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Clinical & Experimental Metastasis
Published in: Clinical & Experimental Metastasis 5/2013

01-06-2013 | Research Paper

Hyaluronan synthesis inhibitor supplements the inhibitory effects of zoledronic acid on bone metastasis of lung cancer

Authors: Naohisa Futamura, Hiroshi Urakawa, Eisuke Arai, Eiji Kozawa, Naoki Ishiguro, Yoshihiro Nishida

Published in: Clinical & Experimental Metastasis | Issue 5/2013

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Abstract

Hyaluronan is known to have pivotal roles in the growth, migration and invasion of malignant tumors. Bone metastases are critical lesions greatly impairing the quality of patients with malignancies. We investigated whether hyaluronan synthesis inhibitor supplements the inhibitory effects of zoledronic acid, which is a conventional therapeutic agent for bone metastasis. We examined the effects of methylumbelliferone, an inhibitor of hyaluronan synthesis and/or ZA on the tumorigenicity of one murine lung carcinoma and two human (A549, SK-MES-1) lung cancer cell lines in vitro. The interaction between methylumbelliferone and zoledronic acid was analyzed using Calcucyn software. With a murine bone metastasis model of lung cancer in vivo, we investigated the inhibitory effects and interaction of the two drugs on the progression of metastatic bone lesions. Methylumbelliferone or zoledronic acid treatment individually suppressed proliferation, migration and invasion of 3 cell lines, and combination treatment showed synergistic effects. Although methylumbelliferone as a single agent did not enhance apoptotic activity, it showed additive effects on apoptotic activity to those of zoledronic acid. Co-localization of CD44 and ezrin, which might be a pathway of hyaluronan signaling, was abrogated by methylumbelliferone treatment. Combination therapy showed additive inhibitory effects on metastatic bone lesions in vivo, which paralleled the inhibition of hyaluronan accumulation by methylumbelliferone, and inhibition of osteoclastogenesis. Although the detailed mechanisms underlying the synergistic or additive inhibitory effects of these two drugs should be further analyzed, inhibition of hyaluronan synthesis by methylumbelliferone is a promising novel therapeutic candidate for bone metastasis of lung cancer in addition to zoledronic acid.
Literature
1.
Ferlay J, Parkin DM, Steliarova-Foucher E (2010) Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer 46:765–781PubMedCrossRef
2.
Woodward RM, Martin ML, Cronin KA, Cutler DM (2007) The value of medical interventions for lung cancer in the elderly. Results from SEER-CMHSF. Cancer 110:2511–2518PubMedCrossRef
3.
Coleman RE (2001) Metastatic bone disease, clinical features, pathophysiology and treatment strategies. Cancer Treat Rev 27:165–176PubMedCrossRef
4.
Tamura T, Shomori K, Nakabayashi M, Fujii N, Ryoke K, Ito H (2011) Zoledronic acid, a third-generation bisphosphonate, inhibits cellular growth and induces apoptosis in oral carcinoma cell lines. Oncol Rep 25:1139–1143PubMedCrossRef
5.
Di Salvatore M, Orlandi A, Bagala C, Quirino M, Cassano A, Astone A, Barone C (2011) Anti-tumour and anti-angiogenetic effects of zoledronic acid on human non-small-cell lung cancer cell line. Cell Prolif 44:139–146PubMedCrossRef
