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Adjuvant therapeutic potential of moderate hypothermia for glioblastoma

  • Laboratory Investigation
  • Published:
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Abstract

Purpose

Glioblastoma is the most common malignant brain tumor, currently treated by surgery followed by concomitant radiotherapy and temozolomide-based chemotherapy. Despite these treatments, median survival is only 15 months as a result of tumor recurrence in the resection margins. Here, we propose therapeutic hypothermia - known to have neuroprotective effects - as an adjuvant treatment to maintain residual glioblastoma cells in a dormant state, and thus prevent tumor recurrence.

Methods

In vitro experiments were performed on healthy tissue with primary human astrocytes, and four human glioblastoma cell lines: A172, U251, U87, and T98G. We explored the adjuvant potential of moderate hypothermia (28 °C) by studying the reversibility of its inhibitory effects on cell proliferation and comparing them to currently used temozolomide.

Results

Moderate hypothermia reduced healthy cell growth, but also inhibited glioblastoma cell proliferation even after rewarming. Indeed, hypothermic preconditioning duration strongly enhanced inhibitory effects from 35% after 3 days to 100% after 30 days. In contrast, moderate (28 °C) and severe (23 °C) preconditioning induced similar results. Finally, moderate hypothermia had more uniform inhibitory effects than temozolomide, which reduced proliferation by between 15% and 95%, and also potentiated the effects of the latter.

Conclusion

Moderate hypothermia shows promise as an adjuvant therapy for glioblastoma through its inhibition of cell proliferation beyond direct conditioning and potentiation of the effects of chemotherapy. If in vivo preclinical results corroborate our findings, therapeutic hypothermia applied at the resection margins could probably inhibit tumor growth, delay tumor recurrence and reduce inter-patient variability.

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Availability of data and material

The datasets generated and analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgments

We thank Maighread Gallagher-Gambarelli from TWS Editing for providing linguistic support and suggestions on language usage for the manuscript.

Funding

No funds, grants, or other support was received for conducting this study.

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Authors and Affiliations

  1. Univ. Grenoble Alpes, CEA, LETI, Clinatec, 38000, Grenoble, France

    Clémentine Fulbert, Stéphan Chabardès & David Ratel

  2. Neurosurgery Department, CHU Grenoble Alpes, 38000, Grenoble, France

    Stéphan Chabardès

  3. Univ. Grenoble Alpes, Inserm U1216, Grenoble Institut des Neurosciences, 38000, Grenoble, France

    Stéphan Chabardès

Authors
  1. Clémentine Fulbert
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  3. David Ratel
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Contributions

All authors contributed to the study conception. Methodology, material preparation, data collection and data analysis were performed by Clémentine Fulbert. The first draft of the manuscript was written by Clémentine Fulbert and David Ratel commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Clémentine Fulbert or David Ratel.

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Fulbert, C., Chabardès, S. & Ratel, D. Adjuvant therapeutic potential of moderate hypothermia for glioblastoma. J Neurooncol 152, 467–482 (2021). https://doi.org/10.1007/s11060-021-03704-y

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