{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T09:34:32Z","timestamp":1776418472748,"version":"3.51.2"},"reference-count":43,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,3,9]],"date-time":"2021-03-09T00:00:00Z","timestamp":1615248000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001655","name":"Deutscher Akademischer Austauschdienst","doi-asserted-by":"publisher","award":["91736294"],"award-info":[{"award-number":["91736294"]}],"id":[{"id":"10.13039\/501100001655","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Plumbagin is a plant-derived naphthoquinone that is widely used in traditional Asian medicine due to its anti-inflammatory and anti-microbial properties. Additionally, plumbagin is cytotoxic for cancer cells due to its ability to trigger reactive oxygen species (ROS) formation and subsequent apoptosis. Since it was reported that plumbagin may inhibit the differentiation of bone resorbing osteoclasts in cancer-related models, we wanted to elucidate whether plumbagin interferes with cytokine-induced osteoclastogenesis. Using C57BL\/6 mice, we unexpectedly found that plumbagin treatment enhanced osteoclast formation and that this effect was most pronounced when cells were pre-treated for 24 h with plumbagin before subsequent M-CSF\/RANKL stimulation. Plumbagin caused a fast induction of NFATc1 signalling and mTOR-dependent activation of p70S6 kinase which resulted in the initiation of protein translation. In line with this finding, we observed an increase in RANK surface expression after Plumbagin stimulation that enhanced the responsiveness for subsequent RANKL treatment. However, in Balb\/c mice and Balb\/c-derived RAW264.7 macrophages, these findings could not be corroborated and osteoclastogenesis was inhibited. Our results suggest that the effects of plumbagin depend on the model system used and can therefore either trigger or inhibit osteoclast formation.<\/jats:p>","DOI":"10.3390\/ijms22052779","type":"journal-article","created":{"date-parts":[[2021,3,9]],"date-time":"2021-03-09T12:08:01Z","timestamp":1615291681000},"page":"2779","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Plumbagin, a Biomolecule with (Anti)Osteoclastic Properties"],"prefix":"10.3390","volume":"22","author":[{"given":"Sevinj","family":"Sultanli","sequence":"first","affiliation":[{"name":"Zentrum f\u00fcr Infektiologie, Medizinische Mikrobiologie und Hygiene, Universit\u00e4tsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4804-1296","authenticated-orcid":false,"given":"Soni","family":"Ghumnani","sequence":"additional","affiliation":[{"name":"Department of Zoology, Savitribai Phule Pune University, Pune 411007, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richa","family":"Ashma","sequence":"additional","affiliation":[{"name":"Department of Zoology, Savitribai Phule Pune University, Pune 411007, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3739-9329","authenticated-orcid":false,"given":"Katharina F.","family":"Kubatzky","sequence":"additional","affiliation":[{"name":"Zentrum f\u00fcr Infektiologie, Medizinische Mikrobiologie und Hygiene, Universit\u00e4tsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.tranon.2019.10.012","article-title":"Bone Metastasis: Current State of Play","volume":"13","author":"Turpin","year":"2020","journal-title":"Transl. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.jbo.2016.02.008","article-title":"The role of osteoclasts in breast cancer bone metastasis","volume":"5","author":"Vargas","year":"2016","journal-title":"J. Bone Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1053\/ctrv.2000.0210","article-title":"Metastatic bone disease: Clinical features, pathophysiology and treatment strategies","volume":"27","author":"Coleman","year":"2001","journal-title":"Cancer Treat. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"343","DOI":"10.3389\/fphar.2017.00343","article-title":"Potential of Central, Eastern and Western Africa Medicinal Plants for Cancer Therapy: Spotlight on Resistant Cells and Molecular Targets","volume":"8","author":"Mbaveng","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2677","DOI":"10.1091\/mbc.e14-04-0916","article-title":"How Taxol\/paclitaxel kills cancer cells","volume":"25","author":"Weaver","year":"2014","journal-title":"Mol. Biol. Cell."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Seca, A.M.L., and Pinto, D. (2018). Plant Secondary Metabolites as Anticancer Agents: Successes in Clinical Trials and Therapeutic Application. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19010263"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1016\/j.fct.2019.01.018","article-title":"Emerging role of plumbagin: Cytotoxic potential and pharmaceutical relevance towards cancer therapy","volume":"125","author":"Tripathi","year":"2019","journal-title":"Food Chem. Toxicol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"14902","DOI":"10.3390\/molecules190914902","article-title":"1,4-naphthoquinones: From oxidative damage to cellular and inter-cellular signaling","volume":"19","author":"Klotz","year":"2014","journal-title":"Molecules"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1002\/mc.20031","article-title":"Plumbagin induces reactive oxygen species, which mediate apoptosis in human cervical cancer cells","volume":"40","author":"Srinivas","year":"2004","journal-title":"Mol. Carcinog."