6.
Zarogoulidis K, Boutsikou E, Zarogoulidis P, Eleftheriadou E, Kontakiotis T, Lithoxopoulou H, Tzanakakis G, Kanakis I, Karamanos NK (2009) The impact of zoledronic acid therapy in survival of lung cancer patients with bone metastasis. Int J Cancer 125:1705–1709PubMedCrossRef
7.
Nicolatou-Galitis O, Papadopoulou E, Sarri T, Boziari P, Karayianni A, Kyrtsonis MC, Repousis P, Barbounis V, Migliorati CA (2011) Osteonecrosis of the jaw in oncology patients treated with bisphosphonates: prospective experience of a dental oncology referral center. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 112:195–202PubMedCrossRef
8.
Fraser JR, Laurent TC, Laurent UB (1997) Hyaluronan: its nature, distribution, functions and turnover. J Intern Med 242:27–33PubMedCrossRef
9.
Toole BP (2004) Hyaluronan: from extracellular glue to pericellular cue. Nat Rev Cancer 4:528–539PubMedCrossRef
10.
Turley EA, Noble PW, Bourguignon LY (2002) Signaling properties of hyaluronan receptors. J Biol Chem 277:4589–4592PubMedCrossRef
11.
Knudson W, Biswas C, Li XQ, Nemec RE, Toole BP (1989) The role and regulation of tumour-associated hyaluronan. Ciba Found Symp 143:150–159PubMed
12.
Pirinen RT, Tammi RH, Tammi MI, Paakko PK, Parkkinen JJ, Agren UM, Johansson RT, Viren MM, Tormanen U, Soini YM, Kosma VM (1998) Expression of hyaluronan in normal and dysplastic bronchial epithelium and in squamous cell carcinoma of the lung. Int J Cancer 79:251–255PubMedCrossRef
13.
Bertrand P, Girard N, Delpech B, Duval C, d’Anjou J, Dauce JP (1992) Hyaluronan (hyaluronic acid) and hyaluronectin in the extracellular matrix of human breast carcinomas: comparison between invasive and non-invasive areas. Int J Cancer 52:1–6PubMedCrossRef
14.
Nishida Y, Knudson W, Knudson CB, Ishiguro N (2005) Antisense inhibition of hyaluronan synthase-2 in human osteosarcoma cells inhibits hyaluronan retention and tumorigenicity. Exp Cell Res 307:194–203PubMedCrossRef
15.
Hosono K, Nishida Y, Knudson W, Knudson CB, Naruse T, Suzuki Y, Ishiguro N (2007) Hyaluronan oligosaccharides inhibit tumorigenicity of osteosarcoma cell lines MG-63 and LM-8 in vitro and in vivo via perturbation of hyaluronan-rich pericellular matrix of the cells. Am J Pathol 171:274–286PubMedCrossRef
16.
Urakawa H, Nishida Y, Knudson W, Knudson CB, Arai E, Kozawa E, Futamura N, Wasa J, Ishiguro N (2012) Therapeutic potential of hyaluronan oligosaccharides for bone metastasis of breast cancer. J Orthop Res 30:662–672PubMedCrossRef
17.
Arai E, Nishida Y, Wasa J, Urakawa H, Zhuo L, Kimata K, Kozawa E, Futamura N, Ishiguro N (2011) Inhibition of hyaluronan retention by 4-methylumbelliferone suppresses osteosarcoma cells in vitro and lung metastasis in vivo. Br J Cancer 105:1839–1849PubMedCrossRef
18.
Kultti A, Pasonen-Seppanen S, Jauhiainen M, Rilla KJ, Karna R, Pyoria E, Tammi RH, Tammi MI (2009) 4-Methylumbelliferone inhibits hyaluronan synthesis by depletion of cellular UDP-glucuronic acid and downregulation of hyaluronan synthase 2 and 3. Exp Cell Res 315:1914–1923PubMedCrossRef
19.
Edward M, Quinn JA, Pasonen-Seppanen SM, McCann BA, Tammi RH (2010) 4-Methylumbelliferone inhibits tumour cell growth and the activation of stromal hyaluronan synthesis by melanoma cell-derived factors. Br J Dermatol 162:1224–1232PubMedCrossRef
20.
