Butein, a tetrahydroxychalcone, suppresses cancer‐induced osteoclastogenesis through inhibition of receptor activator of nuclear factor‐kappaB ligand signaling

Osteoclastogenesis is associated with aging and various age‐related inflammatory chronic diseases, including cancer. Receptor activator of nuclear factor‐kappaB (NF‐κB) ligand (RANKL), a member of the tumor necrosis factor superfamily, has been implicated as a major mediator of bone resorption, suggesting that agents that can suppress RANKL signaling might inhibit osteoclastogenesis, a process closely linked to bone resorption. We therefore investigated whether butein, a tetrahydroxychalcone, could inhibit RANKL signaling and suppress osteoclastogenesis induced by RANKL or tumor cells. We found that human multiple myeloma cells (MM.1S and U266), breast tumor cells (MDA‐MB‐231) and prostate tumor cells (PC‐3) induced differentiation of macrophages to osteoclasts, as indicated by tartrate‐resistant acid phosphatase (TRAP)‐positive cells, and that butein suppressed this process. The chalcone also suppressed the expression of RANKL by the tumor cells. We further found that butein suppressed RANKL‐induced NF‐κB activation and that this suppression correlated with the inhibition of IκBα kinase and suppression of phosphorylation and degradation of IκBα, an inhibitor of NF‐κB. Finally, butein also suppressed the RANKL‐induced differentiation of macrophages to osteoclasts in a dose‐dependent and time‐dependent manner. Collectively, our results indicate that butein suppresses the osteoclastogenesis induced by tumor cells and by RANKL, by suppression of the NF‐κB activation pathway.

[1]  N. Akhtar,et al.  Butrin, Isobutrin, and Butein from Medicinal Plant Butea monosperma Selectively Inhibit Nuclear Factor-κB in Activated Human Mast Cells: Suppression of Tumor Necrosis Factor-α, Interleukin (IL)-6, and IL-8 , 2010, Journal of Pharmacology and Experimental Therapeutics.

[2]  B. Aggarwal,et al.  Butein Suppresses Constitutive and Inducible Signal Transducer and Activator of Transcription (STAT) 3 Activation and STAT3-Regulated Gene Products through the Induction of a Protein Tyrosine Phosphatase SHP-1 , 2009, Molecular Pharmacology.

[3]  S. Meloche,et al.  The IKK-related kinases: from innate immunity to oncogenesis , 2008, Cell Research.

[4]  J. Shabanowitz,et al.  TAB4 Stimulates TAK1-TAB1 Phosphorylation and Binds Polyubiquitin to Direct Signaling to NF-κB* , 2008, Journal of Biological Chemistry.

[5]  S. Ralston,et al.  Aminobisphosphonates Cause Osteoblast Apoptosis and Inhibit Bone Nodule Formation In Vitro , 2008, Calcified Tissue International.

[6]  G. Emons,et al.  Expression of osteoprotegerin and receptor activator of nuclear factor-κB ligand (RANKL) in HCC70 breast cancer cells and effects of treatment with gonadotropin-releasing hormone on RANKL expression , 2008, Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology.

[7]  M. Carroll,et al.  An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells. , 2007, Blood.

[8]  J. D. Vos,et al.  Targeting NF‐κB pathway with an IKK2 inhibitor induces inhibition of multiple myeloma cell growth , 2007, British journal of haematology.

[9]  B. Aggarwal,et al.  Butein, a Tetrahydroxychalcone, Inhibits Nuclear Factor (NF)-κB and NF-κB-regulated Gene Expression through Direct Inhibition of IκBα Kinase β on Cysteine 179 Residue* , 2007, Journal of Biological Chemistry.

[10]  M. Somerfield,et al.  American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  B. Aggarwal,et al.  Fisetin, an Inhibitor of Cyclin-Dependent Kinase 6, Down-Regulates Nuclear Factor-κB-Regulated Cell Proliferation, Antiapoptotic and Metastatic Gene Products through the Suppression of TAK-1 and Receptor-Interacting Protein-Regulated IκBα Kinase Activation , 2007, Molecular Pharmacology.

