STAT3, a transcriptional mediator of oncogenic signaling, is constitutively active in ~70% of human cancers. The development of STAT3 inhibitors remains an active area of research as no inhibitors have yet to be approved for the treatment of human cancer. Herein, we revealed that bruceantinol (BOL) is a novel STAT3 inhibitor demonstrating potent antitumor activity in in vitro and in vivo human colorectal cancer (CRC) models. BOL strongly inhibited STAT3 DNA-binding ability (IC50 = 2.4 pM), blocked the constitutive and IL-6-induced STAT3 activation in a dose- and time-dependent manner, and suppressed transcription of STAT3 target genes encoding anti-apoptosis factors (MCL-1, PTTG1, and survivin) and cell-cycle regulators (c-Myc). Structure–activity relationship studies demonstrated that the C15 side chain on BOL affected its ability to bind STAT3. Administration of 4 mg/kg BOL significantly inhibited CRC tumor xenografts [p < 0.001], but no effect was observed in a STAT3−/− tumor model. Additional studies showed that BOL effectively sensitized MEK inhibitors through repression of p-STAT3 and MCL-1 induction, known resistance mechanisms of MEK inhibition. Taken together, our findings suggest BOL is a novel therapeutic STAT3 inhibitor that can be used either alone or in combination with MEK inhibitors for the treatment of human CRC.

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  1. 1.

    USPST Force, Bibbins-Domingo K, Grossman DC, Curry SJ, Davidson KW, Epling JW Jr, et al. Screening for Colorectal Cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2016;315:2564–75.

  2. 2.

    Kohne CH, Lenz HJ. Chemotherapy with targeted agents for the treatment of metastatic colorectal cancer. Oncologist. 2009;14:478–88.

  3. 3.

    Markowitz SD, Bertagnolli MM. Molecular origins of cancer: molecular basis of colorectal cancer. N Engl J Med. 2009;361:2449–60.

  4. 4.

    Morikawa T, Baba Y, Yamauchi M, Kuchiba A, Nosho K, Shima K, et al. STAT3 expression, molecular features, inflammation patterns, and prognosis in a database of 724 colorectal cancers. Clin Cancer Res. 2011;17:1452–62.

  5. 5.

    Cragg GM, Newman DJ. Natural products: a continuing source of novel drug leads. Biochim Biophys Acta. 2013;1830:3670–95.

  6. 6.

    Demain AL, Vaishnav P. Natural products for cancer chemotherapy. Microb Biotechnol. 2011;4:687–99.

  7. 7.

    Yan Z, Guo GF, Zhang B. Research of Brucea javanica against cancer. Chin J Integr Med. 2016;23:153–60.

  8. 8.

    Zhao M, Lau ST, Leung PS, Che CT, Lin ZX. Seven quassinoids from Fructus Bruceae with cytotoxic effects on pancreatic adenocarcinoma cell lines. Phytother Res. 2011;25:1796–800.

  9. 9.

    Yang J, Li S, Xie C, Ye H, Tang H, Chen L, et al. Anti-inflammatory activity of ethyl acetate fraction of the seeds of Brucea Javanica. J Ethnopharmacol. 2013;147:442–6.

  10. 10.

    Wiseman CL, Yap HY, Bedikian AY, Bodey GP, Blumenschein GR. Phase II trial of bruceantin in metastatic breast carcinoma. Am J Clin Oncol. 1982;5:389–91.

  11. 11.

    Arseneau JC, Wolter JM, Kuperminc M, Ruckdeschel JC. A Phase II study of Bruceantin (NSC-165, 563) in advanced malignant melanoma. Invest New Drugs. 1983;1:239–42.

  12. 12.

    Cuendet M, Christov K, Lantvit DD, Deng Y, Hedayat S, Helson L, et al. Multiple myeloma regression mediated by bruceantin. Clin Cancer Res. 2004;10:1170–9.

  13. 13.

    Castelletti D, Fiaschetti G, Di Dato V, Ziegler U, Kumps C, De Preter K, et al. The quassinoid derivative NBT-272 targets both the AKT and ERK signaling pathways in embryonal tumors. Mol Cancer Ther. 2010;9:3145–57.

  14. 14.

    Wu S, Guo Z, Hopkins CD, Wei N, Chu E, Wipf P, et al. Bis-cyclopropane analog of disorazole C1 is a microtubule-destabilizing agent active in ABCB1-overexpressing human colon cancer cells. Oncotarget. 2015;6:40866–79.

  15. 15.

    Zhou C, Tong Y, Wawrowsky K, Melmed S. PTTG acts as a STAT3 target gene for colorectal cancer cell growth and motility. Oncogene. 2014;33:851–61.

  16. 16.

    Lee HJ, Zhuang G, Cao Y, Du P, Kim HJ, Settleman J. Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells. Cancer Cell. 2014;26:207–21.

  17. 17.

    Oh SB, Hwang CJ, Song SY, Jung YY, Yun HM, Sok CH, et al. Anti-cancer effect of tectochrysin in NSCLC cells through overexpression of death receptor and inactivation of STAT3. Cancer Lett. 2014;353:95–103.

  18. 18.

