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Glycosylated triptolide affords a potent in vivo therapeutic activity to hepatocellular carcinoma in mouse model

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Abstract

While studies have demonstrated the therapeutic potential of triptolide for different cancers including hepatocellular carcinoma (HCC), its development is greatly hurdled by lacking tumor targeting and poor solubility. To address these issues, triptolide was bonded to different site of glucose/glucose analogues via different linkage resulting in triptolide glycoconjugates, which were evaluated with several of xenograft HCC models. Our studies indicated that triptolide linked to the C-6 OH of glucose has better anti-HCC activity with minimal toxicity, which was exampled by conjugate 3. 3 significantly reverses tumor growth in GLUT1 overexpressed xenograft HCC models; it also doses dependently decreases tumor burden and reduce tumor lung metastasis in a highly metastatic orthotopic HCC model, as well increases the survival rate of tumor burdening mice. The present study sheds light on the understanding of the relationship between the structural of glycoconjugates and selective delivery of toxic drug to tumor overexpressing of GLUTs such as HCC.

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References

  1. Fujiwara N, Friedman SL, Goossens N, Hoshida Y. Risk factors and prevention of hepatocellular carcinoma in the ear of precision medicine. J Hepatol 2018;68:526–49.

    Article  Google Scholar 

  2. LIovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Primers 7, 2021, https://doi.org/10.1038/s41572-021-00245-6. Published Online: 21 January 2021.

  3. Anwanwan D, Singh SK, Singh S, Saikam V, Singh R. Challenges in liver cancer and possible treatment approaches. Biochim Biochys Acta Rev Cancer. 2020;1873:188314. https://doi.org/10.1016/j.bbcan.2019.188314

    Article  CAS  Google Scholar 

  4. Bruix J, Raoul J-L, Sherman M, Maazaferro V, Bolondi L, Craxi A, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J Hepatol 2012;5794:821–9.

    Article  Google Scholar 

  5. Kudo M, Finn RS, Qin S, Han K-H, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomized phase 3 non-inferiority trial. Lancet 2018;391:1163–73.

    Article  CAS  Google Scholar 

  6. Tang W, Chen Z, Zhang W, Cheng Y, Zhang B, Wu F, et al. The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects. Signal Transduct Target Ther 2020;5:87. https://doi.org/10.1038/s41392-020-0187-x

    Article  Google Scholar 

  7. Fu R, Jiang S, Li J, Chen H, Zhang X. Activation of the HGF/c-MET axis promotes Lenvatinib resistance in hepatocellular carcinoma cells with high c-MET expression. Med Oncol 2020;27:24. https://doi.org/10.1007/s12032-020-01350-4

    Article  CAS  Google Scholar 

  8. Sangro B, Sarobe P, Hervás-Stubbs S, Melero I. Advances in immunotherapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2021;18:525–43.

    Article  Google Scholar 

  9. Xu W, Liu K, Chen M, Sun J-Y, McCaughan GW, Lu X-J, et al. Immunotherapy for hepatocellular carcinoma: recent advances and future perspectives. Ther Adv Med Oncol 2019;11:1758835919862692. https://doi.org/10.1177/1758835919862692

    Article  CAS  Google Scholar 

  10. Pfister D, Núñez NG, Pinyol R, Govaere O, Pinter M, Szydlowska M, et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature. 2021;592:450–6.

    Article  CAS  Google Scholar 

  11. Phillips PA, Dudeja V, McCarroll JA, Borja-Cacho D, Dawra RK, Grizzle WE, et al. Triptolide induces pancreatic cancer cell death via inhibition of heat shock protein 70. Cancer Res. 2007;67:9407–16.

    Article  CAS  Google Scholar 

  12. Vispé S, DeVries L, Créancier L, Besse J, Bréand S, Hobson DJ, et al. Triptolide is an inhibitor of RNA polymerase I and II dependent transcription leading predominantly to down-regulation of short-lived mRNA. Mol Cancer Ther. 2009;8:2780–90.

    Article  Google Scholar 

  13. Titov DV, Gilman B, He Q-L, Bhat S, Low W-K, Dang Y, et al. XPB, a subunit of TFIIH, is a target of the natural product triptolide. Nat Chem Biol 2011;7:182–8.

    Article  CAS  Google Scholar 

  14. Lou Y, Jie J, Wang Y. Triptolide inhibits transcription factor NF-KappaB and induces apoptosis of multiple myeloma cells. Leuk Res 2005;29:99–105.

    Article  CAS  Google Scholar 

  15. Noel P, Hussein S, Ng S, Antal CE, Lin W, Rodela E, et al. Triptolide targets super-enhancer networks in pancreatic cancer cells and cancer-associated fibroblasts. Oncogenesis. 2020;9:100 https://doi.org/10.1038/s41389-020-00285-9

    Article  CAS  Google Scholar 

  16. Jiang X, Cao G, Gao G, Wang W, Zhao J, Gao C. Triptolide decreases tumor-associated macrophages infiltration and M2 polarization to remodel colon cancer immune microenvironment via inhibiting tumor derived CXCL12. J Cell Physiol 2021;236:193–204.

