Abstract
Bone metastasis is a common and serious complication in advanced cancers such as breast cancer, prostate cancer, and multiple myeloma. Agents that prevent bone loss could be used to develop an alternative therapy for bone metastasis. RANKL, a member of the tumor necrosis factor superfamily, has been shown to play a significant role in cancer-associated bone loss. In this study, we examined the efficacy of the natural compound andrographolide (AP), a diterpenoid lactone isolated from the traditional Chinese and Indian medicinal plant Andrographis paniculata, in reducing breast cancer-induced osteolysis. AP prevented human breast cancer-induced bone loss by suppressing RANKL-mediated and human breast cancer cell-induced osteoclast differentiation. Molecular analysis revealed that AP prevented osteoclast function by inhibiting RANKL-induced NF-κB and ERK signaling pathway in lower dose (20 μM), as well as inducing apoptosis at higher dose (40 μM). Thus, AP is a potent inhibitor of breast cancer-induced bone metastasis.
Similar content being viewed by others
References
Coleman R (2001) Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev 27:165–176
Roodman GD (2004) Mechanisms of bone metastasis. N Engl J Med 350:1655–1664
Guise TA (2000) Molecular mechanisms of osteolytic bone metastases. Cancer 88:2892–2898
Mundy GR (2002) Metastasis: metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2:584–593
Roodman GD, Dougall WC (2008) RANK ligand as a therapeutic target for bone metastases and multiple myeloma. Cancer Treat Rev 34:92–101
Bhatia P, Sanders MM, Hansen MF (2005) Expression of receptor activator of nuclear factor-kappaB is inversely correlated with metastatic phenotype in breast carcinoma. Clin Cancer Res 11:162–165
De Leenheer E, Mueller GS, Vanderkerken K, Croucher PI (2004) Evidence of a role for RANKL in the development of myeloma bone disease. Curr Opin Pharmacol 4:340–346
Farrugia AN, Atkins GJ, To LB, Pan B, Horvath N, Kostakis P, Findlay DM, Bardy P, Zannettino AC (2003) Receptor activator of nuclear factor-κB ligand expression by human myeloma cells mediates osteoclast formation in vitro and correlates with bone destruction in vivo. Cancer Res 63:5438–5445
Keller ET, Brown J (2004) Prostate cancer bone metastases promote both osteolytic and osteoblastic activity. J Cell Biochem 91:718–729
Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast differentiation and activation. Nature 423:337–342
Feng X (2005) RANKing intracellular signaling in osteoclasts. IUBMB Life 57:389–395
Kurata T, Nakagawa K (2012) Efficacy and safety of denosumab for the treatment of bone metastases in patients with advanced cancer. Jpn J Clin Oncol 42:663–669
Lipton A, Balakumaran A (2012) Denosumab for the treatment of cancer therapy-induced bone loss and prevention of skeletal-related events in patients with solid tumors. Expert Rev Clin Pharmacol 5:359–371
Mackiewicz-Wysocka M, Pankowska M, Wysocki PJ (2012) Progress in the treatment of bone metastases in cancer patients. Expert Opin Invest Drugs 21:785–795
Paller CJ, Carducci MA, Philips GK (2012) Management of bone metastases in refractory prostate cancer–role of denosumab. Clin Interv Aging 7:363
Hillner BE, Ingle JN, Berenson JR, Janjan NA, Albain KS, Lipton A, Yee G, Biermann JS, Chlebowski RT, Pfister DG (2000) American society of clinical oncology guideline on the role of bisphosphonates in breast cancer. J Clin Oncol 18:1378–1391
