RETRACTED ARTICLE: α-santalol inhibits the angiogenesis and growth of human prostate tumor growth by targeting vascular endothelial growth factor receptor 2-mediated AKT/mTOR/P70S6K signaling pathway
Tóm tắt
VEGF receptor 2 (VEGFR2) inhibitors, as efficient antiangiogenesis agents, have been applied in the cancer treatment. However, recently, most of these anticancer drugs have some adverse effects. Discovery of novel VEGFR2 inhibitors as anticancer drug candidates is still needed. We used α-santalol and analyzed its inhibitory effects on human umbilical vein endothelial cells (HUVECs) and Prostate tumor cells (PC-3 or LNCaP) in vitro. Tumor xenografts in nude mice were used to examine the in vivo activity of α-santalol. α-santalol significantly inhibits HUVEC proliferation, migration, invasion, and tube formation. Western blot analysis indicated that α-santalol inhibited VEGF-induced phosphorylation of VEGFR2 kinase and the downstream protein kinases including AKT, ERK, FAK, Src, mTOR, and pS6K in HUVEC, PC-3 and LNCaP cells. α-santalol treatment inhibited ex vivo and in vivo angiogenesis as evident by rat aortic and sponge implant angiogenesis assay. α-santalol significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model. The antiangiogenic effect by CD31 immunohistochemical staining indicated that α-santalol inhibited tumorigenesis by targeting angiogenesis. Furthermore, α-santalol reduced the cell viability and induced apoptosis in PC-3 cells, which were correlated with the downregulation of AKT, mTOR and P70S6K expressions. Molecular docking simulation indicated that α-santalol form hydrogen bonds and aromatic interactions within the ATP-binding region of the VEGFR2 kinase unit. α-santalol inhibits angiogenesis by targeting VEGFR2 regulated AKT/mTOR/P70S6K signaling pathway, and could be used as a potential drug candidate for cancer therapy.
Tài liệu tham khảo
Folkman J: Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995, 1: 27-31. 10.1038/nm0195-27
Ferrara N: VEGF and the quest for tumor angiogenesis factors. Nat Rev Cancer. 2002, 2: 795-803. 10.1038/nrc909
Carmeliet P, Jain RK: Angiogenesis in cancer and other diseases. Nature. 2000, 407: 249-257. 10.1038/35025220
Stetler Stevenson WG: Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention. J Clin Invest. 1999, 103: 1237-1241. 10.1172/JCI6870
Gomez DE, Alonso DF, Yoshiji H, Thorgeirsson UP: Tissue inhibitors of metalloproteinases: structure, regulation and biological functions. Eur J Cell Biol. 1997, 74: 111-122.
Valente P, Fassina G, Melchiori A, Masiello L, Cilli M, Vacca A, Onisto M, Santi L, Stetler-Stevenson WG, Albini A: TIMP-2 over-expression reduces invasion and angiogenesis and protects B16F10 melanoma cells from apoptosis. Int J Cancer. 1998, 75: 246-253. 10.1002/(SICI)1097-0215(19980119)75:2<246::AID-IJC13>3.0.CO;2-B
Abdollahi A, Folkman J: Evading tumour evasion: current concepts and perspectives of anti-angiogenic cancer therapy. Drug Resist Updat. 2010, 13: 16-28. 10.1016/j.drup.2009.12.001
Zhang X, Dwivedi C: Skin cancer chemoprevention by α-santalol. Front Biosci (Schol Ed). 2011, 3: 777-787. 10.2741/s186
Dwivedi C, Guan X, Harmsen WL, Voss AL, Goetz-Parten DE, Koopman EM, Johnson KM, Valluri HB, Matthees DP: Chemopreventive effects of alpha santalol on skin tumor development in CD-1 and SENCAR mice. Cancer Epidemiol Biomarkers Prev. 2003, 12: 151-156.
Dwivedi C, Valluri HB, Guan X, Agarwal R: Chemopreventive effects of alpha-santalol on ultraviolet B radiation-induced skin tumor development in SKH-1 hairless mice. Carcinogenesis. 2006, 27: 1917-1922. 10.1093/carcin/bgl058
Bommareddy A, Hora J, Cornish B, Dwivedi C: Chemoprevention by alphasantalol on UVB radiation-induced skin tumor development in mice. Anticancer Res. 2007, 27: 2185-2188.
