Toosendanin demonstrates promising antitumor efficacy in osteosarcoma by targeting STAT3
Open accessAbstract
Signal transducer and activator of transcription 3(STAT3) is an emerging target for cancer therapy. In this study, we identify Toosendanin (TSN) is an effective inhibitor of STAT3, leading to the impediment of various oncogenic processes in osteosarcoma. TSN selectively inactivates phospho-STAT3 (Tyr-705); subsequent molecular docking and in vitro SPR analysis uncover TSN directly binds to the SH2 domain of STAT3. Consequently, TSN blocks STAT3 dimerization and impairs the complex formation of STAT3 and epidermal growth factor receptor (EGFR). In an animal tumor model study, TSN is well tolerated, inhibits osteosarcoma growth and metastasis. In another osteosarcoma patient-derived xenografts (PDX) model, we find TSN triggers strong inhibitory effects on patient-derived tumors. Further studies show that TSN also displays activity against other solid tumors. Our preclinical work therefore supports that TSN acts as a novel inhibitor of STAT3 that blocks tumorigenesis in ostoesarcoma.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
TSN had demonstrated antitumor activity by targeting STAT3 regulation.
“TSN had demonstrated antitumor activity by targeting STAT3 regulation (32, 33), thus providing a valid foundation for this investigation.”
From Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer (2022) · cites this paper as [32]
Zhang et al. reported that TSN directly bound to the SH2 domain of STAT3 with a Kd value of 240 nM, leading to impediment of oncogenic processes in osteosarcoma.
“Zhang et al. also reported that TSN directly bound to the SH2 domain of STAT3 with a Kd value of 240 nM, leading to the impediment of various oncogenic processes in osteosarcoma (32)”
From Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer (2022) · cites this paper as [32]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Darnell, J. E., Kerr, L. M., & Stark, G. R. (1994) · Science · doi:10.1126/science.8197455 · Cited by 6,080 · see citing works
Zhang, X., Yue, P., Fletcher, S., Zhao, W., Gunning, P. T., & Turkson, J. (2010) · Biochemical Pharmacology · doi:10.1016/j.bcp.2010.01.001 · Cited by 179 · see citing works
Flagged first, then by citations
Research works printed but not linked: 41
- Chun J, Li RJ, Cheng MS, Kim YS. Alantolactone selectively suppresses STAT3 activation and exhibits potent anticancer activity in MDA-MB-231 cells. Cancer Lett 2015; 357: 393–403. 25434800
- Devarajan E, Huang S. STAT3 as a central regulator of tumor metastases. Curr Mol Med 2009; 9: 626–633. 19601811
- Zhang T, Li S, Li J, Yin F, Hua Y, Wang Z et al. Natural product pectolinarigenin inhibits osteosarcoma growth and metastasis via SHP-1-mediated STAT3 signaling inhibition. Cell Death Dis 2016; 7: e2421. 27735939 PMC5133974
- Yu H, Jove R. The STATs of cancer—new molecular targets come of age. Nat Rev Cancer 2004; 4: 97–105. 14964307
- Real PJ, Sierra A, De Juan A, Segovia JC, Lopez-Vega JM, Fernandez-Luna JL. Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells. Oncogene 2002; 21: 7611–7618. 12400004
- Zhang X, Sun Y, Pireddu R, Yang H, Urlam MK, Lawrence HR et al. A novel inhibitor of STAT3 homodimerization selectively suppresses STAT3 activity and malignant transformation. Cancer Res 2013; 73: 1922–1933. 23322008 PMC4030628
- Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 2009; 9: 798–809. 19851315 PMC4856025
- Bharadwaj U, Eckols TK, Kolosov M, Kasembeli MM, Adam A, Torres D et al. Drug-repositioning screening identified piperlongumine as a direct STAT3 inhibitor with potent activity against breast cancer. Oncogene 2015; 34: 1341–1353. 24681959 PMC4182178
- Hayakawa F, Sugimoto K, Harada Y, Hashimoto N, Ohi N, Kurahashi S et al. A novel STAT inhibitor, OPB-31121, has a significant antitumor effect on leukemia with STAT-addictive oncokinases. Blood Cancer J 2013; 3: e166. 24292418 PMC3880446