Ernst E (2004) Andrographis paniculata in the treatment of upper respiratory tract infections: a systematic review of safety and efficacy. Planta Med 70:293–298
Melchior J, Palm S, Wikman G (1997) Controlled clinical study of standardized Andrographis paniculata extract in common cold: a pilot trial. Phytomedicine 3:315–318
Negi AS, Kumar J, Luqman S, Shanker K, Gupta M, Khanuja S (2008) Recent advances in plant hepatoprotectives: a chemical and biological profile of some important leads. Med Res Rev 28:746–772
Puri A, Saxena R, Saxena R, Saxena K, Srivastava V, Tandon J (1993) Immunostimulant agents from Andrographis paniculata. J Nat Prod 56:995–999
Roxas M, Jurenka J (2007) Colds and influenza: a review of diagnosis and conventional, botanical, and nutritional considerations. Altern Med Rev 12:25–48
Thamlikitkul V, Dechatiwongse T, Theerapong S, Chantrakul C, Boonroj P, Punkrut W, Ekpalakorn W, Boontaeng N, Taechaiya S, Petcharoen S (1991) Efficacy of Andrographis paniculata, Nees for pharyngotonsillitis in adults. J Med Assoc Thai 74:437
Zhi-ling G, Hua-yue Z, Xin-hua Z (1995) An experimental study of the mechanism of andrographis paniculata nees (APN) in alleviating the Ca(2+)-overloading in the process of myocardial ischemie reperfusion. J Tongji Med Univ 15:205–208
Rajagopal S, Kumar RA, Deevi DS, Satyanarayana C, Rajagopalan R (2003) Andrographolide, a potential cancer therapeutic agent isolated from Andrographis paniculata. J Exp Ther Oncol 3:147–158
Wang L-J, Zhou X, Wang W, Tang F, Qi C-L, Yang X, Wu S, Lin Y-Q, Wang J-T, Geng J-G (2011) Andrographolide inhibits oral squamous cell carcinogenesis through NF-κB inactivation. J Dent Res 90:1246–1252
Chen H-W, Lin A-H, Chu H-C, Li C-C, Tsai C-W, Chao C-Y, Wang C-J, Lii C-K, Liu K-L (2011) Inhibition of TNF-α-induced inflammation by andrographolide via down-regulation of the PI3K/Akt signaling pathway. J Nat Prod 74:2408–2413
Chiou WF, Lin JJ, Chen CF (1998) Andrographolide suppresses the expression of inducible nitric oxide synthase in macrophage and restores the vasoconstriction in rat aorta treated with lipopolysaccharide. Br J Pharmacol 125:327–334
Shen YC, Chen CF, Chiou WF (2002) Andrographolide prevents oxygen radical production by human neutrophils: possible mechanism (s) involved in its anti-inflammatory effect. Br J Pharmacol 135:399–406
Handa S, Sharma A (1990) Hepatoprotective activity of andrographolide against galactosamine and paracetamol intoxication in rats. Indian J Med Res 92:284
Trivedi NP, Rawal UM, Patel BP (2009) Potency of andrographolide as an antitumor compound in BHC-induced liver damage. Integr Cancer Ther 8:177–189
Jiang X, Yu P, Jiang J, Zhang Z, Wang Z, Yang Z, Tian Z, Wright SC, Larrick JW, Wang Y (2009) Synthesis and evaluation of antibacterial activities of andrographolide analogues. Eur J Med Chem 44:2936–2943
Miller FR, Santner SJ, Tait L, Dawson PJ (2000) MCF10DCIS. com xenograft model of human comedo ductal carcinoma in situ. J Natl Cancer Inst 92:1185–1186
Nangia-Makker P, Raz T, Tait L, Shekhar MP, Li H, Balan V, Makker H, Fridman R, Maddipati K, Raz A (2013) Ocimum gratissimum retards breast cancer growth and progression and is a natural inhibitor of matrix metalloproteases. Cancer Biol Ther 14:1
Nangia-Makker P, Tait L, Shekhar MP, Palomino E, Hogan V, Piechocki MP, Funasaka T, Raz A (2007) Inhibition of breast tumor growth and angiogenesis by a medicinal herb: Ocimum gratissimum. Int J Cancer 121:884–894
