[en] The phloroglucinol derivative hyperforin, a major bioactive constituent of St. John's wort, is increasingly recognized as being able to regulate a variety of pathobiological processes and, thus, to possess potential therapeutic properties. In the context of cancer, hyperforin induces the apoptosis of cancer cells, inhibits angiogenesis and suppresses metastasis formation. Here, we report a new pharmacological function of hyperforin and its stabilized derivative aristoforin, namely the suppression of lymphatic endothelial cell (LEC) growth and lymphangiogenesis. At concentrations less than 10 M, we found that these compounds induce cell cycle arrest of LECs, and at higher concentrations induce apoptosis. The loss of mitochondrial membrane potential and the activation of caspase-9 during the induction of apoptosis indicate that the intrinsic pathway of apoptosis is stimulated by these compounds, similar to the situation in tumor cells. In thoracic duct ring outgrowth assays, hyperforin and aristoforin both inhibited lymphangiogenesis, as evidenced by the suppression of lymphatic capillary outgrowth. In an in vivo animal model, both compounds were able to inhibit tumor-induced lymphangiogenesis. Together these data substantiate a new role for hyperforin and its derivatives as suppressors of lymphangiogenesis, and support their further investigation as potential anticancer drugs that target tumor growth and metastasis at multiple levels.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Rothley, M.
Schmid, A.
Thiele, W.
Schacht, V.
Plaumann, D.
Gartner, M.
Yektaoglu, A.
Bruyere, F.
Noël, Agnès ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire appliquée à l'homme
Giannis, A.
Sleeman, J. P.
Language :
English
Title :
Hyperforin and aristoforin inhibit lymphatic endothelial cell proliferation in vitro and suppress tumor-induced lymphangiogenesis in vivo
Publication date :
2009
Journal title :
International Journal of Cancer
ISSN :
0020-7136
eISSN :
1097-0215
Publisher :
Wiley Liss, Inc., New York, United States - New York
Linde K, Ramirez G, Mulrow CD, Pauls A, Weidenhammer W, Melchart D. St John's wort for depression - an overview and meta-analysis of randomised clinical trials. BMJ 1996;313:253-8.
Schempp CM, Winghofer B, Ludtke R, Simon-Haarhaus B, Schopf E, Simon JC. Topical application of St John's wort (Hypericum perforatum L.) and of its metabolite hyperforin inhibits the allostimulatory capacity of epidermal cells. Br J Dermatol 2000;142:979-84.
Erdelmeier CA. Hyperforin, possibly the major non-nitrogenous secondary metabolite of Hypericum perforatum L. Pharmacopsychiatry 1998;31(Suppl 1):2-6.
Bystrov NS, Chernov BK, Dobrynin VN. The structure of hyperforin. Tetrahedron Lett 1975;32:2791-4.
Quiney C, Billard C, Salanoubat C, Fourneron JD, Kolb JP. Hyperforin, a new lead compound against the progression of cancer and leukemia? Leukemia 2006;20:1519-25.
Medina MA, Martinez-Poveda B, Amores-Sanchez MI, Quesada AR. Hyperforin: more than an antidepressant bioactive compound? Life Sci 2006;79:105-11.
Schempp CM, Kirkin V, Simon-Haarhaus B, Kersten A, Kiss J, Termeer CC, Gilb B, Kaufmann T, Borner C, Sleeman JP, Simon JC. Inhibition of tumour cell growth by hyperforin, a novel anticancer drug from St. John's wort that acts by induction of apoptosis. Oncogene 2002;21:1242-50.
Hostanska K, Bommer S, Weber M, Krasniqi B, Saller R. Comparison of the growth-inhibitory effect of Hypericum perforatum L. extracts, differing in the concentration of phloroglucinols and flavonoids, on leukaemia cells. J Pharm Pharmacol 2003;55:973-80.
Dona M, Dell'Aica I, Pezzato E, Sartor L, Calabrese F, Della Barbera M, Donella-Deana A, Appendino G, Borsarini A, Caniato R, Garbisa S. Hyperforin inhibits cancer invasion and metastasis. Cancer Res 2004;64:6225-32.
Quiney C, Billard C, Faussat AM, Salanoubat C, Ensaf A, Nait-Si Y, Fourneron JD, Kolb JP. Pro-apoptotic properties of hyperforin in leukemic cells from patients with B-cell chronic lymphocytic leukemia. Leukemia 2006;20:491-7.