    Article  CAS  Google Scholar 

  17. Dai D, Yuan H, Musser JH. Triptolide prodrugs having high aqueous solubility. U S Pat 6. 2003;548:537 B1.

    Google Scholar 

  18. Hurteloup PP, Brandely-Talbot M, Triptolide derivaties for use in the treatment of acute myeloid leukemia. PCT Patent 2008/087202 A1, July 24, 2008.

  19. Georg EG, Patil SP, Saluja AK, Chugh R, Vickers SM. Triptolide Prodrugs. U S Pat 8. 2013;507:552 B2.

    Google Scholar 

  20. Peng Z, Liu M, Du Q, Yang Y, Song W, Chen Y, Water-soluble triptolide derivative and preparation method and application thereof. CN Patent 110003304A, July 12, 2019.

  21. Lin Y, Huang X, Yan D, Water-soluble triptolide prodrug with polyethylene glycol as carrier as well as preparation method and application thereof. CN Patent 104629036A, May 20, 2015.

  22. Zeng H, Zhang Z, Yan M, Zhang L, Song J, Yuan Y, et al. Pbreparation method and application of triptolide-carboxylation chitosan coupling drug.. CN Patent 109464675 B, October 29, 2021.

  23. Kitzen JJEM, de Jonge MJA, Lamers CHJ, Eskens FALM, van der Biessen D, van Doorn L, et al. Phase I dose-escalation study of F60008, a novel apoptosis inducer, in patients with advanced solid tumors. Eur J Cancer 2009;45:1764–72.

    Article  CAS  Google Scholar 

  24. Phase II open label trial of minnelideTM in patients with chemotherapy refactory metastatic pancreatic cancer Propper, D; Han, H; Von Hoff, D; Borazanci, E; Reya, T; Ghergurovich G; et al. AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA.

  25. Roshan SK, Spano AD, McKinney AM, Nascene DR. Potentially reversible acute cerebellar toxicity associated with Minnelide. Neuroradiology. 2017;59:419–21.

    Article  Google Scholar 

  26. Zhang K, Ma Y, Guo Y, Sun T, Wu J, Pangeni RP, et al. Cetuximab-triptolide conjugate suppresses the growth of EGFR-overexpressing lung cancers through targeting RNA polymerase II. Mol Ther Oncolytics 2020;18:304–16.

    Article  CAS  Google Scholar 

  27. Hayashi M, Madokoro H, Yamada K, Nishida H, Morimoto C, Sakamoto M, et al. Novel antibody-drug conjugate with anti-CD26 humanized monoclonal antibody and transcription factor IIH(TFIIH) inhibitor, triptolide, inhibits tumor growth via impairing mRNA synthesis. Cancer. 2019;11:1138 https://doi.org/10.3390/cancers11081138

    Article  CAS  Google Scholar 

  28. He Q, Minn II, Wang Q, Xu P, Head SA, Datan E, et al. Targeted Delivery and Sustained Antitumor Activity of Triptolide through Glucose Conjugation. Angew Chem Int Ed Engl. 2016;55:12035–9.

    Article  CAS  Google Scholar 

  29. Datan E, Minn II, Xu P, He Q, Ahn H, Yu B, et al. A glucose-triptolide conjugate selective targets cancer cells under hypoxia. iScience. 2020, 23, https://doi.org/10.1016/j.isci.2020.101536

  30. LIoyd KP, Ojelabi OA, De Zutter JK, Carruthers A. Reconciling contradictory findings: glucose transporter 1(GLUT1) functions as an oligomer of allosteric, alternating access transporters. J Bio Chem 2017;292:21035–46.

    Article  Google Scholar 

  31. Patra M, Awuah SG, Lippard SJ. Chemical approach to position isomers of glucose-platinum conjugates reveals specific cancer targeting through glucose-transporter-medicated uptake in vitro and in vivo. J Am Chem Soc 2016;138:12541–51.

    Article  CAS  Google Scholar 

  32. Patel RV, Park SW. An evolving role of piperazine moieties in drug design and discovery. Mini Rev Med Chem 2013;13:1579–601.

    Article  CAS  Google Scholar 

  33. Korotcov AV, Ye Y, Chen Y, Zhang F, Huang S, Lin S, et al. Glucosamine-linked near-infrared fluorescent probes for imaging of solid tumor xenograft. Mol Imaging Biol 2012;14:443–51.

    Article  Google Scholar 

  34. Lu W, Navidpour L, Taylor SD. An expedient synthesis of benzyl 2,3,4,-tri-O-benzyl-beta-D-glucopyranoside and benzyl 2,3,4,-tri-O-benzyl-beta-D-mannopyranoside. Carbohydr Res 2005;340:1213–7.

    Article  CAS  Google Scholar 

  35. Esienach PA, Soeth E, Röder C, Klöppel G, Tepel J, Kalthoff H, et al. Dipeptidase 1 (DPEP1) is a marker for the transition from low-grade to high-grade intraepithelial neoplasia and adverse prognostic factor in colorectal cancer. Br J Cancer 2013;109:694–703.

