Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

S670, an amide derivative of 3-O-acetyl-11-keto-β-boswellic acid, induces ferroptosis in human glioblastoma cells by generating ROS and inhibiting STX17-mediated fusion of autophagosome and lysosome

Acta Pharmacologica Sinica volume 45, pages 209–222 (2024)Cite this article

Abstract

Glioblastoma (GBM) is the most common malignant tumor in the brain with temozolomide (TMZ) as the only approved chemotherapy agent. GBM is characterized by susceptibility to radiation and chemotherapy resistance and recurrence as well as low immunological response. There is an urgent need for new therapy to improve the outcome of GBM patients. We previously reported that 3-O-acetyl-11-keto-β-boswellic acid (AKBA) inhibited the growth of GBM. In this study we characterized the anti-GBM effect of S670, a synthesized amide derivative of AKBA, and investigated the underlying mechanisms. We showed that S670 dose-dependently inhibited the proliferation of human GBM cell lines U87 and U251 with IC50 values of around 6 μM. Furthermore, we found that S670 (6 μM) markedly stimulated mitochondrial ROS generation and induced ferroptosis in the GBM cells. Moreover, S670 treatment induced ROS-mediated Nrf2 activation and TFEB nuclear translocation, promoting protective autophagosome and lysosome biogenesis in the GBM cells. On the other hand, S670 treatment significantly inhibited the expression of SXT17, thus impairing autophagosome-lysosome fusion and blocking autophagy flux, which exacerbated ROS accumulation and enhanced ferroptosis in the GBM cells. Administration of S670 (50 mg·kg−1·d−1, i.g.) for 12 days in a U87 mouse xenograft model significantly inhibited tumor growth with reduced Ki67 expression and increased LC3 and LAMP2 expression in the tumor tissues. Taken together, S670 induces ferroptosis by generating ROS and inhibiting STX17-mediated fusion of autophagosome and lysosome in GBM cells. S670 could serve as a drug candidate for the treatment of GBM.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: S670 inhibited the proliferation of GBM cells in vitro.
Fig. 2: S670 stimulated ROS generation in GBM cells and induced ferroptosis.
Fig. 3: S670 induced protective autophagy via Nrf2 activation.
Fig. 4: S670 induced lysosome biogenesis via ROS-stimulated TFEB nuclear translocation.
Fig. 5: S670 impaired autophagosome-lysosome fusion by inhibiting STX17, which exacerbated ferroptosis.
Fig. 6: S670 suppressed tumor growth in a U87 mouse xenograft model.
Fig. 7: Proposed mechanistic scheme of the anti-GBM activity of S670.

Similar content being viewed by others

References

  1. Ostrom QT, Patil N, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS. CBTRUS Statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2013-2017. Neuro Oncol. 2020;22:iv1–iv96.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Weller M, Wick W, Aldape K, Brada M, Berger M, Pfister SM, et al. Glioma. Nat Rev Dis Prim. 2015;1:15017.

    Article  PubMed  Google Scholar 

  3. Rong L, Li N, Zhang Z. Emerging therapies for glioblastoma: current state and future directions. J Exp Clin Cancer Res. 2022;41:142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. van Solinge TS, Nieland L, Chiocca EA, Broekman MLD. Advances in local therapy for glioblastoma - taking the fight to the tumour. Nat Rev Neurol. 2022;18:221–36.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Stockwell BR. Ferroptosis turns 10: emerging mechanisms, physiological functions, and therapeutic applications. Cell. 2022;185:2401–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Liu T, Zhu C, Chen X, Guan G, Zou C, Shen S, et al. Ferroptosis, as the most enriched programmed cell death process in glioma, induces immunosuppression and immunotherapy resistance. Neuro Oncol. 2022;24:1113–25.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Shi J, Yang N, Han M, Qiu C. Emerging roles of ferroptosis in glioma. Front Oncol. 2022;12:993316.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Xia L, Gong M, Zou Y, Wang Z, Wu B, Zhang S, et al. Apatinib induces ferroptosis of glioma cells through modulation of the VEGFR2/Nrf2 pathway. Oxid Med Cell Longev. 2022;2022:9925919.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Zhang L, Song J, Kong L, Yuan T, Li W, Zhang W, et al. The strategies and techniques of drug discovery from natural products. Pharmacol Ther. 2020;216:107686.