- Picci P. Osteosarcoma (osteogenic sarcoma). Orphanet J Rare Dis 2007; 2: 6. 17244349 PMC1794406
- Isakoff MS, Bielack SS, Meltzer P, Gorlick R. Osteosarcoma: current treatment and a collaborative pathway to success. J Clin Oncol 2015; 33: 3029–3035. 26304877 PMC4979196
- Fossey SL, Liao AT, McCleese JK, Bear MD, Lin J, Li PK et al. Characterization of STAT3 activation and expression in canine and human osteosarcoma. BMC Cancer 2009; 9: 81. 19284568 PMC2666757
- Ryu K, Choy E, Yang C, Susa M, Hornicek FJ, Mankin H et al. Activation of signal transducer and activator of transcription 3 (Stat3) pathway in osteosarcoma cells and overexpression of phosphorylated-Stat3 correlates with poor prognosis. J Orthop Res 2010; 28: 971–978. 20063378
- Butler MS. Natural products to drugs: natural product-derived compounds in clinical trials. Nat Prod Rep 2008; 25: 475–516. 18497896
- Bharti AC, Donato N, Aggarwal BB. Curcumin (diferuloylmethane) inhibits constitutive and IL-6-inducible STAT3 phosphorylation in human multiple myeloma cells. J Immunol 2003; 171: 3863–3871. 14500688
- Kotha A, Sekharam M, Cilenti L, Siddiquee K, Khaled A, Zervos AS et al. Resveratrol inhibits Src and Stat3 signaling and induces the apoptosis of malignant cells containing activated Stat3 protein. Mol Cancer Ther 2006; 5: 621–629. 16546976
- Cao L, Qu D, Wang H, Zhang S, Jia C, Shi Z et al. Toosendanin exerts an anti-cancer effect in glioblastoma by inducing estrogen receptor beta- and p53-mediated apoptosis. Int J Mol Sci 2016; 17: 1928. PMC5133924 27869737
- Nair RR, Tolentino JH, Hazlehurst LA. Role of STAT3 in transformation and drug resistance in CML. Front Oncol 2012; 2: 30. 22649784 PMC3355894
- Hsieh FC, Cheng G, Lin J. Evaluation of potential Stat3-regulated genes in human breast cancer. Biochem Biophys Res Commun 2005; 335: 292–299. 16081048
- Sakai I, Takeuchi K, Yamauchi H, Narumi H, Fujita S. Constitutive expression of SOCS3 confers resistance to IFN-alpha in chronic myelogenous leukemia cells. Blood 2002; 100: 2926–2931. 12351404
- Stahl N, Farruggella TJ, Boulton TG, Zhong Z, Darnell JE Jr, Yancopoulos GD. Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors. Science 1995; 267: 1349–1353. 7871433
- Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol 2002; 29: 15–18. 12516034
- Nicolson GL. Organ specificity of tumor metastasis: role of preferential adhesion, invasion and growth of malignant cells at specific secondary sites. Cancer Metastasis Rev 1988; 7: 143–188. 3293836
- Nakajima M, Chop AM. Tumor invasion and extracellular matrix degradative enzymes: regulation of activity by organ factors. Semin Cancer Biol 1991; 2: 115–127. 1655116
- Kang Y, Massague J. Epithelial-mesenchymal transitions: twist in development and metastasis. Cell 2004; 118: 277–279. 15294153
- Malaney P, Nicosia SV, Dave V. One mouse, one patient paradigm: New avatars of personalized cancer therapy. Cancer Lett 2014; 344: 1–12. 24157811 PMC4092874
- Marangoni E, Vincent-Salomon A, Auger N, Degeorges A, Assayag F, de Cremoux P et al. A new model of patient tumor-derived breast cancer xenografts for preclinical assays. Clin Cancer Res 2007; 13: 3989–3998. 17606733
- Haan S, Hemmann U, Hassiepen U, Schaper F, Schneider-Mergener J, Wollmer A et al. Characterization and binding specificity of the monomeric STAT3-SH2 domain. J Biol Chem 1999; 274: 1342–1348. 9880505
- Hao W, Hu Y, Niu C, Huang X, Chang CP, Gibbons J et al. Discovery of the catechol structural moiety as a Stat3 SH2 domain inhibitor by virtual screening. Bioorg Med Chem Lett 2008; 18: 4988–4992. 18768317
- Ferrara N. VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer 2002; 2: 795–803. 12360282
- Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J et al. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 2002; 21: 2000–2008. 11960372
- Valastyan S, Weinberg RA. Tumor metastasis: molecular insights and evolving paradigms. Cell 2011; 147: 275–292. 22000009 PMC3261217