Tait LR, Pauley RJ, Santner SJ, Heppner GH, Heng HH, Rak JW, Miller FR (2007) Dynamic stromal-epithelial interactions during progression of MCF10DCIS. com xenografts. Int J Cancer 120:2127–2134
Hsu H, Lacey DL, Dunstan CR, Solovyev I, Colombero A, Timms E, Tan H-L, Elliott G, Kelley MJ, Sarosi I (1999) Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci USA 96:3540–3545
Qin A, Cheng TS, Lin Z, Cao L, Chim SM, Pavlos NJ, Xu J, Zheng MH, Dai KR (2012) Prevention of wear particle-induced osteolysis by a novel V-ATPase inhibitor saliphenylhalamide through inhibition of osteoclast bone resorption. PLoS One 7:e34132
Wang C, Steer JH, Joyce DA, Yip KH, Zheng MH, Xu J (2003) 12-O-tetradecanoylphorbol-13-acetate (TPA) inhibits osteoclastogenesis by suppressing RANKL-induced NF-κB activation. J Bone Miner Res 18:2159–2168
Akama KT, Albanese C, Pestell RG, Van Eldik LJ (1998) Amyloid beta-peptide stimulates nitric oxide production in astrocytes through an NF-κB-dependent mechanism. Proc Natl Acad Sci USA 95:5795–5800
Steer JH, Kroeger KM, Abraham LJ, Joyce DA (2000) Glucocorticoids suppress tumor necrosis factor-alpha expression by human monocytic THP-1 cells by suppressing transactivation through adjacent NF-kappaB and c-Jun-activating transcription factor-2 binding sites in the promoter. J Biol Chem 275:18432–18440. doi:10.1074/jbc.M906304199
Wedemeyer C, Xu J, Neuerburg C, Landgraeber S, Malyar NM, von Knoch F, Gosheger G, von Knoch M, Löer F, Saxler G (2007) Particle-induced osteolysis in three-dimensional micro-computed tomography. Calcif Tissue Int 81:394–402
Chikatsu N, Takeuchi Y, Tamura Y, Fukumoto S, Yano K, Tsuda E, Ogata E, Fujita T (2000) Interactions between cancer and bone marrow cells induce osteoclast differentiation factor expression and osteoclast-like cell formation in vitro. Biochem Biophys Res Commun 267:632–637
Franzoso G, Carlson L, Xing L, Poljak L, Shores EW, Brown KD, Leonardi A, Tran T, Boyce BF, Siebenlist U (1997) Requirement for NF-kappaB in osteoclast and B-cell development. Genes Dev 11:3482–3496
Soysa N, Alles N (2009) NF-κB functions in osteoclasts. Biochem Biophys Res Commun 378:1–5
DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M (1997) A cytokine-responsive IκB kinase that activates the transcription factor NF-κB. Nature 388:548–554
Monje P, Hernández-Losa J, Lyons RJ, Castellone MD, Gutkind JS (2005) Regulation of the transcriptional activity of c-Fos by ERK A novel role for the prolyl isomerase PIN1. J Biol Chem 280:35081–35084
Ang E, Liu Q, Qi M, Liu HG, Yang X, Chen H, Zheng MH, Xu J (2011) Mangiferin attenuates osteoclastogenesis, bone resorption, and RANKL-induced activation of NF-κB and ERK. J Cell Biochem 112:89–97
Kim HJ, Lee Y, Chang E-J, Kim H-M, Hong S-P, Lee ZH, Ryu J, Kim H-H (2007) Suppression of osteoclastogenesis by N,N-dimethyl-d-erythro-sphingosine: a sphingosine kinase inhibition-independent action. Mol Pharmacol 72:418–428
Ikeda F, Nishimura R, Matsubara T, Tanaka S, Inoue J-I, Reddy SV, Hata K, Yamashita K, Hiraga T, Watanabe T (2004) Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation. J Clin Invest 114:475–484
Matsumoto M, Sudo T, Saito T, Osada H, Tsujimoto M (2000) Involvement of p38 mitogen-activated protein kinase signaling pathway in osteoclastogenesis mediated by receptor activator of NF-κB ligand (RANKL). J Biol Chem 275:31155–31161
David J-P, Sabapathy K, Hoffmann O, Idarraga MH, Wagner EF (2002) JNK1 modulates osteoclastogenesis through both c-Jun phosphorylation-dependent and-independent mechanisms. J Cell Sci 115:4317–4325