    Article  CAS  PubMed  Google Scholar 

  10. Lu S, Wang XZ, He C, Wang L, Liang SP, Wang CC, et al. ATF3 contributes to brucine-triggered glioma cell ferroptosis via promotion of hydrogen peroxide and iron. Acta Pharmacol Sin. 2021;42:1690–702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhan S, Lu L, Pan SS, Wei XQ, Miao RR, Liu XH, et al. Targeting NQO1/GPX4-mediated ferroptosis by plumbagin suppresses in vitro and in vivo glioma growth. Br J Cancer. 2022;127:364–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wang Z, Ding Y, Wang X, Lu S, Wang C, He C, et al. Pseudolaric acid B triggers ferroptosis in glioma cells via activation of Nox4 and inhibition of xCT. Cancer Lett. 2018;428:21–33.

    Article  CAS  PubMed  Google Scholar 

  13. Chen TC, Chuang JY, Ko CY, Kao TJ, Yang PY, Yu CH, et al. AR ubiquitination induced by the curcumin analog suppresses growth of temozolomide-resistant glioblastoma through disrupting GPX4-mediated redox homeostasis. Redox Biol. 2020;30:101413.

    Article  CAS  PubMed  Google Scholar 

  14. Feng Y, He D, Yao Z, Klionsky DJ. The machinery of macroautophagy. Cell Res. 2014;24:24–41.

    Article  CAS  PubMed  Google Scholar 

  15. Onorati AV, Dyczynski M, Ojha R, Amaravadi RK. Targeting autophagy in cancer. Cancer. 2018;124:3307–18.

    Article  PubMed  Google Scholar 

  16. Ishaq M, Ojha R, Sharma AP, Singh SK. Autophagy in cancer: recent advances and future directions. Semin Cancer Biol. 2020;66:171–81.

    Article  PubMed  Google Scholar 

  17. Taylor MA, Das BC, Ray SK. Targeting autophagy for combating chemoresistance and radioresistance in glioblastoma. Apoptosis. 2018;23:563–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sanati M, Binabaj MM, Ahmadi SS, Aminyavari S, Javid H, Mollazadeh H, et al. Recent advances in glioblastoma multiforme therapy: a focus on autophagy regulation. Biomed Pharmacother. 2022;155:113740.

    Article  CAS  PubMed  Google Scholar 

  19. Siddiqui MZ. Boswellia serrata, a potential antiinflammatory agent: an overview. Indian J Pharm Sci. 2011;73:255–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Efferth T, Oesch F. Anti-inflammatory and anti-cancer activities of frankincense: targets, treatments and toxicities. Semin Cancer Biol. 2022;80:39–57.

    Article  CAS  PubMed  Google Scholar 

  21. Siddiqui A, Shah Z, Jahan RN, Othman I, Kumari Y. Mechanistic role of boswellic acids in Alzheimer’s disease: emphasis on anti-inflammatory properties. Biomed Pharmacother. 2021;144:112250.

    Article  CAS  PubMed  Google Scholar 

  22. Gong Y, Jiang X, Yang S, Huang Y, Hong J, Ma Y, et al. The biological activity of 3-O-acetyl-11-keto-β-boswellic acid in nervous system diseases. Neuromolecular Med. 2022;24:374–84.

  23. Li W, Liu J, Fu W, Zheng X, Ren L, Liu S, et al. 3-O-acetyl-11-keto-β-boswellic acid exerts anti-tumor effects in glioblastoma by arresting cell cycle at G2/M phase. J Exp Clin Cancer Res. 2018;37:132.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Li W, Ren L, Zheng X, Liu J, Wang J, Ji T, et al. 3-O-Acetyl-11-keto- β -boswellic acid ameliorated aberrant metabolic landscape and inhibited autophagy in glioblastoma. Acta Pharm Sin B. 2020;10:301–12.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Mendonsa AM, Na TY, Gumbiner BM. E-cadherin in contact inhibition and cancer. Oncogene. 2018;37:4769–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Cao ZQ, Wang Z, Leng P. Aberrant N-cadherin expression in cancer. Biomed Pharmacother. 2019;118:109320.

    Article  CAS  PubMed  Google Scholar 

  27. Marefati N, Beheshti F, Memarpour S, Bayat R, Naser Shafei M, Sadeghnia HR, et al. The effects of acetyl-11-keto-β-boswellic acid on brain cytokines and memory impairment induced by lipopolysaccharide in rats. Cytokine. 2020;131:155107.

    Article  CAS  PubMed  Google Scholar 

  28. Yang Y, Karakhanova S, Hartwig W, D’Haese JG, Philippov PP, Werner J, et al. Mitochondria and mitochondrial ROS in cancer: novel targets for anticancer therapy. J Cell Physiol. 2016;231:2570–81.

    Article  CAS  PubMed  Google Scholar 

  29. Su LJ, Zhang JH, Gomez H, Murugan R, Hong X, Xu D, et al. Reactive oxygen species-induced lipid peroxidation in apoptosis, autophagy, and ferroptosis. Oxid Med Cell Longev. 2019;2019:5080843.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Gan B. Mitochondrial regulation of ferroptosis. J Cell Biol. 2021;220:e202105043.