[12]  W. Dougall,et al.  The RANK/RANKL/OPG triad in cancer-induced bone diseases , 2007, Cancer and Metastasis Reviews.

[13]  H. Yoshikawa,et al.  Parthenolide, a Natural Inhibitor of Nuclear Factor-κB, Inhibits Lung Colonization of Murine Osteosarcoma Cells , 2007, Clinical Cancer Research.

[14]  D. Sohn,et al.  2',4',6'-Tris(methoxymethoxy) chalcone attenuates hepatic stellate cell proliferation by a heme oxygenase-dependent pathway. , 2006, Biochemical pharmacology.

[15]  R. Coleman.  Clinical Features of Metastatic Bone Disease and Risk of Skeletal Morbidity , 2006, Clinical Cancer Research.

[16]  Y. Kadono,et al.  Molecular Mechanism of the Life and Death of the Osteoclast , 2006, Annals of the New York Academy of Sciences.

[17]  S. M. Sims,et al.  Regulation of cancer cell migration and bone metastasis by RANKL , 2006, Nature.

[18]  J. Body,et al.  A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer. , 2006, Clinical cancer research : an official journal of the American Association for Cancer Research.

[19]  S. Kook,et al.  Flavonoids purified from Rhus verniciflua Stokes actively inhibit cell growth and induce apoptosis in human osteosarcoma cells. , 2005, Biochimica et biophysica acta.

[20]  Shiuan Chen,et al.  The plant polyphenol butein inhibits testosterone-induced proliferation in breast cancer cells expressing aromatase. , 2005, Life sciences.

[21]  Georg Schett,et al.  IκB kinase (IKK)β, but not IKKα, is a critical mediator of osteoclast survival and is required for inflammation-induced bone loss , 2005, The Journal of experimental medicine.

[22]  T. Mizoguchi,et al.  Prostaglandin E2 Enhances Osteoclastic Differentiation of Precursor Cells through Protein Kinase A-dependent Phosphorylation of TAK1* , 2005, Journal of Biological Chemistry.

[23]  S. Akira,et al.  Osteoclast Differentiation Is Impaired in the Absence of Inhibitor of κB Kinase α* , 2004, Journal of Biological Chemistry.

[24]  Y. Jang,et al.  Extract from Rhus verniciflua Stokes is capable of inhibiting the growth of human lymphoma cells. , 2004, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[25]  M. Gillespie,et al.  Myeloma cells can directly contribute to the pool of RANKL in bone bypassing the classic stromal and osteoblast pathway of osteoclast stimulation , 2004, British journal of haematology.

[26]  B. Aggarwal,et al.  Curcumin (Diferuloylmethane) Inhibits Receptor Activator of NF-κB Ligand-Induced NF-κB Activation in Osteoclast Precursors and Suppresses Osteoclastogenesis1 , 2004, The Journal of Immunology.

[27]  J. Martens,et al.  Partitioning and plasticity of repressive histone methylation states in mammalian chromatin. , 2003, Molecular cell.

[28]  A. Lipton.  Bisphosphonate therapy in the oncology setting , 2003, Expert opinion on emerging drugs.

[29]  D. Goeddel,et al.  The IκB Function of NF-κB2 p100 Controls Stimulated Osteoclastogenesis , 2003, The Journal of experimental medicine.

[30]  Sujay K. Singh,et al.  Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor–κB and IκBα kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis , 2003 .

[31]  M. Karin,et al.  Missing Pieces in the NF-κB Puzzle , 2002, Cell.

[32]  R. Bataille,et al.  Myeloma cells induce imbalance in the osteoprotegerin/osteoprotegerin ligand system in the human bone marrow environment. , 2001, Blood.

[33]  J. Michaeli,et al.  Multiple myeloma disrupts the TRANCE/ osteoprotegerin cytokine axis to trigger bone destruction and promote tumor progression , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[34]  R. Coleman.  Metastatic bone disease: clinical features, pathophysiology and treatment strategies. , 2001, Cancer treatment reviews.

[35]  A. Mizokami,et al.  Osteoprotegerin inhibits prostate cancer-induced osteoclastogenesis and prevents prostate tumor growth in the bone. , 2001, The Journal of clinical investigation.

