Escin, a Pentacyclic Triterpene, Chemosensitizes Human Tumor Cells through Inhibition of Nuclear Factor-κB Signaling Pathway

被引:59
作者
Harikumar, Kuzhuvelil B.
Sung, Bokyung
Pandey, Manoj K.
Guha, Sushovan [2 ]
Krishnan, Sunil [3 ]
Aggarwal, Bharat B. [1 ]
机构
[1] Univ Texas MD Anderson Canc Ctr, Cytokine Res Lab, Dept Expt Therapeut, Houston, TX 77030 USA
[2] Univ Texas MD Anderson Canc Ctr, Dept Gastroenterol Hepatol & Nutr, Houston, TX 77030 USA
[3] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA
基金
美国国家卫生研究院;
关键词
AESCULUS-TURBINATA BLUME; REGULATED GENE-PRODUCTS; HORSE CHESTNUT; ENDOTHELIAL-CELLS; ACTIVATION; SEEDS; RATS; IIA; IA; APOPTOSIS;
D O I
10.1124/mol.109.062760
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Agents that can enhance tumor cell apoptosis and inhibit invasion have potential for the treatment of cancer. Here, we report the identification of escin, a pentacyclic triterpenoid from horse chestnut that exhibits antitumor potential against leukemia and multiple myeloma. Whether examined by esterase staining, phosphatidyl-serine staining, DNA breakage, or caspase-mediated poly(ADP-ribose) polymerase cleavage, escin potentiated tumor necrosis factor (TNF)-induced apoptosis but inhibited tumor cell invasion. This correlated with the down-regulation of bcl-2, cellular inhibitor of apoptosis protein-2, cyclin D1, cyclooxygenase-2, intercellular adhesion molecule-1, matrix metalloproteinase-9, and vascular endothelial growth factor, which are all regulated by the activation of the transcription factor NF-kappa B. When examined by electrophoretic mobility shift assay, the triterpenoid suppressed nuclear factor-kappa B (NF-kappa B) activation induced by TNF and other inflammatory agents, and this correlated with the inhibition of I kappa B alpha phosphorylation and degradation, inhibition of I kappa B kinase complex (IKK) activation, suppression of p65 phosphorylation and nuclear translocation, and abrogation of NF-kappa B-dependent reporter activity. Overall, our results demonstrate that escin inhibits activation of NF-kappa B through inhibition of IKK, leading to down-regulation of NF-kappa B-regulated cell survival and metastatic gene products and thus resulting in sensitization of cells to cytokines and chemotherapeutic agents.
引用
收藏
页码:818 / 827
页数:10
相关论文
共 29 条
[1]   Nuclear factor-κ-B:: The enemy within [J].
Aggarwal, BB .
CANCER CELL, 2004, 6 (03) :203-208
[2]   Salinosporamide A (NPI-0052) potentiates apoptosis, suppresses osteoclastogenesis, and inhibits invasion through down-modulation of NF-κB-regulated gene products [J].
Ahn, Kwang Seok ;
Sethi, Gautam ;
Chao, Ta-Hsiang ;
Neuteboom, Saskia T. C. ;
Chaturvedi, Madan M. ;
Palladino, Michael A. ;
Younes, Anas ;
Aggarwal, Bharat B. .
BLOOD, 2007, 110 (07) :2286-2295
[3]   Effect of aescine on hypoxia-induced activation of human endothelial cells [J].
Arnould, T ;
Janssens, D ;
Michiels, C ;
Remacle, J .
EUROPEAN JOURNAL OF PHARMACOLOGY, 1996, 315 (02) :227-233
[4]  
Chaturvedi MM, 2000, METHOD ENZYMOL, V319, P585
[5]   Characterization of the intracellular domain of receptor activator of NF-κB (RANK) -: Interaction with tumor necrosis factor receptor-associated factors and activation of NF-κB and c-Jun N-terminal kinase [J].
Darnay, BG ;
Haridas, V ;
Ni, J ;
Moore, PA ;
Aggarwal, BB .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (32) :20551-20555
[6]   Escin: Inhibiting inflammation and promoting gastrointestinal transit to attenuate formation of postoperative adhesions - Invited Commentary [J].
Fu, FH ;
Hou, YZ ;
Jiang, WL ;
Wang, RH ;
Liu, K .
WORLD JOURNAL OF SURGERY, 2005, 29 (12) :1614-1622
[7]   Effects of escin on indinavir crystallization time in the urine of patients with HIV-I infection:: A multicenter, randomized, open-label, controlled, four-period crossover trial [J].
Grases, F ;
Garía-González, R ;
Redondo, E ;
Costa-Bauzá, A ;
Simonet, BM ;
Sartini, RP ;
Bassa, A ;
Gallegos, C ;
Payeras, A ;
Saro, D ;
Martinez, AI ;
Cifuentes, C ;
Homar, F ;
Murillo, JA ;
Fernández, C ;
Riera, M ;
Conte, A .
CLINICAL THERAPEUTICS, 2004, 26 (12) :2045-2055
[8]  
Hacker H., Sci. Signal, DOI [DOI 10.1126/STKE.3572006RE13, 10.1126/stke.3572006re13]
[9]   Anti-obesity effects of escins extracted from the seeds of Aesculus turbinata BLUME (Hippocastanaceae) [J].
Hu, Jiang-Ning ;
Zhu, Xue-Mei ;
Han, Li-Kun ;
Saito, Masato ;
Sun, Yin-Shi ;
Yoshikawa, Masayuki ;
Kimura, Yoshiyuki ;
Zheng, Yi-Nan .
CHEMICAL & PHARMACEUTICAL BULLETIN, 2008, 56 (01) :12-16
[10]  
Hu XM, 2004, ACTA PHARMACOL SIN, V25, P1267