  31. Zhao C, Yu D, He Z, Bao L, Feng L, Chen L, et al. Endoplasmic reticulum stress-mediated autophagy activation is involved in cadmium-induced ferroptosis of renal tubular epithelial cells. Free Radic Biol Med. 2021;175:236–48.

    Article  CAS  PubMed  Google Scholar 

  32. Chen X, Yu C, Kang R, Kroemer G, Tang D. Cellular degradation systems in ferroptosis. Cell Death Differ. 2021;28:1135–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhou J, Li XY, Liu YJ, Feng J, Wu Y, Shen HM, et al. Full-coverage regulations of autophagy by ROS: from induction to maturation. Autophagy. 2022;18:1240–55.

    Article  CAS  PubMed  Google Scholar 

  34. Katsuragi Y, Ichimura Y, Komatsu M. p62/SQSTM1 functions as a signaling hub and an autophagy adaptor. FEBS J. 2015;282:4672–8.

    Article  CAS  PubMed  Google Scholar 

  35. Hill SM, Wrobel L, Rubinsztein DC. Post-translational modifications of Beclin 1 provide multiple strategies for autophagy regulation. Cell Death Differ. 2019;26:617–29.

    Article  CAS  PubMed  Google Scholar 

  36. Xu F, Hua C, Tautenhahn HM, Dirsch O, Dahmen U. The role of autophagy for the regeneration of the aging liver. Int J Mol Sci. 2020;21:3606.

  37. Lu Z, Ren Y, Yang L, Jia A, Hu Y, Zhao Y, et al. Inhibiting autophagy enhances sulforaphane-induced apoptosis via targeting NRF2 in esophageal squamous cell carcinoma. Acta Pharm Sin B. 2021;11:1246–60.

    Article  CAS  PubMed  Google Scholar 

  38. Sharma G, Guardia CM, Roy A, Vassilev A, Saric A, Griner LN, et al. A family of PIKFYVE inhibitors with therapeutic potential against autophagy-dependent cancer cells disrupt multiple events in lysosome homeostasis. Autophagy. 2019;15:1694–718.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Saftig P, Haas A. Turn up the lysosome. Nat Cell Biol. 2016;18:1025–7.

    Article  CAS  PubMed  Google Scholar 

  40. Eskelinen EL. Roles of LAMP-1 and LAMP-2 in lysosome biogenesis and autophagy. Mol Asp Med. 2006;27:495–502.

    Article  CAS  Google Scholar 

  41. Zhao C, Qiu S, He J, Peng Y, Xu H, Feng Z, et al. Prodigiosin impairs autophagosome-lysosome fusion that sensitizes colorectal cancer cells to 5-fluorouracil-induced cell death. Cancer Lett. 2020;481:15–23.

    Article  CAS  PubMed  Google Scholar 

  42. Hu P, Li H, Sun W, Wang H, Yu X, Qing Y, et al. Cholesterol-associated lysosomal disorder triggers cell death of hematological malignancy: Dynamic analysis on cytotoxic effects of LW-218. Acta Pharm Sin B. 2021;11:3178–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Peng P, Jia D, Cao L, Lu W, Liu X, Liang C, et al. Akebia saponin E, as a novel PIKfyve inhibitor, induces lysosome-associated cytoplasmic vacuolation to inhibit proliferation of hepatocellular carcinoma cells. J Ethnopharmacol. 2021;266:113446.

    Article  CAS  PubMed  Google Scholar 

  44. Hossain MI, Marcus JM, Lee JH, Garcia PL, Singh V, Shacka JJ, et al. Restoration of CTSD (cathepsin D) and lysosomal function in stroke is neuroprotective. Autophagy. 2021;17:1330–48.

    Article  CAS  PubMed  Google Scholar 

  45. Hinton T, Johnston GAR. GABA-enriched teas as neuro-nutraceuticals. Neurochem Int. 2020;141:104895.

    Article  CAS  PubMed  Google Scholar 

  46. Zhang X, Cheng X, Yu L, Yang J, Calvo R, Patnaik S, et al. MCOLN1 is a ROS sensor in lysosomes that regulates autophagy. Nat Commun. 2016;7:12109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Fu R, Deng Q, Zhang H, Hu X, Li Y, Liu Y, et al. A novel autophagy inhibitor berbamine blocks SNARE-mediated autophagosome-lysosome fusion through upregulation of BNIP3. Cell Death Dis. 2018;9:243.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Zhang L, Qiang P, Yu J, Miao Y, Chen Z, Qu J, et al. Identification of compound CA-5f as a novel late-stage autophagy inhibitor with potent anti-tumor effect against non-small cell lung cancer. Autophagy. 2019;15:391–406.