Schempp CM, Kiss J, Kirkin V, Averbeck M, Simon-Haarhaus B, Kremer B, Termeer CC, Sleeman J, Simon JC. Hyperforin acts as an angiogenesis inhibitor. Planta Med 2005;71:999-1004.
Martinez-Poveda B, Quesada AR, Medina MA. Hyperforin, a bioactive compound of St. John's Wort, is a new inhibitor of angiogenesis targeting several key steps of the process. Int J Cancer 2005;117:775-80.
Quiney C, Billard C, Mirshahi P, Fourneron JD, Kolb JP. Hyperforin inhibits MMP-9 secretion by B-CLL cells and microtubule formation by endothelial cells. Leukemia 2006;20:583-9.
Orth HC, Schmidt PC. Stability and stabilization of hyperforin. Pharm Ind 2000;62:60-3.
Gartner M, Muller T, Simon JC, Giannis A, Sleeman JP. Aristoforin, a novel stable derivative of hyperforin, is a potent anticancer agent. Chembiochem 2005;6:171-7.
Thiele W, Sleeman JP. Tumor-induced lymphangiogenesis: a target for cancer therapy? J Biotechnol 2006;124:224-41.
Eccles S, Paon L, Sleeman JP. Lymphatic metastasis: importance and new insights into cellular and molecular mechanisms. Clin Exp Metastasis 2007;24:619-36.
Karpanen T, Alitalo K. Molecular biology and pathology of lymphangiogenesis. Annu Rev Pathol 2008;3:367-97.
Krishnan J, Kirkin V, Steffen A, Hegen M, Weih D, Tomarev S, Wilting J, Sleeman JP. Differential in vivo and in vitro expression of vascular endothelial growth factor (VEGF)-C and VEGF-D in tumors and its relationship to lymphatic metastasis in immunocompetent rats. Cancer Res 2003;63:713-22.
Achen MG, Stacker SA. Molecular control of lymphatic metastasis. Ann N Y Acad Sci 2008;1131:225-34.
Kirkin V, Thiele W, Baumann P, Mazitschek R, Rohde K, Fellbrich G, Weich H, Waltenberger J, Giannis A, Sleeman JP. MAZ51, an indolinone that inhibits endothelial cell and tumor cell growth in vitro, suppresses tumor growth in vivo. Int J Cancer 2004;112:986-93.
Bruyère F, Melen-Lamalle L, Blacher S, Roland G, Thiry M, Moons L, Frankenne F, Carmeliet P, Alitalo K, Libert C, Sleeman JP, Foidart JM, et al. Modeling lymphangiogenesis in a three-dimensional culture system. Nat Methods 2008;5:384-5.
Abramoff MD, Magelhaes PJ, Ram SJ. Image Processing with ImageJ. Biophotonics Int 2004;11:36-42.
Wetterwald A, Hoffstetter W, Cecchini MG, Lanske B, Wagner C, Fleisch H, Atkinson M. Characterization and cloning of the E11 antigen, a marker expressed by rat osteoblasts and osteocytes. Bone 1996;18:125-32.
Hengartner MO. The biochemistry of apoptosis. Nature 2000;407:770-6.
Moore LB, Parks DJ, Jones SA, Bledsoe RK, Consler TG, Stimmel JB, Goodwin B, Liddle C, Blanchard SG, Willson TM, Collins JL, Kliewer SA. Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands. J Biol Chem 2000;275:15122-7.
Wentworth JM, Agostini M, Love J, Schwabe JW, Chatterjee VK. St John's wort, a herbal antidepressant, activates the steroid X receptor. J Endocrinol 2000;166:R11-R16.
Kliewer SA, Goodwin B, Willson TM. The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism. Endocr Rev 2002;23:687-702.
Krusekopf S, Roots I. St. John's wort and its constituent hyperforin concordantly regulate expression of genes encoding enzymes involved in basic cellular pathways. Pharmacogenet Genomics 2005;15:817-29.
Zhou C, Tabb MM, Sadatrafiei A, Grun F, Sun A, Blumberg B. Hyperforin, the active component of St. John's wort, induces IL-8 expression in human intestinal epithelial cells via a MAPK-dependent, NF-kappaB-independent pathway. J Clin Immunol 2004;24:623-36.
Kumar V, Mdzinarishvili A, Kiewert C, Abbruscato T, Bickel U, van der Schyf CJ, Klein J. NMDA receptor-antagonistic properties of hyperforin, a constituent of St. John's Wort. J Pharmacol Sci 2006;102:47-54.
