Identification of β-escin as a novel inhibitor of signal transducer and activator of transcription 3/janus-activated kinase 2 signaling pathway that suppresses proliferation and induces apoptosis in human hepatocellular carcinoma cells

Journal of Pharmacology and Experimental Therapeutics

Volumn 334, Issue 1, 2010, Pages 285-293

  Tan, Sandra Min Li ^a   Li, Feng ^a   Rajendran, Peramaiyan ^a   Kumar, Alan Prem ^a,b   Hui, Kam M ^c   Sethi, Gautam ^a  

^a NATIONAL UNIVERSITY OF SINGAPORE   (Singapore)

^b NATIONAL UNIVERSITY OF SINGAPORE   (Singapore)

^c DIVISION OF MEDICAL ONCOLOGY   (Singapore)

Author keywords

[No Author keywords available]

Indexed keywords

BETA ESCIN; CYCLIN D1; DOXORUBICIN; JANUS KINASE 1; JANUS KINASE 2; JANUS KINASE 3; PACLITAXEL; PROTEIN BCL 2; PROTEIN BCL XL; PROTEIN MCL 1; PROTEIN TYROSINE PHOSPHATASE; STAT3 PROTEIN; SURVIVIN; VASCULOTROPIN;

APOPTOSIS; ARTICLE; CANCER CELL; CELL PROLIFERATION; CELL SURVIVAL; DOWN REGULATION; DRUG MECHANISM; ENZYME ACTIVATION; HUMAN; HUMAN CELL; LIVER CELL CARCINOMA; PRIORITY JOURNAL; PROTEIN EXPRESSION;

ANTINEOPLASTIC AGENTS, PHYTOGENIC; APOPTOSIS; BLOTTING, WESTERN; CARCINOMA, HEPATOCELLULAR; CELL LINE, TUMOR; CELL PROLIFERATION; ESCIN; HUMANS; IMMUNOHISTOCHEMISTRY; JANUS KINASE 2; LIVER NEOPLASMS; PHOSPHORYLATION; SIGNAL TRANSDUCTION; STAT3 TRANSCRIPTION FACTOR;

EID: 77953753016     PISSN: 00223565     EISSN: 15210103     Source Type: Journal    
DOI: 10.1124/jpet.110.165498     Document Type: Article

References (40)