    Article  Google Scholar 

  36. Stein M, Lin H, Jeyamohan C, Dvorzhinski D, Gounder M, Bray K, et al. Targeting tumor metabolism with 2-deoxyglucose in patients with castrate-resistant prostate cancer and advanced malignancies. Prostate 2010;70:1388–94.

    Article  CAS  Google Scholar 

  37. Pajak B, Siwiak E, Soltyka M, Priebe A, Zieliński R, Fokt I, et al. 2-Deoxy-D-glucose and its analogs: from diagnostic to therapeutic agents. Int J Mol Sci 2020;21:234 https://doi.org/10.3390/ijms21010234

    Article  CAS  Google Scholar 

  38. Bucher C, Gilmour R. Fluorine-directed glycosylation. Angew, Chem, Int, Ed, Engl. 2010;49:8724–8.

    Article  CAS  Google Scholar 

  39. Somasundaram D, Balasubramanain KK, Shanmugasundaram B. Simple and mild stereoselctive O-glycosidation using 1,2-anhydrosugars under neutral conditions. Tetrahedron Lett. 2019;60:764–7.

    Article  CAS  Google Scholar 

  40. Qi B, Wang X, Zhou Y, Han Q, He L, Gong T, et al. A renal-targeted triptolide aminoglycoside(TPAG) conjugate for lowering system toxicities of triptolide. Fitoterapia. 2015;103:242–51.

    Article  CAS  Google Scholar 

  41. Yang S, Chen J, Guo Z, Xu X-M, Wang L, Per X-F, et al. Triptolide inhibits the growth and metastasis of solid tumors. Mol Cancer Ther 2003;2:65–72.

    CAS  Google Scholar 

  42. Xu L, Qiu Y, Xu H, Ao W, Lam W, Yang X. Acute and subacute toxicity studies on triptolide and triptolide-loaded polymeric micelles following intravenous administration in rodents. Food Chem Toxicol 2013;57:371–9.

    Article  CAS  Google Scholar 

  43. Mohd Abdul Rashid MB, Toh TB, Silv A, Nurrul Abdullah L, Ho C-M, Ho D, et al. Identification and optimization of combinatorial glucose metabolism inhibitors in hepatocellular carcinomas. J Lab Autom 2015;20:423–37.

    Article  Google Scholar 

  44. Katyal S, Oliver JH 3rd, Peterson MS, Ferris JV, Carr BS, Baron RL. Extrahepatic metastases of hepatocellular carcinoma. Radiology 2000;216:698–703.

    Article  CAS  Google Scholar 

  45. Li Y, Tang ZY, Ye SL, Liu YK, Chen J, Xue Q, et al. Establishment of cell clones with different metastatic potential from the metastatic hepatocellular carcinoma cell line MHCC97. World J Gastroenterol. 2001;7:630–636.

    Article  CAS  Google Scholar 

  46. Yao X, Hu J-F, Daniels M, Yien H, Liu H, Sharan H, et al. A novel orthotopic tumor model to study growth factor and oncogenes in hepatocarcinogenesis. Clin Cancer Res 2003;9:2719–26.

    CAS  Google Scholar 

  47. Testa B, Mayer JM, Concepts in prodrug design to overcome pharmacokinetic problems. In Pharmacokinetic Optimization in Drug Research; Testa, B. et al., Ed.; Wiley-VCH, 2001; 85–95.

  48. Swindlem M, Makimn A, Herron A, Clubb F Jr, Frazier K. Swine as models in biomedical research and toxicology testing. Vet Pathol 2012;49:344–56.

    Article  Google Scholar 

  49. Shang R-Z, Qu S-B, Wang D-S. Reprogramming of glucose metabolism in hepatocellular carcinoma: progress and prospects. World J Gastroenterol. 2016;22:9933–43.

    Article  CAS  Google Scholar 

  50. Amann T, Maegdefrau U, Hartmann A, Agaimy A, Marienhagen J, Weiss TS, et al. GLUT1 Expression is increased in hepatocellular carcinoma and promotes tumorigenesis. Am J Pathol 2009;174:1544–1552.

    Article  CAS  Google Scholar 

  51. Lei Y, Hu Q, Gu J. Expressions of carbohydrate response element binding protein and glucose transporters in liver cancer and clinical significance. Pathol Oncol Res 2020;26:1331–40.

    Article  CAS  Google Scholar 

  52. Barnett JE, Holman GD, Munday KA. Structural requirements for binding to the sugar-transport system of the human erythrocyte. Biochem J. 1973;131:211–21.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Reyoung Drug Discovery Co., Ltd., 720 Cailun Road, Bldg 2, Room 602, Pudong New District, Shanghai, 201203, China

    Jian Xue, Feng Pan & Tengcong Long

  2. Reyoung Corporation, 704 Quince Orchard Road, Suite 215, Gaithersburg, MD, 20878, USA

    Frank Shujie Hou

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  1. Jian Xue
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Xue, J., Pan, F., Long, T. et al. Glycosylated triptolide affords a potent in vivo therapeutic activity to hepatocellular carcinoma in mouse model. Med Chem Res 32, 254–270 (2023). https://doi.org/10.1007/s00044-022-03008-4

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