellular Trafficking in Living Cells
    Albertazzi, Lorenzo
    Serresi, Michela
    Albanese, Alberto
    Beltram, Fabio
    [J]. MOLECULAR PHARMACEUTICS, 2010, 7 (03) : 680 - 688
  • [2] Glioblastoma Treatments: An Account of Recent Industrial Developments
    Alphandery, Edouard
    [J]. FRONTIERS IN PHARMACOLOGY, 2018, 9
  • [3] Mining the Wnt pathway for cancer therapeutics
    Barker, Nick
    Clevers, Hans
    [J]. NATURE REVIEWS DRUG DISCOVERY, 2006, 5 (12) : 997 - 1014
  • [4] Celecoxib inhibits invasion and metastasis via a cyclooxygenase 2-independent mechanism in an in vitro model of Ewing sarcoma
    Barlow, Meade
    Edelman, Morris
    Glick, Richard D.
    Steinberg, Bettie M.
    Soffer, Samuel Z.
    [J]. JOURNAL OF PEDIATRIC SURGERY, 2012, 47 (06) : 1223 - 1227
  • [5] Celecoxib inhibits Ewing sarcoma cell migration via actin modulation
    Behr, Christopher A.
    Hesketh, Anthony J.
    Barlow, Meade
    Glick, Richard D.
    Symons, Marc
    Steinberg, Bettie M.
    Soffer, Samuel Z.
    [J]. JOURNAL OF SURGICAL RESEARCH, 2015, 198 (02) : 424 - 433
  • [6] Connecting COX-2 and Wnt in cancer
    Buchanan, FG
    DuBois, RN
    [J]. CANCER CELL, 2006, 9 (01) : 6 - 8
  • [7] Perspectives of Dendrimer-based Nanoparticles in Cancer Therapy
    Castro, Ricardo, I
    Forero-Doria, Oscar
    Guzman, Luis
    [J]. ANAIS DA ACADEMIA BRASILEIRA DE CIENCIAS, 2018, 90 (02): : 2331 - 2346
  • [8] Chamberlain MC, 2010, EXPERT REV NEUROTHER, V10, P1537, DOI [10.1586/ern.10.32, 10.1586/ERN.10.32]
  • [9] PPARγ regulated CIDEA affects pro-apoptotic responses in glioblastoma
    Chatterjee, A.
    Mondal, P.
    Ghosh, S.
    Mehta, V. S.
    Sen, E.
    [J]. CELL DEATH DISCOVERY, 2015, 1
  • [10] The independence of and associations among apoptosis, autophagy, and necrosis
    Chen, Qi
    Kang, Jian
    Fu, Caiyun
    [J]. SIGNAL TRANSDUCTION AND TARGETED THERAPY, 2018, 3