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Biochanin A Sensitizes Glioblastoma to Temozolomide by Inhibiting Autophagy

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Abstract

Resistance to temozolomide (TMZ) chemotherapy is the main reason for treatment failure in patients with glioblastoma (GBM). In the present study, we investigated biochanin A (BCA) a potent sensitizer of TMZ in GBM. We observed that BCA significantly enhanced cell sensitivity to TMZ in vitro and in vivo. Mechanistically, the specific chemosensitizing effect of BCA is mediated by autophagy inhibition. Moreover, by performing a molecular docking analysis, we demonstrated that BCA interacts with AMPK residues and impairs autophagy by regulating the AMPK/ULK1 pathway. These results suggest that BCA is a potential therapeutic agent that sensitizes GBM to TMZ and provide new insight into its therapeutic potential in chemoresistant GBM.

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All data generated or analyzed during this study are included in this published article. Requests for material should be made to the corresponding authors.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (81960541/82060455), the Natural Science Foundation of Gansu Province (/20JR10RA741/21JR7RA426/21JR7RA420), Key Lab of Neurology of Gansu Province (grant number 20JR10RA766), the Fundamental Research Funds for the Central University (lzujbky-2021-kb33), the Lanzhou Science and Technology Bureau Project (2021-RC-97), the Cuiying Science and Technology fund (CYXZ-01), Cuiying Graduate Supervisor Applicant Training Program (201803), and Special fund project for doctoral training (YJS-BD-13) of Lanzhou University Second Hospital.

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Authors and Affiliations

  1. Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, 730030, Gansu, China

    Qiang Dong, Qiao Li, Lei Duan, Hang Yin, Guoqiang Yuan & Yawen Pan

  2. Key Laboratory of Neurology of Gansu Province, Lanzhou University Second Hospital, Lanzhou, 730030, Gansu, People’s Republic of China

    Qiang Dong, Lei Duan, Hang Yin, Xiaoqing Wang, Yang Liu, Guoqiang Yuan & Yawen Pan

  3. Department of Anatomy and Histology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730030, Gansu, China

    Degui Wang

  4. Key Laboratory of Urological Diseases of Gansu Province, Lanzhou, Gansu, 730030, People’s Republic of China

    Lanlan Li

  5. Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, 430000, China

    Jie Wang

Authors
  1. Qiang Dong
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  2. Degui Wang
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  7. Hang Yin
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  9. Yang Liu
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  10. Guoqiang Yuan
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  11. Yawen Pan
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Contributions

YW Pan, GQ Yuan, and DG Wang designed the experiments; Q Dong, LL Li, Q Li, and H Yin performed the experiments; XQ Wang, Y Liu, and Lei Duan helped to perform the experiments; Q Dong and Q Li analyzed the data; J Wang prepared the figures for the manuscript. Q Dong, GQ Yuan, and YW Pan wrote the manuscript. All authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Guoqiang Yuan or Yawen Pan.

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All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Highlights

BCA can increase the sensitivity of TMZ in vitro and in vivo.

BCA can inhibit the autophagy of GBM cells through AMPK/ULK1 signaling pathway.

BCA sensitizes glioblastoma cells to TMZ by inhibiting autophagy.

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Dong, Q., Wang, D., Li, L. et al. Biochanin A Sensitizes Glioblastoma to Temozolomide by Inhibiting Autophagy. Mol Neurobiol 59, 1262–1272 (2022). https://doi.org/10.1007/s12035-021-02674-6

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