[36]  Youn-Chul Kim,et al.  Butein, a plant polyphenol, induces apoptosis concomitant with increased caspase-3 activity, decreased Bcl-2 expression and increased Bax expression in HL-60 cells. , 2001, Pharmacology & toxicology.

[37]  S. Wei.  Receptor Activator of Nuclear Factor- B Ligand Activates Nuclear Factor- B in Osteoclast Precursors , 2001 .

[38]  Shi Wei,et al.  Receptor Activator of Nuclear Factor-κB Ligand Activates Nuclear Factor-κB in Osteoclast Precursors. , 2001, Endocrinology.

[39]  D L Lacey,et al.  RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[40]  E. Ogata,et al.  Interactions between cancer and bone marrow cells induce osteoclast differentiation factor expression and osteoclast-like cell formation in vitro. , 2000, Biochemical and biophysical research communications.

[41]  M. Kobori,et al.  Flavonoids Inhibit Cell Growth and Induce Apoptosis in B16 Melanoma 4A5 Cells , 2000, Bioscience, biotechnology, and biochemistry.

[42]  W. McBride,et al.  Inhibition of NF-κB, Clonogenicity, and Radiosensitivity of Human Cancer Cells , 1999 .

[43]  Michael Karin,et al.  The Beginning of the End: IκB Kinase (IKK) and NF-κB Activation* , 1999, The Journal of Biological Chemistry.

[44]  T. Martin,et al.  Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. , 1999, Endocrine reviews.

[45]  S. Morony,et al.  Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[46]  N. Udagawa,et al.  A new member of tumor necrosis factor ligand family, ODF/OPGL/TRANCE/RANKL, regulates osteoclast differentiation and function. , 1999, Biochemical and biophysical research communications.

[47]  S. Morony,et al.  OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis , 1999, Nature.

[48]  E. Zandi,et al.  NF-κB-inducing Kinase and IκB Kinase Participate in Human T-cell Leukemia Virus I Tax-mediated NF-κB Activation* , 1998, The Journal of Biological Chemistry.

[49]  G Shimamoto,et al.  Osteoprotegerin: A Novel Secreted Protein Involved in the Regulation of Bone Density , 1997, Cell.

[50]  C. Yit,et al.  Cytotoxic effect of butein on human colon adenocarcinoma cell proliferation. , 1994, Cancer letters.

[51]  W. Dougall,et al.  RANKL acts directly on RANK‐expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes , 2008, The Prostate.

[52]  T. Giordano,et al.  NF-κB in breast cancer cells promotes osteolytic bone metastasis by inducing osteoclastogenesis via GM-CSF , 2007, Nature Medicine.

[53]  B. Aggarwal,et al.  Butein, a tetrahydroxychalcone, inhibits nuclear factor (NF)-kappaB and NF-kappaB-regulated gene expression through direct inhibition of IkappaBalpha kinase beta on cysteine 179 residue. , 2007, The Journal of biological chemistry.

[54]  E. Terpos,et al.  Bisphosphonate treatment for multiple myeloma. , 2004, Drugs of today.

[55]  S. Akira,et al.  Osteoclast differentiation is impaired in the absence of inhibitor of kappa B kinase alpha. , 2004, The Journal of biological chemistry.

[56]  B. Aggarwal,et al.  Curcumin (diferuloylmethane) inhibits receptor activator of NF-kappa B ligand-induced NF-kappa B activation in osteoclast precursors and suppresses osteoclastogenesis. , 2004, Journal of immunology.

[57]  L. To,et al.  Receptor activator of nuclear factor-kappaB ligand expression by human myeloma cells mediates osteoclast formation in vitro and correlates with bone destruction in vivo. , 2003, Cancer research.

[58]  Sujay K. Singh,et al.  Curcumin (Diferuloylmethane) Downregulates the Constitutive Activation of Nuclear Factor κB and IκBα Kinase in Human Multiple Myeloma Cells Leading to Suppression of Proliferation and Induction of Apoptosis , 2002 .

[59]  W. McBride,et al.  Inhibition of NF-kappaB, clonogenicity, and radiosensitivity of human cancer cells. , 1999, Journal of the National Cancer Institute.