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6940953","DOI":"10.1155\/2020\/6940953","article-title":"Anticancer Effects and Mechanisms of Action of Plumbagin: Review of Research Advances","volume":"2020","author":"Yin","year":"2020","journal-title":"Biomed. Res. Int."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.mrgentox.2015.06.004","article-title":"Plumbagin alters telomere dynamics, induces DNA damage and cell death in human brain tumour cells","volume":"793","author":"Khaw","year":"2015","journal-title":"Mutat. Res. Genet. Toxicol. Environ. Mutagen."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"967","DOI":"10.2174\/156652412802480871","article-title":"Plumbagin inhibits breast tumor bone metastasis and osteolysis by modulating the tumor-bone microenvironment","volume":"12","author":"Li","year":"2012","journal-title":"Curr. Mol. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1158\/1535-7163.MCT-11-0731","article-title":"Plumbagin inhibits osteoclastogenesis and reduces human breast cancer-induced osteolytic bone metastasis in mice through suppression of RANKL signaling","volume":"11","author":"Sung","year":"2012","journal-title":"Mol. Cancer Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1097\/01.shk.0000142249.08135.e9","article-title":"Innate immune response in Th1-and Th2-dominant mouse strains","volume":"22","author":"Watanabe","year":"2004","journal-title":"Shock"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"185","DOI":"10.3389\/fimmu.2017.00185","article-title":"Pasteurella multocida Toxin Triggers RANKL-Independent Osteoclastogenesis","volume":"8","author":"Chakraborty","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2287","DOI":"10.1002\/jbmr.2584","article-title":"Alternative NF-kappaB Regulates RANKL-Induced Osteoclast Differentiation and Mitochondrial Biogenesis via Independent Mechanisms","volume":"30","author":"Zeng","year":"2015","journal-title":"J. Bone Miner. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e8","DOI":"10.4110\/in.2018.18.e8","article-title":"Regulation of Osteoclast Differentiation by Cytokine Networks","volume":"18","author":"Amarasekara","year":"2018","journal-title":"Immune Netw."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.yexcr.2004.07.035","article-title":"Reactive oxygen species mediate RANK signaling in osteoclasts","volume":"301","author":"Ha","year":"2004","journal-title":"Exp. Cell Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.cyto.2018.06.013","article-title":"From macrophage to osteoclast-How metabolism determines function and activity","volume":"112","author":"Kubatzky","year":"2018","journal-title":"Cytokine"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/nrm.2017.95","article-title":"AMPK: Guardian of metabolism and mitochondrial homeostasis","volume":"19","author":"Herzig","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"473","DOI":"10.4161\/15384101.2014.991572","article-title":"mTOR coordinates protein synthesis, mitochondrial activity and proliferation","volume":"14","author":"Morita","year":"2015","journal-title":"Cell Cycle"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1038\/nri2062","article-title":"Osteoimmunology: Shared mechanisms and crosstalk between the immune and bone systems","volume":"7","author":"Takayanagi","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"122","DOI":"10.2174\/138945011793591626","article-title":"Complex interactions between phytochemicals. The multi-target therapeutic concept of phytotherapy","volume":"12","author":"Efferth","year":"2011","journal-title":"Curr. Drug Targets"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1002\/ptr.867","article-title":"Synthesis of plumbagin derivatives and their inhibitory activities against Ehrlich ascites carcinoma in vivo and Leishmania donovani Promastigotes in vitro","volume":"16","author":"Hazra","year":"2002","journal-title":"Phytother. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/0162-3109(95)00027-Q","article-title":"Modulatory effect of plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) on macrophage functions in BALB\/c mice. I. Potentiation of macrophage bactericidal activity","volume":"30","author":"Abdul","year":"1995","journal-title":"Immunopharmacology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1038\/s12276-020-0384-2","article-title":"ROS in cancer therapy: The bright side of the moon","volume":"52","author":"Perillo","year":"2020","journal-title":"Exp. Mol. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2074","DOI":"10.1038\/s41467-017-02092-0","article-title":"Peritoneal tissue-resident macrophages are metabolically poised to engage microbes using tissue-niche fuels","volume":"8","author":"Davies","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"373","DOI":"10.3389\/fcimb.2017.00373","article-title":"Neutrophils to the ROScue: Mechanisms of NADPH Oxidase Activation and Bacterial Resistance","volume":"7","author":"Nguyen","year":"2017","journal-title":"Front. Cell Infect. Microbiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1007\/s10753-013-9768-y","article-title":"Plumbagin, a vitamin K3 analogue, abrogates lipopolysaccharide-induced oxidative stress, inflammation and endotoxic shock via NF-kappaB suppression","volume":"37","author":"Checker","year":"2014","journal-title":"Inflammation"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1124\/jpet.110.170852","article-title":"Anti-inflammatory and analgesic effect of plumbagin through inhibition of nuclear factor-kappaB activation","volume":"335","author":"Luo","year":"2010","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.jneuroim.2017.09.007","article-title":"The attenuating effects of plumbagin on pro-inflammatory cytokine expression in LPS-activated BV-2 microglial cells","volume":"313","author":"Messeha","year":"2017","journal-title":"J. Neuroimmunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.fct.2013.11.027","article-title":"Plumbagin inhibits LPS-induced inflammation through the inactivation of the nuclear factor-kappa B and mitogen activated protein kinase signaling pathways in RAW 264.7 cells","volume":"64","author":"Wang","year":"2014","journal-title":"Food Chem. Toxicol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"162","DOI":"10.2119\/molmed.2015.00250","article-title":"Plumbagin Protects Mice from Lethal Sepsis by Modulating Immunometabolism Upstream of PKM2","volume":"22","author":"Zhang","year":"2016","journal-title":"Mol. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1084\/jem.20110367","article-title":"Mitochondrial reactive oxygen species drive proinflammatory cytokine production","volume":"208","author":"Naik","year":"2011","journal-title":"J. Exp. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1111\/ejh.12436","article-title":"The effect of the dual PI3K and mTOR inhibitor BEZ235 on tumour growth and osteolytic bone disease in multiple myeloma","volume":"94","author":"Gan","year":"2015","journal-title":"Eur. J. Haematol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"54","DOI":"10.3389\/fcell.2017.00054","article-title":"Regulation of Osteoclast Growth and Fusion by mTOR\/raptor and mTOR\/rictor\/Akt","volume":"5","author":"Tiedemann","year":"2017","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.lfs.2018.03.038","article-title":"Continuous application of compressive force induces fusion of osteoclast-like RAW264.7 cells via upregulation of RANK and downregulation of LGR4","volume":"201","author":"Matsuike","year":"2018","journal-title":"Life Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1139\/bcb-2017-0243","article-title":"Reduced miR-144-3p expression in serum and bone mediates osteoporosis pathogenesis by targeting RANK","volume":"96","author":"Wang","year":"2018","journal-title":"Biochem. Cell Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"10104","DOI":"10.1096\/fj.201802691RR","article-title":"The alarmin S100A9 hampers osteoclast differentiation from human circulating precursors by reducing the expression of RANK","volume":"33","author":"Blom","year":"2019","journal-title":"FASEB J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"103200","DOI":"10.1016\/j.etap.2019.103200","article-title":"Bioinformatic and experimental data decipher the pharmacological targets and mechanisms of plumbagin against hepatocellular carcinoma","volume":"70","author":"Zhou","year":"2019","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3068","DOI":"10.1073\/pnas.93.7.3068","article-title":"Protein-tyrosine phosphatase activity regulates osteoclast formation and function: Inhibition by alendronate","volume":"93","author":"Schmidt","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2067","DOI":"10.1002\/eji.1830200927","article-title":"Resistance to murine cutaneous leishmaniasis is mediated by TH1 cells, but disease-promoting CD4+ cells are different from TH2 cells","volume":"20","author":"Moll","year":"1990","journal-title":"Eur. J. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.imbio.2017.09.001","article-title":"Influence of Pasteurella multocida Toxin on the differentiation of dendritic cells into osteoclasts","volume":"223","author":"Chakraborty","year":"2018","journal-title":"Immunobiology"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/5\/2779\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:35:44Z","timestamp":1760160944000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/5\/2779"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,9]]},"references-count":43,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["ijms22052779"],"URL":"https:\/\/doi.org\/10.3390\/ijms22052779","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,9]]}}}