Lee J-H, Jin H, Shim H-E, Kim H-N, Ha H, Lee ZH (2010) Epigallocatechin-3-gallate inhibits osteoclastogenesis by down-regulating c-Fos expression and suppressing the nuclear factor-κB signal. Mol Pharmacol 77:17–25
Lee S, Woo K, Kim S, Kim H-M, Kwack K, Lee Z, Kim H-H (2002) The phosphatidylinositol 3-kinase, p38, and extracellular signal-regulated kinase pathways are involved in osteoclast differentiation. Bone 30:71–77
Karin M, Lin A (2002) NF-κB at the crossroads of life and death. Nat Immunol 3:221–227
Kucharczak J, Simmons MJ, Fan Y, Gelinas C (2003) To be, or not to be: NF-kappaB is the answer–role of Rel/NF-kappaB in the regulation of apoptosis. Oncogene 22:8961–8982. doi:10.1038/sj.onc.1207230
Pahl HL (1999) Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene 18:6853
Chen C-L, Lin C-F, Wan S-W, Wei L-S, Chen M-C, Yeh T-M, Liu H-S, Anderson R, Lin Y-S (2013) Anti-dengue virus nonstructural protein 1 antibodies cause NO-mediated endothelial cell apoptosis via ceramide-regulated glycogen synthase kinase-3β and NF-κB activation. J Immunol 191:1744–1752
Ghosh Sankar KM (2002) Missing pieces in the NF-kappaB puzzle. Cell 109(Suppl):81–96
Puszynski K, Bertolusso R, Lipniacki T (2009) Crosstalk between p53 and nuclear factor-κB systems: pro-and anti-apoptotic functions of NF-κB. IET Syst Biol 3:356–367
Radhakrishnan SK, Kamalakaran S (2006) Pro-apoptotic role of NF-κB: implications for cancer therapy. Biochim Biophys Acta 1766:53–62
Cory S, Adams JM (2002) The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer 2:647–656
Emoto Y, Manome Y, Meinhardt G, Kisaki H, Kharbanda S, Robertson M, Ghayur T, Wong W, Kamen R, Weichselbaum R (1995) Proteolytic activation of protein kinase C delta by an ICE-like protease in apoptotic cells. EMBO J 14:6148
Porter AG, Jänicke RU (1999) Emerging roles of caspase-3 in apoptosis. Cell Death Differ 6:99
Xue D, Shaham S, Horvitz HR (1996) The Caenorhabditis elegans cell-death protein CED-3 is a cysteine protease with substrate specificities similar to those of the human CPP32 protease. Genes Dev 10:1073–1083
Garcia M, Jemal A, Ward E, Center M, Hao Y, Siegel R, Thun M (2007) Global cancer facts and figures 2007. American Cancer Society, Atlanta
Society AC (2007) Breast cancer facts and figures 2007–2008. American Cancer Society, Atlanta
Coleman R, Smith P, Rubens R (1998) Clinical course and prognostic factors following bone recurrence from breast cancer. Br J Cancer 77:336
Coleman RE (1997) Skeletal complications of malignancy. Cancer 80:1588–1594
Costa L, Major PP (2009) Effect of bisphosphonates on pain and quality of life in patients with bone metastases. Nat Clin Pract Oncol 6:163–174
Body J (2002) Calcitonin for the long-term prevention and treatment of postmenopausal osteoporosis. Bone 30:75S
Haskell SG (2003) Selective estrogen receptor modulators. South Med J 96:469–476
Rodan GA, Martin TJ (2000) Therapeutic approaches to bone diseases. Science 289:1508–1514
Tremollieres F, Lopes P (2002) Specific estrogen receptor modulators (SERMs). Presse Med 31(28):1323–1328
Watts NB (2003) Bisphosphonate treatment of osteoporosis. Clin Geriatr Med 19(2):395–414
Wood AJJ, Eastell R (1998) Treatment of postmenopausal osteoporosis. N Engl J Med 338:736–746
Mariotti A (2008) Bisphosphonates and osteonecrosis of the jaws. J Dent Educ 72:919–929
Gevorgyan A, Enepekides DJ (2008) Bisphosphonate-induced necrosis of the jaws: a reconstructive nightmare. Curr Opin Otolaryngol Head Neck Surg 16:325–330