    Liao LL, Kupchan SM, Horwitz SB. Mode of action of the antitumor compound bruceantin, an inhibitor of protein synthesis. Mol Pharmacol. 1976;12:167–76.

  19. 19.

    Vartanian S, Ma TP, Lee J, Haverty PM, Kirkpatrick DS, Yu K, et al. Application of mass spectrometry profiling to establish brusatol as an inhibitor of global protein synthesis. Mol Cell Proteom. 2016;15:1220–31.

  20. 20.

    Lam W, Bussom S, Guan F, Jiang Z, Zhang W, Gullen EA, et al. The four-herb Chinese medicine PHY906 reduces chemotherapy-induced gastrointestinal toxicity. Sci Transl Med. 2010;2:45ra59.

  21. 21.

    Bhattacharya S, Ray RM, Johnson LR. STAT3-mediated transcription of Bcl-2, Mcl-1 and c-IAP2 prevents apoptosis in polyamine-depleted cells. Biochem J. 2005;392:335–44.

  22. 22.

    Bowman T, Broome MA, Sinibaldi D, Wharton W, Pledger WJ, Sedivy JM, et al. Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis. Proc Natl Acad Sci USA. 2001;98:7319–24.

  23. 23.

    Mata-Greenwood E, Cuendet M, Sher D, Gustin D, Stock W, Pezzuto JM. Brusatol-mediated induction of leukemic cell differentiation and G(1) arrest is associated with down-regulation of c-myc. Leukemia. 2002;16:2275–84.

  24. 24.

    Vultur A, Villanueva J, Krepler C, Rajan G, Chen Q, Xiao M, et al. MEK inhibition affects STAT3 signaling and invasion in human melanoma cell lines. Oncogene. 2014;33:1850–61.

  25. 25.

    Zhao C, Xiao H, Wu X, Li C, Liang G, Yang S, et al. Rational combination of MEK inhibitor and the STAT3 pathway modulator for the therapy in K-Ras mutated pancreatic and colon cancer cells. Oncotarget. 2015;6:14472–87.

  26. 26.

    Gurel G, Blaha G, Moore PB, Steitz TA. U2504 determines the species specificity of the A-site cleft antibiotics: the structures of tiamulin, homoharringtonine, and bruceantin bound to the ribosome. J Mol Biol. 2009;389:146–56.

  27. 27.

    Huang W, Dong Z, Chen Y, Wang F, Wang CJ, Peng H, et al. Small-molecule inhibitors targeting the DNA-binding domain of STAT3 suppress tumor growth, metastasis and STAT3 target gene expression in vivo. Oncogene. 2016;35:783–92.

  28. 28.

    Jung KH, Yoo W, Stevenson HL, Deshpande D, Shen H, Gagea M, et al. Multi-functional effects of a small-molecule STAT3 inhibitor on NASH and HCC in mice. Clin Cancer Res. 2017;23:5537–46.

  29. 29.

    Li Y, Rogoff HA, Keates S, Gao Y, Murikipudi S, Mikule K, et al. Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Pro Natl Acad Sci USA. 2015;112:1839–44.

  30. 30.

    Sen M, Thomas SM, Kim S, Yeh JI, Ferris RL, Johnson JT, et al. First-in-human trial of a STAT3 decoy oligonucleotide in head and neck tumors: implications for cancer therapy. Cancer Discov. 2012;2:694–705.

  31. 31.

    Zhao C, Wang W, Yu W, Jou D, Wang Y, Ma H, et al. A novel small molecule STAT3 inhibitor, LY5, inhibits cell viability, colony formation, and migration of colon and liver cancer cells. Oncotarget. 2016;7:12917–26.

  32. 32.

    Wei N, Chu E, Wipf P, Schmitz JC. Protein kinase d as a potential chemotherapeutic target for colorectal cancer. Mol Cancer Ther. 2014;13:1130–41.

  33. 33.

    Wei N, Chu E, Wu SY, Wipf P, Schmitz JC. The cytotoxic effects of regorafenib in combination with protein kinase D inhibition in human colorectal cancer cells. Oncotarget. 2015;6:4745–56.

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This project was supported, in part, by funds from the UPCI NCI Cancer Center Support Grant Developmental Funds (P30CA047904). This project used the UPCI Cytometry Facility and the UPCI Animal Facility, which are supported, in part, by P30CA047904. This project also was supported, in part, by Grants (No. 81202556) from the China National Natural Sciences Foundation. This project is funded, in part, under a grant with the Pennsylvania Department of Health.

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  1. Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    • Ning Wei
    • , Benjamin J. Marks
    • , Edward Chu
    •  & John C. Schmitz
  2. Cancer Therapeutics Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA

    • Ning Wei
    • , Benjamin J. Marks
    • , Edward Chu
    •  & John C. Schmitz
  3. Basic Medical Science College, Liaoning University of Traditional Chinese Medicine, Shenyang, China

    • Jun Li
  4. Computational Modeling & Simulation Program, University of Pittsburgh, Pittsburgh, PA, USA

    • Cheng Fang
  5. Department of Oncology, Taishan Medical University, Taian City, China

    • Jin Chang
  6. University of Athens Medical School, Athens, Greece

    • Vasiliki Xirou
    •  & Nick K. Syrigos


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Correspondence to Ning Wei or John C. Schmitz.

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