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Combined treatment with 2′-hydroxycinnamaldehyde and temozolomide suppresses glioblastoma tumorspheres by decreasing stemness and invasiveness

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Abstract

Introduction

Glioblastoma (GBM) is the most common and aggressive human primary brain malignancy. The key properties of GBM, stemness and invasiveness, are known to be associated with a highly unfavorable prognosis. Notably, the process of epithelial-mesenchymal transition (EMT) is closely related to the progression of GBM. On the basis of reports that 2′-hydroxycinnamaldehyde (HCA) and its derivative, 2′-benzoyloxycinnamaldehyde (BCA), suppresses EMT in several human cancer cells, we sought to evaluate the therapeutic efficacy of HCA and BCA, alone and in combination with temozolomide (TMZ), on GBM tumorspheres (TSs).

Methods

Two human GBM TSs were treated with HCA, BCA, or TMZ. Therapeutic effects were evaluated by measuring ATP levels, neurosphere formation, 3D-invasion in collagen matrix, and viability. Protein expression profiles after drug treatment were evaluated by western blotting. In vivo anticancer efficacy of drugs was examined in a mouse orthotopic xenograft model.

Results

Combined treatment of GBM TSs with HCA or BCA and TMZ significantly reduced cell viability, stemness, and invasiveness. Expression levels of stemness-, invasiveness-, and mesenchymal transition-associated markers, Zeb1, N-cadherin, and β-catenin, were also substantially decreased by the combined treatment. The combined treatment also reduced tumor growth in a mouse orthotopic xenograft model.

Conclusion

Our findings suggest that HCA and BCA, combined with TMZ, are potential therapeutic agents in the treatment of GBM.

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Acknowledgements

This work was supported by grants from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (Grant No. HI17C2586), the Basic Science Research Program through the National Research Foundation of Korea funded by the MSIP: Ministry of Science, ICT and Future Planning, Republic of Korea (Grant No. NRF-2017M2A2A7A01071036).

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Author notes

  1. Hyewon Jeong and Junseong Park have contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei- ro, Seodaemun-gu, Seoul, 03722, Republic of Korea

    Hyewon Jeong, Junseong Park, Jin-Kyoung Shim, Jae Eun Lee, Jong Hee Chang & Seok-Gu Kang

  2. Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, 03722, Republic of Korea

    Nam Hee Kim, Hyun Sil Kim & Jong In Yook

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  1. Hyewon Jeong
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Correspondence to Seok-Gu Kang.

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All procedures performed in studies involving animals were in accordance with the ethical standards of the Yonsei University College of Medicine Institutional Animal Care and Use Committee. This article does not contain any studies involving human participants performed by any of the authors.

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Jeong, H., Park, J., Shim, JK. et al. Combined treatment with 2′-hydroxycinnamaldehyde and temozolomide suppresses glioblastoma tumorspheres by decreasing stemness and invasiveness. J Neurooncol 143, 69–77 (2019). https://doi.org/10.1007/s11060-019-03151-w

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