Arasada BL, Bommareddy A, Zhang X, Bremmon K, Dwivedi C: Effects of alpha-santalol on proapoptotic caspases and p53 expression in UVB irradiated mouse skin. Anticancer Res. 2008, 28: 129-132.
Bommareddy A, Rule B, VanWert AL, Santha S, Dwivedi C: α-santalol, a derivative of sandalwood oil, induces apoptosis in human prostate cancer cells by causing caspase-3 activation. Phytomedicine. 2012, 19: 804-811. 10.1016/j.phymed.2012.04.003
Matsuo Y, Mimaki Y: α-santalol derivatives from santalum album and their cytotoxic activities. Phytochemistry. 2012, 77: 304-311.
Zhang X, Chen W, Guillermo R, Chandrasekher G, Kaushik RS, Young A, Fahmy H, Dwivedi C: Alpha-santalol, a chemopreventive agent against skin cancer, causes G2/M cell cycle arrest in both p53-mutated human epidermoid carcinoma A431 cells and p53 wild-type human melanoma UACC-62 cells. BMC Res Notes. 2010, 3: 220- 10.1186/1756-0500-3-220
Corey EJ, Kirst HA, Katzenellenbogen JA: A stereospecific total synthesis of a-santalol. J Am Chem Soc. 1970, 1970 (92): 6314-6319.
Saraswati S, Agrawal SS: Brucine, an indole alkaloid from strychnos nuxvomica attenuates VEGF-induced angiogenesis via inhibiting VEGFR2 signaling pathway in vitro and in vivo. Cancer Lett. 2013, 332: 83-93. 10.1016/j.canlet.2013.01.012
Saraswati S, Kanuajia PK, Kumar S, Kumar R, Alhaider AA: Tylophorine, a phenanthraindolizidine alkaloid isolated from tylophora indica exerts antiangiogenic and antitumor activity by targeting vascular endothelial growth factor receptor 2-mediated angiogenesis. Mol Cancer. 2013, 12: 82- 10.1186/1476-4598-12-82
Guo S, Colbert LS, Fuller M, Zhang Y, Gonzalez-Perez RR: Vascular endothelial growth factor receptor-2 in breast cancer. Biochem Biophys Acta. 1806, 2010: 108-121.
Fong TA, Shawver LK, Sun L, Tang C, App H, Powell TJ, Kim YH, Schreck R, Wang X, Risau W, Ullrich A, Hirth KP, McMahon G: SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk- 1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res. 1999, 59: 99-106.
Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N: Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989, 246: 1306-1309. 10.1126/science.2479986
Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J: Vascular-specific growth factors and blood vessel formation. Nature. 2000, 407: 242-248. 10.1038/35025215
Klagsbrun M, D’Amore P: Vascular endothelial growth factor and its receptors. Cytokine Growth Factor Rev. 1996, 7: 259-270. 10.1016/S1359-6101(96)00027-5
Fotsis T, Pepper MS, Aktas E, Breit S, Rasku S, Adlercreutz H, Wähälä K, Montesano R, Schweigerer L: Flavonoids, dietary-derived inhibitors of cell proliferation and in vitro angiogenesis. Cancer Res. 1997, 57: 2916-2921.
Paper DH: Natural products as angiogenesis inhibitors. Planta Med. 1998, 64: 686-695. 10.1055/s-2006-957559
Cao Y, Cao R, Brakenheilm E: Anti-angiogenic mechanisms of diet-derived polyphenols. J Nutr Biochem. 2002, 13: 380-390. 10.1016/S0955-2863(02)00204-8
Tosetti F, Ferrari N, De Flora S, Albini A: Angioprevention: angiogenesis is a common key target for cancer chemopreventive agents. FASEB J. 2002, 16: 2-14. 10.1096/fj.01-0300rev
Dorai T, Aggarwal BB: Role of chemopreventive agents in cancer therapy. Cancer Lett. 2004, 215: 129-140. 10.1016/j.canlet.2004.07.013
Pober JS, Sessa WC: Evolving functions of endothelial cells in inflammation. Nat Rev. 2007, 7: 803-815. 10.1038/nri2171.