Morohashi H, Yoshihara S, Nakai M, Yamaguchi M, Kakizaki I, Kon A, Sasaki M, Takagaki K (2007) Inhibitory effect of 4-methylesculetin on hyaluronan synthesis slows the development of human pancreatic cancer in vitro and in nude mice. Int J Cancer 120:2704–2709CrossRef
21.
Urakawa H, Nishida Y, Wasa J, Arai E, Zhuo L, Kimata K, Kozawa E, Futamura N, Ishiguro N (2012) Inhibition of hyaluronan synthesis in breast cancer cells by 4-methylumbelliferone suppresses tumorigenicity in vitro and metastatic lesions of bone in vivo. Int J Cancer 130:454–466PubMedCrossRef
22.
Tammi R, Rilla K, Pienimali JP, MacCallum DK, Hogg M, Luukkonen M, Hascall VC, Tammi M (2001) Hyaluronan enters keratinocytes by a novel endocytic route for catabolism. J Biol Chem 270:35111–35122CrossRef
23.
Zhu L, Zhuo LS, Kimata K, Yamaguchi E, Watanabe H, Aronica MA, Hascall VC, Baba K (2010) Deficiency in the serum-derived hyaluronan-associated protein-hyaluronan complex enhances airwea hyperresponsiveness in a murine model of asthma. Int Arch Allergy Immunol 153:223–233PubMedCrossRef
24.
Tsuda M, Makino Y, Iwahara T, Nishihara H, Sawa H, Nagashima K, Hanafusa H, Tanaka S (2004) Crk associates with ERM proteins and promotes cell motility toward hyaluronic acid. J Biol Chem 279:46843–46850PubMedCrossRef
25.
Mori T, Kitano K, Terawaki S, Maesaki R, Fukami Y, Hakoshima T (2008) Structural basis for CD44 recognition by ERM proteins. J Biol Chem 283:29602–29612PubMedCrossRef
26.
Iwase A, Shen R, Navarro D, Nanus DM (2004) Direct binding of neutral endopeptidase 24.11 to ezrin/radixin/moesin (ERM) proteins competes with the interaction of CD44 with ERM proteins. J Biol Chem 279:11898–11905PubMedCrossRef
27.
Kakizaki I, Kojima K, Takagaki K, Endo M, Kannagi R, Ito M, Maruo Y, Sato H, Yasuda T, Mita S, Kimata K, Itano N (2004) A novel mechanism for the inhibition of hyaluronan biosynthesis by 4-methylumbelliferone. J Biol Chem 279:33281–33289PubMedCrossRef
28.
Kudo D, Kon A, Yoshihara S, Kakizaki I, Sasaki M, Endo M, Takagaki K (2004) Effect of a hyaluronan synthase suppressor, 4-methylumbelliferone, on B16F–10 melanoma cell adhesion and locomotion. Biochem Biophys Res Commun 321:783–787PubMedCrossRef
29.
Tofuku K, Yokouchi M, Murayama T, Minami S, Komiya S (2006) HAS3-related hyaluronan enhances biological activities necessary for metastasis of osteosarcoma cells. Int J Oncol 29:175–183PubMed
30.
Yoshihara S, Kon A, Kudo D, Nakazawa H, Kakizaki I, Sasaki M, Endo M, Takagaki K (2005) A hyaluronan synthase suppressor, 4-methylumbelliferone, inhibits liver metastasis of melanoma cells. FEBS Lett 579:2722–2726PubMedCrossRef
31.
Ponta H, Sherman L, Herrlich PA (2003) CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol 4:33–45PubMedCrossRef
32.
Jensen PV, Larsson LI (2004) Actin microdomains on endothelial cells: association with CD44, ERM proteins, and signaling molecules during quiescence and wound healing. Histochem Cell Biol 121:361–369PubMedCrossRef
33.
Duterme C, Mertens-Strijthagen J, Tammi M, Flamion B (2009) Two novel functions of hyaluronidase-2 (Hyal2) are formation of the glycocalyx and control of CD44-ERM interactions. J Biol Chem 284:33495–33508PubMedCrossRef
34.
Rachner TD, Singh SK, Schoppet M, Benad P, Bornhauser M, Ellenrieder V, Ebert R, Jakob F, Hofbauer LC (2010) Zoledronic acid induces apoptosis and changes the TRAIL/OPG ratio in breast cancer cells. Cancer Lett 287:109–116PubMedCrossRef