- Xiong H, Hong J, Du W, Lin YW, Ren LL, Wang YC et al. Roles of STAT3 and ZEB1 proteins in E-cadherin down-regulation and human colorectal cancer epithelial-mesenchymal transition. J Biol Chem 2012; 287: 5819–5832. 22205702 PMC3285352
- Lu X, Ji C, Tong W, Lian X, Wu Y, Fan X et al. Integrated analysis of microRNA and mRNA expression profiles highlights the complex and dynamic behavior of toosendanin-induced liver injury in mice. Sci Rep 2016; 6: 34225. 27703232 PMC5050432
- Su Y, Luo X, He BC, Wang Y, Chen L, Zuo GW et al. Establishment and characterization of a new highly metastatic human osteosarcoma cell line. Clin Exp Metastasis 2009; 26: 599–610. 19363654
- Li J, Zhang T, Yang F, He Y, Dai F, Gao D et al. Inhibition of breast cancer progression by a novel histone deacetylase inhibitor, LW479, by down-regulating EGFR expression. Br J Pharmacol 2015; 172: 3817–3830. 25884486 PMC4523338
- Wang J, Zhang L, Chen G, Zhang J, Li Z, Lu W et al. Small molecule 1'-acetoxychavicol acetate suppresses breast tumor metastasis by regulating the SHP-1/STAT3/MMPs signaling pathway. Breast Cancer Res Treat 2014; 148: 279–289. 25301089
- Zhang T, Chen Y, Li J, Yang F, Wu H, Dai F et al. Antitumor action of a novel histone deacetylase inhibitor, YF479, in breast cancer. Neoplasia 2014; 16: 665–677. 25220594 PMC4234873
- Zhang T, Li J, Dong Y, Zhai D, Lai L, Dai F et al. Cucurbitacin E inhibits breast tumor metastasis by suppressing cell migration and invasion. Breast Cancer Res Treat 2012; 135: 445–458. 22842972
- Eckert MA, Lwin TM, Chang AT, Kim J, Danis E, Ohno-Machado L et al. Twist1-induced invadopodia formation promotes tumor metastasis. Cancer Cell 2011; 19: 372–386. 21397860 PMC3072410
- Zhang H, Cohen AL, Krishnakumar S, Wapnir IL, Veeriah S, Deng G et al. Patient-derived xenografts of triple-negative breast cancer reproduce molecular features of patient tumors and respond to mTOR inhibition. Breast Cancer Res 2014; 16: R36. 24708766 PMC4053092
Cited by
Sorted by citations
Jin, J., Wu, Y., Zhao, Z., Wu, Y., Zhou, Y.-D., Liu, S., Sun, Q., Yang, G., Lin, J., Nagle, D. G., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.160606 · Cited by 57 · see citing works
“Zhang et al. also reported that TSN directly bound to the SH2 domain of STAT3 with a K d value of 240 nM, leading to the impediment of various oncogenic processes in osteosarcoma (32) and suggesting that TSN is a good natural compound targeting STAT3.”
- Authors
- Zhang, T., Li, J., Yin, F., Lin, B., Wang, Z., Xu, J., Wang, H., Zuo, D., Wang, G., Hua, Y., & Cai, Z.
- Affiliations
- Shanghai Jiao Tong University (CN)
- Corresponding author
- Zhang, T
- Hua, Y
- Cai, Z
- Venue
- Oncogene
- Published
- 2017-08-07
- Volume
- 36
- Issue
- 47
- Pages
- 6627-6639
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC5702716
- OpenAlex
- W2744886175
- Cited by
- 132
- References
- 2
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 12 · 2023: 10 · 2022: 20 · 2021: 27 · 2020: 16 · 2019: 19 · 2018: 12
- FWCI
- 5.67
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-02-15)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Oncogene (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81502604, BXJ201732)
- Science and Technology Commission of Shanghai Municipality (14140904000)
- Shanghai Hospital Development Center (SHDC12013107)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
- Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
- Keywords
- toosendanin, osteosarcoma, STAT3, STAT3 inhibitor, SH2 domain binding, STAT3 dimerization, metastasis, patient-derived xenografts, anticancer activity, natural products
- MeSH terms
- Animals, Bone Neoplasms, Drugs, Chinese Herbal, Humans, Male, Mice, Inbred BALB C, Mice, Nude, Phosphorylation, Osteosarcoma, Triterpenes, src Homology Domains, Surface Plasmon Resonance, Xenograft Model Antitumor Assays, Plant Bark, Meliaceae, Cell Line, Tumor, STAT3 Transcription Factor, Mice, Protein Multimerization, Carcinogenesis, ErbB Receptors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