Leuner K, Kazanski V, Muller M, Essin K, Henke B, Gollasch M, Harteneck C, Muller WE. Hyperforin - a key constituent of St. John's wort specifically activates TRPC6 channels. FASEB J 2007;21:4101-11.
Lee JY, Duke RK, Tran VH, Hook JM, Duke CC. Hyperforin and its analogues inhibit CYP3A4 enzyme activity. Phytochemistry 2006;67:2550-60.
Albert D, Zundorf I, Dingermann T, Muller WE, Steinhilber D, Werz O. Hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase. Biochem Pharmacol 2002;64:1767-75.
Gey C, Kyrylenko S, Hennig L, Nguyen LH, Buttner A, Pham HD, Giannis A. Phloroglucinol derivatives guttiferone G, aristoforin, and hyperforin: inhibitors of human sirtuins SIRT1 and SIRT2. Angew Chem Int Ed Engl 2007;46:5219-22.
Vaziri H, Dessain SK, Ng Eaton E, Imai SI, Frye RA, Pandita TK, Guarente L, Weinberg RA. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 2001;107:149-59.
Sauve AA, Wolberger C, Schramm VL, Boeke JD. The biochemistry of sirtuins. Annu Rev Biochem 2006;75:435-65.
Potente M, Urbich C, Sasaki K, Hofmann WK, Heeschen C, Aicher A, Kollipara R, DePinho RA, Zeiher AM, Dimmeler S. Involvement of Foxo transcription factors in angiogenesis and postnatal neovascularization. J Clin Invest 2005;115:2382-92.
Daitoku H, Hatta M, Matsuzaki H, Aratani S, Ohshima T, Miyagishi M, Nakajima T, Fukamizu A. Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proc Natl Acad Sci USA 2004;101:10042-7.
Matsuzaki H, Daitoku H, Hatta M, Aoyama H, Yoshimochi K, Fukamizu A. Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation. Proc Natl Acad Sci USA 2005;102:11278-83.
Furuyama T, Kitayama K, Shimoda Y, Ogawa M, Sone K, Yoshida-Araki K, Hisatsune H, Nishikawa S, Nakayama K, Ikeda K, Motoyama N, Mori N. Abnormal angiogenesis in Foxo1 (Fkhr)-deficient mice. J Biol Chem 2004;279:34741-9.
Hosaka T, Biggs WH, III, Tieu D, Boyer AD, Varki NM, Cavenee WK, Arden KC. Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification. Proc Natl Acad Sci USA 2004;101:2975-80.
North BJ, Marshall BL, Borra MT, Denu JM, Verdin E. The human Sir2 ortholog, SIRT2, is an NAD1-dependent tubulin deacetylase. Mol Cell 2003;11:437-44.
Zhang Y, Li N, Caron C, Matthias G, Hess D, Khochbin S, Matthias P. HDAC-6 interacts with and deacetylates tubulin and microtubules in vivo. Embo J 2003;22:1168-79.
Dryden SC, Nahhas FA, Nowak JE, Goustin AS, Tainsky MA. Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle. Mol Cell Biol 2003;23:3173-85.
Kroemer G. Mitochondrial control of apoptosis: an introduction. Biochem Biophys Res Commun 2003;304:433-5.
Blomen VA, Boonstra J. Cell fate determination during G1 phase progression. Cell Mol Life Sci 2007;64:3084-104
Weber CC, Kressmann S, Fricker G, Muller WE. Modulation of P-glycoprotein function by St John's wort extract and its major constituents. Pharmacopsychiatry 2004;37:292-8.
Quiney C, Billard C, Faussat AM, Salanoubat C, Kolb JP. Hyperforin inhibits P-gp and BCRP activities in chronic lymphocytic leukaemia cells and myeloid cells. Leuk Lymphoma 2007;48:1587-99.
Dell'Aica I, Niero R, Piazza F, Cabrelle A, Sartor L, Colalto C, Brunetta E, Lorusso G, Benelli R, Albini A, Calabrese F, Agostini C, et al. Hyperforin blocks neutrophil activation of matrix metalloproteinase-9, motility and recruitment, and restrains inflammation-triggered angiogenesis and lung fibrosis. J Pharmacol Exp Ther 2007;321:492-500.
Augustin HG. Vascular morphogenesis in the ovary. Baillieres Best Pract Res Clin Obstet Gynaecol 2000;14:867-82.