    Article  CAS  PubMed  Google Scholar 

  49. Tian X, Teng J, Chen J. New insights regarding SNARE proteins in autophagosome-lysosome fusion. Autophagy. 2021;17:2680–8.

    Article  CAS  PubMed  Google Scholar 

  50. Button RW, Roberts SL, Willis TL, Hanemann CO, Luo S. Accumulation of autophagosomes confers cytotoxicity. J Biol Chem. 2017;292:13599–614.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Whitmarsh-Everiss T, Laraia L. Small molecule probes for targeting autophagy. Nat Chem Biol. 2021;17:653–64.

    Article  CAS  PubMed  Google Scholar 

  52. Tomar MS, Kumar A, Srivastava C, Shrivastava A. Elucidating the mechanisms of temozolomide resistance in gliomas and the strategies to overcome the resistance. Biochim Biophys Acta Rev Cancer. 2021;1876:188616.

    Article  CAS  PubMed  Google Scholar 

  53. Ulasov I, Fares J, Timashev P, Lesniak MS. Editing cytoprotective autophagy in glioma: an unfulfilled potential for therapy. Trends Mol Med. 2020;26:252–62.

    Article  CAS  PubMed  Google Scholar 

  54. Wang J, Qi Q, Zhou W, Feng Z, Huang B, Chen A, et al. Inhibition of glioma growth by flavokawain B is mediated through endoplasmic reticulum stress induced autophagy. Autophagy. 2018;14:2007–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Wang F, Gómez-Sintes R, Boya P. Lysosomal membrane permeabilization and cell death. Traffic. 2018;19:918–31.

    Article  CAS  PubMed  Google Scholar 

  56. Xu H, Zhu Y, Chen X, Yang T, Wang X, Song X, et al. Mystery of methamphetamine-induced autophagosome accumulation in hippocampal neurons: loss of syntaxin 17 in defects of dynein-dynactin driving and autophagosome-late endosome/lysosome fusion. Arch Toxicol. 2021;95:3263–84.

    Article  CAS  PubMed  Google Scholar 

  57. Compter I, Eekers DBP, Hoeben A, Rouschop KMA, Reymen B, Ackermans L, et al. Chloroquine combined with concurrent radiotherapy and temozolomide for newly diagnosed glioblastoma: a phase IB trial. Autophagy. 2021;17:2604–12.

    Article  CAS  PubMed  Google Scholar 

  58. Jiapaer S, Furuta T, Tanaka S, Kitabayashi T, Nakada M. Potential strategies overcoming the temozolomide resistance for glioblastoma. Neurol Med Chir. 2018;58:405–21.

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by Beijing Natural Science Foundation (7212157). This work was also supported by CAMS Innovation Fund for Medical Sciences (2021-I2M-1-029 and 2022-I2M-JB-011), National Natural Science Foundation of China (81703536, 82073311), Natural Science Foundation of Sichuan Province (2022JDTD0025). We thank Biorender (https://app.biorender.com/) and Figdraw (https://www.figdraw.com/) for the assistance of figure drawing.

Author information

Authors and Affiliations

  1. The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China

    Yi-hui Yang, Wan Li, Li-wen Ren, Hong Yang, Yi-zhi Zhang, Sen Zhang, Yue Hao, Guan-hua Du & Jin-hua Wang

  2. Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China

    Yi-hui Yang, Wan Li, Li-wen Ren, Hong Yang, Yi-zhi Zhang, Sen Zhang, Yue Hao, Guan-hua Du & Jin-hua Wang

  3. Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China

    Dong-ke Yu, Rong-sheng Tong & Jian-you Shi

Authors
  1. Yi-hui Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Li-wen Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hong Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yi-zhi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sen Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yue Hao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dong-ke Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Rong-sheng Tong
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Guan-hua Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jian-you Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jin-hua Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YHY performed most of the experiments and wrote the manuscript. LWR and WL curated and analyzed the data. YZZ, SZ, HY and YH assisted in animal experiments. JYS designed the amide derivatives of AKBA. DKY and RST synthesized the amide derivatives of AKBA. GHD, JYS and JHW revised the manuscript. JHW conceived and designed the work. All the authors approved the final draft.

Corresponding authors

Correspondence to Jian-you Shi or Jin-hua Wang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, Yh., Li, W., Ren, Lw. et al. S670, an amide derivative of 3-O-acetyl-11-keto-β-boswellic acid, induces ferroptosis in human glioblastoma cells by generating ROS and inhibiting STX17-mediated fusion of autophagosome and lysosome. Acta Pharmacol Sin 45, 209–222 (2024). https://doi.org/10.1038/s41401-023-01157-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41401-023-01157-9

Keywords

Search

Advanced search

Quick links