Khosla S (2001) Minireview: the OPG/RANKL/RANK system. Endocrinology 142:5050–5055
Canon J, Bryant R, Roudier M, Osgood T, Jones J, Miller R, Coxon A, Radinsky R, Dougall WC (2010) Inhibition of RANKL increases the anti-tumor effect of the EGFR inhibitor panitumumab in a murine model of bone metastasis. Bone 46:1613–1619
Canon JR, Roudier M, Bryant R, Morony S, Stolina M, Kostenuik PJ, Dougall WC (2008) Inhibition of RANKL blocks skeletal tumor progression and improves survival in a mouse model of breast cancer bone metastasis. Clin Exp Metastasis 25:119–129
Morony S, Capparelli C, Sarosi I, Lacey DL, Dunstan CR, Kostenuik PJ (2001) Osteoprotegerin inhibits osteolysis and decreases skeletal tumor burden in syngeneic and nude mouse models of experimental bone metastasis. Cancer Res 61:4432–4436
Teitelbaum SL, Ross FP (2003) Genetic regulation of osteoclast development and function. Nat Rev Genet 4:638–649
Iotsova V, Caamaño J, Loy J, Yang Y, Lewin A, Bravo R (1997) Osteopetrosis in mice lacking NF-κB1 and NF-κB2. Nat Med 3:1285–1289
Xing L, Bushnell TP, Carlson L, Tai Z, Tondravi M, Siebenlist U, Young F, Boyce BF (2002) NF-kappaB p50 and p52 expression is not required for RANK-expressing osteoclast progenitor formation but is essential for RANK- and cytokine-mediated osteoclastogenesis. J Bone Miner Res 17:1200–1210. doi:10.1359/jbmr.2002.17.7.1200
Ruocco MG, Karin M (2007) Control of osteoclast activity and bone loss by IKK subunits: new targets for therapy. Adv Exp Med Biol 602:125–134
Ruocco MG, Maeda S, Park JM, Lawrence T, Hsu L-C, Cao Y, Schett G, Wagner EF, Karin M (2005) IκB kinase (IKK) β, but not IKKα, is a critical mediator of osteoclast survival and is required for inflammation-induced bone loss. J Exp Med 201:1677–1687
Lee ZH, Kim H-H (2003) Signal transduction by receptor activator of nuclear factor kappaB in osteoclasts. Biochem Biophys Res Commun 305:211–214
Biswas DK, Shi Q, Baily S, Strickland I, Ghosh S, Pardee AB, Iglehart JD (2004) NF-κB activation in human breast cancer specimens and its role in cell proliferation and apoptosis. Proc Natl Acad Sci USA 101:10137–10142
Acknowledgments
This work was supported by the Program for Innovative Research Team of Shanghai Municipal Education Commission (Phase I), a grant from the Innovative Research from Shanghai Municipal Education Commission (13YZ031), a grant for scientific research from the National Natural Science Foundation for the Youth of China (No. 81201364), grant from the scientific research foundation for returned overseas Chinese scholars from the state human resource ministry, the Key National Basic Research Program of China (Grant No. 2012CB619101), a scientific research grant for youth of Shanghai (Grant No. ZZjdyx 2097), a scientific research grant from 985 project--stem cell and regenerative medicine centre, a scientific research grant from Zhejiang National Science Foundation (Grant No.Y2110653), and the Major Basic Research of Science and Technology Commission of Shanghai Municipality (Grant No. 11DJ1400303).
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Zanjing Zhai, Xinhua Qu and Wei Yan have contributed equally to this study.
Rights and permissions
About this article
Cite this article
Zhai, Z., Qu, X., Yan, W. et al. Andrographolide prevents human breast cancer-induced osteoclastic bone loss via attenuated RANKL signaling. Breast Cancer Res Treat 144, 33–45 (2014). https://doi.org/10.1007/s10549-014-2844-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-014-2844-7