35.
Boissier S, Magnetto S, Frappart L, Cuzin B, Ebetino FH, Delmas PD, Clezardin P (1997) Bisphosphonates inhibit prostate and breast carcinoma cell adhesion to unmineralized and mineralized bone extracellular matrices. Cancer Res 57:3890–3894PubMed
36.
Boissier S, Ferreras M, Peyruchaud O, Magnetto S, Ebetino FH, Colombel M, Delmas P, Delaisse JM, Clezardin P (2000) Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res 60:2949–2954PubMed
37.
Hiraga T, Williams PJ, Ueda A, Tamura D, Yoneda T (2004) Zoledronic acid inhibits visceral metastases in the 4T1/luc mouse breast cancer model. Clin Cancer Res 10:4559–4567PubMedCrossRef
38.
Santini D, Virzi V, Fratto ME, Bertoldo F, Sabbatini R, Berardi R, Calipari N, Ottaviani D, Ibrahim T (2010) Can we consider zoledronic acid a new antitumor agent? Recent evidence in clinical setting. Curr Cancer Drug Targets 10:46–54PubMedCrossRef
39.
Almubarak H, Jones A, Chaisuparat R, Zhang M, Meiller TF, Scheper MA (2011) Zoledronic acid directly suppresses cell proliferation and induces apoptosis in highly tumorigenic prostate and breast cancers. J Carcinog 10:2PubMedCrossRef
40.
Neville-Webbe HL, Coleman RE (2010) Bisphosphonates and RANK ligand inhibitors for the treatment and prevention of metastatic bone disease. Eur J Cancer 46:1211–1222PubMedCrossRef
41.
Lokeshwar VB, Lopez LE, Munoz D, Chi A, Shirodkar SP, Lokeshwar SD, Escudero DO, Dhir N, Altman N (2010) Antitumor activity of hyaluronic acid synthesis inhibitor 4-methylumbelliferone in prostate cancer cells. Cancer Res 70:2613–2623PubMedCrossRef
42.
Hung TT, Chan J, Russell PJ, Power CA (2011) Zoledronic acid preserves bone structure and increases survival but does not limit tumour incidence in a prostate cancer bone metastasis model. PLoS ONE 6:e19389PubMedCrossRef
43.
Dass CR, Choong PF (2007) Zoledronic acid inhibits osteosarcoma growth in an orthotopic model. Mol Cancer Ther 6:3263–3270PubMedCrossRef
44.
Zarogoulidis K, Boutsikou E, Zarogoulidis P, Eleftheriadou E, Kontakiotis T, Lithoxopoulou H, Tzanakakis G, Kanakis I, Karamanos NK (2009) The impact of zoledronic acid therapy in survival of lung cancer patients with bone metastasis. Int J Cancer 125:1705–1709PubMedCrossRef
45.
Santini D, Caraglia M, Vincenzi B, Holen I, Scarpa S, Budillon A, Tonini G (2006) Mechanisms of disease: preclinical reports of antineoplastic synergistic action of bisphosphonates. Nat Clin Pract Oncol 3:325–338PubMedCrossRef
46.
Dedes PG, Gialeli C, Tsonis AI, Kanakis I, Theocharis AD, Kletsas D, Tzanakakis GN, Karamanos NK (2012) Expression of matrix macromolecules and functional properties of breast cancer cells are modulated by the bisphosphonate zoledronic acid. Biochim Biophys Acta 1820:1926–1939PubMedCrossRef
Metadata
Title
Hyaluronan synthesis inhibitor supplements the inhibitory effects of zoledronic acid on bone metastasis of lung cancer
Authors
Naohisa Futamura
Hiroshi Urakawa
Eisuke Arai
Eiji Kozawa
Naoki Ishiguro
Yoshihiro Nishida
Publication date
01-06-2013
Publisher
Springer Netherlands
Published in
Clinical & Experimental Metastasis / Issue 5/2013
Print ISSN: 0262-0898
Electronic ISSN: 1573-7276
DOI
https://doi.org/10.1007/s10585-012-9563-4

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