Dvorak HF, Nagy JA, Feng D, Brown LF, Dvorak AM: Vascular permeability factor/vascular endothelial growth factor and the significance of microvascular hyperpermeability in angiogenesis. Curr Top Microbiol Immunol. 1999, 237: 97-132.
Zachary I: Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family. Cardiovasc Res. 2001, 49: 568-581. 10.1016/S0008-6363(00)00268-6
Matsuo M, Yamada S, Koizumi K, Sakurai H, Saiki I: Tumor-derived fibroblast growth factor-2 exerts lymphangiogenic effects through Akt/mTOR/p70S6kinase pathway in rat lymphatic endothelial cells. Eur J Cancer. 2007, 43: 1748-1754. 10.1016/j.ejca.2007.04.024
Li W, Tan D, Zhang Z, Liang JJ, Brown RE: Activation of Akt-mTORp70S6K pathway in angiogenesis in hepatocellular carcinoma. Oncol Rep. 2008, 20: 713-719.
Eliceiri BP, Puente XS, Hood JD, Stupack DG, Schlaepfer DD, Huang XZ, Sheppard D, Cheresh DA: ASrc-mediated coupling of focal adhesion kinase to integrin alpha(v)beta5 in vascular endothelial growth factor signaling. J Cell Biol. 2002, 157: 149-160. 10.1083/jcb.200109079
Pang X, Yi Z, Zhang X, Sung B, Qu W, Lian X, Aggarwal BB, Liu M: Acetyl- 11-keto-β-boswellic acid inhibits prostate tumor growth by suppressing vascular endothelial growth factor receptor 2–mediated angiogenesis. Cancer Res. 2009, 69: 5893- 10.1158/0008-5472.CAN-09-0755
Trott O, Olson AJ: AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J Computational Chem. 2010, 31: 455-461.
Gasteiger J, Marsili M: Iterative partial equalization of orbital electronegativity-A rapid access to atomic charges. Tetrahedron. 1980, 36: 3219-3228. 10.1016/0040-4020(80)80168-2.
Wallace AC, Laskowski RA, Thorton JM: LIGPLOT: a program to generate schematic diagram of protein ligand interactions. Protein Eng. 1995, 8: 127-134. 10.1093/protein/8.2.127
Zhang S, Cao Z, Tian H, Shen G, Ma Y, Xie H, Liu Y, Zhao C, Deng S, Yang Y, Zheng R, Li W, Zhang N, Liu S, Wang W, Dai L, Shi S, Cheng L, Pan Y, Feng S, Zhao X, Deng H, Yang S, Wei Y: SKLB1002, a novel potent inhibitor of VEGF receptor 2 signaling, inhibits angiogenesis and tumor growth in vivo. Clin Cancer Res. 2011, 17: 4439-4450. 10.1158/1078-0432.CCR-10-3109
Agarwal C, Singh RP, Agarwal R: Grape seed extract induces apoptotic death of human prostate carcinoma DU145 cells via caspases activation accompanied by dissipation of mitochondrial membrane potential and cytochrome c release. Carcinogenesis. 2002, 23: 1869-1876. 10.1093/carcin/23.11.1869
Saraswati S, Pandey M, Mathur R, Agrawal SS: Boswellic acid inhibits inflammatory angiogenesis in a murine sponge model. Microvasc Res. 2011, 82: 263-268. 10.1016/j.mvr.2011.08.002
Agrawal SS, Saraswati S, Mathur R, Pandey M: Brucine, a plant derived alkaloid inhibits inflammatory angiogenesis in a murine sponge model. Biomedicine and Preventive Nutrition. 2011, 1 (3): 180-185. 10.1016/j.bionut.2011.06.014.
Saraswati S, Agrawal SS: Strychnine inhibits inflammatory angiogenesis in mice via down regulation of VEGF, TNF-α and TGF-β. Microvasc Res. 2013, 87: 7-13.
Agrawal SS, Saraswati S, Mathur R, Pandey M: Antitumor properties of boswellic acid against Ehrlich ascites cells bearing mouse. Food Chem Toxicol. 2011, 49: 1924-1934. 10.1016/j.fct.2011.04.007
Agrawal SS, Saraswati S, Mathur R, Pandey M: Cytotoxic and antitumor effects of brucine on Ehrlich ascites tumor and human cancer cell line. Life Sci. 2011, 89 (5–6): 147-158.