1. Aggarwal BB, Kunnumakkara AB, Harikumar KB, Gupta SR, Tharakan ST, Koca C, Dey S, and Sung B (2009) Signal transducer and activator of transcription-3, inflammation, and cancer: how intimate is the relationship? Ann NY Acad Sci 1171:59-76.
2. Bhardwaj A, Sethi G, Vadhan-Raj S, Bueso-Ramos C, Takada Y, Gaur U, Nair AS, Shishodia S, and Aggarwal BB (2007) Resveratrol inhibits proliferation, induces apoptosis, and overcomes chemoresistance through down-regulation of STAT3 and nuclear factor-κB-regulated antiapoptotic and cell survival gene products in human multiple myeloma cells. Blood 109:2293-2302.
3. Bhutani M, Pathak AK, Nair AS, Kunnumakkara AB, Guha S, Sethi G, and Aggarwal BB (2007) Capsaicin is a novel blocker of constitutive and interleukin-6-inducible STAT3 activation. Clin Cancer Res 13:3024-3032.
4. Brierley MM and Fish EN (2005) Stats: multifaceted regulators of transcription. J Interferon Cytokine Res 25:733-744.
5. Bruix J, Boix L, Sala M, and Llovet JM (2004) Focus on hepatocellular carcinoma. Cancer Cell 5:215-219.
6. Calvisi DF, Ladu S, Gorden A, Farina M, Conner EA, Lee JS, Factor VM, and Thorgeirsson SS (2006) Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology 130:1117-1128.
7. Chen RH, Chang MC, Su YH, Tsai YT, and Kuo ML (1999) Interleukin-6 inhibits transforming growth factor-β-induced apoptosis through the phosphatidylinositol 3-kinase/Akt and signal transducers and activators of transcription 3 pathways. J Biol Chem 274:23013-23019. (Pubitemid 129529128)
8. Epling-Burnette PK, Liu JH, Catlett-Falcone R, Turkson J, Oshiro M, Kothapalli R, Li Y, Wang JM, Yang-Yen HF, Karras J, et al. (2001) Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression. J Clin Invest 107:351-362.
9. Fuke H, Shiraki K, Sugimoto K, Tanaka J, Beppu T, Yoneda K, Yamamoto N, Ito K, Masuya M, and Takei Y (2007) Jak inhibitor induces S phase cell-cycle arrest and augments TRAIL-induced apoptosis in human hepatocellular carcinoma cells. Biochem Biophys Res Commun 363:738-744.
10. Garcia R, Bowman TL, Niu G, Yu H, Minton S, Muro-Cacho CA, Cox CE, Falcone R, Fairclough R, Parsons S, et al. (2001) Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells. Oncogene 20:2499-2513.
11. Grases F, García-González R, Redondo E, Costa-Bauzá A, Simonet BM, Sartini RP, Bassa A, Gallegos C, Payeras A, Saro D, et al. (2004) 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. Clin Ther 26:2045-2055.
12. Gritsko T, Williams A, Turkson J, Kaneko S, Bowman T, Huang M, Nam S, Eweis I, Diaz N, Sullivan D, et al. (2006) Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin Cancer Res 12:11-19.
13. Guo W, Xu B, Yang XW, Liu Q, and Cui JR (2003) The anticancer effect of β-escin sodium. Chin Pharmacol Bull 19:351-352.
14. Han Y, Amin HM, Franko B, Frantz C, Shi X, and Lai R (2006) Loss of SHP1 enhances JAK3/STAT3 signaling and decreases proteosome degradation of JAK3 and NPM-ALK in ALK-anaplastic large-cell lymphoma. Blood 108:2796-2803.
15. Harikumar KB, Sung B, Pandey MK, Guha S, Krishnan S, and Aggarwal BB (2010) Escin, a pentacyclic triterpene, chemosensitizes human tumor cells through inhibition of NF-κB signaling pathway. Mol Pharmacol doi:10.1124/mol.109.062760.
16. Ihle JN (1996) STATs: signal transducers and activators of transcription. Cell 84:331-334.
17. Jin C, Li H, He Y, He M, Bai L, Cao Y, Song W, and Dou K (2010) Combination chemotherapy of doxorubicin and paclitaxel for hepatocellular carcinoma in vitro and in vivo. J Cancer Res Clin Oncol 136:267-274.
18. Kerr SH and Kerr DJ (2009) Novel treatments for hepatocellular cancer. Cancer Lett 286:114-120.
19. Kunnumakkara AB, Nair AS, Sung B, Pandey MK, and Aggarwal BB (2009) Boswellic acid blocks signal transducers and activators of transcription 3 signaling, proliferation, and survival of multiple myeloma via the protein tyrosine phosphatase SHP-1. Mol Cancer Res 7:118-128.
20. Lee H, Herrmann A, Deng JH, Kujawski M, Niu G, Li Z, Forman S, Jove R, Pardoll DM, and Yu H (2009) Persistently activated Stat3 maintains constitutive NF-κB activity in tumors. Cancer Cell 15:283-293.
21. Meydan N, Grunberger T, Dadi H, Shahar M, Arpaia E, Lapidot Z, Leeder JS, Freedman M, Cohen A, Gazit A, et al. (1996) Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor. Nature 379:645-648.
22. Moran DM, Mattocks MA, Cahill PA, Koniaris LG, and McKillop IH (2008) Interleukin-6 mediates G(0)/G(1) growth arrest in hepatocellular carcinoma through a STAT 3-dependent pathway. J Surg Res 147:23-33.
23. Newman DJ (2008) Natural products as leads to potential drugs: an old process or the new hope for drug discovery? J Med Chem 51:2589-2599.
24. Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J, Zhang S, Wang T, Sinibaldi D, Coppola D, et al. (2002) Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 21:2000-2008.
25. Niwa Y, Kanda H, Shikauchi Y, Saiura A, Matsubara K, Kitagawa T, Yamamoto J, Kubo T, and Yoshikawa H (2005) Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma. Oncogene 24:6406-6417.
26. Patlolla JM, Raju J, Swamy MV, and Rao CV (2006) β-Escin inhibits colonic aberrant crypt foci formation in rats and regulates the cell cycle growth by inducing p21(waf1/cip1) in colon cancer cells. Mol Cancer Ther 5:1459-1466.
27. Schreiner SJ, Schiavone AP, and Smithgall TE (2002) Activation of STAT3 by the Src family kinase Hck requires a functional SH3 domain. J Biol Chem 277:45680-45687.
28. Seitz SJ, Schleithoff ES, Koch A, Schuster A, Teufel A, Staib F, Stremmel W, Melino G, Krammer PH, Schilling T, et al. (2010) Chemotherapy-induced apoptosis in hepatocellular carcinoma involves the p53 family and is mediated via the extrinsic and the intrinsic pathway. Int J Cancer 126:2049-2066.
29. Sirtori CR (2001) Aescin: pharmacology, pharmacokinetics and therapeutic profile. Pharmacol Res 44:183-193.
30. Song JI and Grandis JR (2000) STAT signaling in head and neck cancer. Oncogene 19:2489-2495. (Pubitemid 30339204)
31. Sun X, Zhang J, Wang L, and Tian Z (2008) Growth inhibition of human hepatocellular carcinoma cells by blocking STAT3 activation with decoy-ODN. Cancer Lett 262:201-213.
32. Thorgeirsson SS, Lee JS, and Grisham JW (2006) Molecular prognostication of liver cancer: end of the beginning. J Hepatol 44:798-805.
33. Wu C, Guan Q, Wang Y, Zhao ZJ, and Zhou GW (2003) SHP-1 suppresses cancer cell growth by promoting degradation of JAK kinases. J Cell Biochem 90:1026-1037.
34. Xiao GM and Wei J (2005) Effects of β-escin on the expression of nuclear factor-κB and tumor necrosis factor-α after traumatic brain injury in rats. J Zhejiang Univ Sci B 6:28-32.
35. Yu H and Jove R (2004) The STATs of cancer-new molecular targets come of age. Nat Rev Cancer 4:97-105. (Pubitemid 38198738)
36. Yu H, Pardoll D, and Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9:798-809.
37. Yue P and Turkson J (2009) Targeting STAT3 in cancer: how successful are we? Expert Opin Investig Drugs 18:45-56.
38. Zhang Q, Raghunath PN, Xue L, Majewski M, Carpentieri DF, Odum N, Morris S, Skorski T, and Wasik MA (2002) Multilevel dysregulation of STAT3 activation in anaplastic lymphoma kinase-positive T/null-cell lymphoma. J Immunol 168:466-474.
39. Zhao BZ, Yang XR, Guo W, and Cui JR (2007) Antiangiogenic effect and possible mechanism of sodium aescinate. Chin J New Drugs 16:1357-1360.
40. Zhou XY, Fu FH, Li Z, Dong QJ, He J, and Wang CH (2009) Escin, a natural mixture of triterpene saponins, exhibits antitumor activity against hepatocellular carcinoma. Planta Med 75:1580-1585.