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Article

The Nrf2 Inhibitor Brusatol Promotes Human Osteosarcoma (MG63) Growth and Blocks EB1089-Induced Differentiation

School of Applied Sciences, University of the West of England, Coldharbour Lane, Bristol BS16 1QY, UK
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Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(19), 9675; https://doi.org/10.3390/ijms26199675
Submission received: 20 August 2025 / Revised: 30 September 2025 / Accepted: 1 October 2025 / Published: 3 October 2025
(This article belongs to the Section Molecular Oncology)

Abstract

Survival rates for those with metastatic osteosarcoma (OS) have not improved over the last four decades. It is imperative that novel approaches to treating and curing OS be sought. We, therefore, turned our attention to Brusatol (Bru), a naturally occurring Nrf2 inhibitor reported to elicit anti-cancer effects in a multitude of tumour models. Importantly there is emerging evidence that Nrf2 is implicated in chemoradiotherapy resistance in OS and that inhibiting Nrf2 may represent a desirable route to treating OS. Surprisingly, using the human OS cell line, MG63, we actually found that Bru promoted cell growth. Compared to control, normoxic cultures, the application of Bru (50 nM) over 3 days led to an increase in cell number by approximately 1.7-fold. A similar outcome occurred for cells under hypoxic conditions, although the extent of cell growth was significantly less at around 1.3-fold. Furthermore, Bru prevented MG63 differentiation in response to co-treatment with the calcitriol analogue, EB1089, and the lipid growth factor, lysophosphatidic acid. The extent of inhibition was profound at approximately 2.8-fold. The application of the Nrf2 activator, dimethyl fumarate, did not rescue these phenotypes. Whilst Bru has shown promise in other cancer models, it would appear, from our findings, that this agent may not be suitable for the treatment of OS.
Keywords: osteosarcoma; brusatol; Nrf2; EB1089; hypoxia; growth; differentiation; alkaline phosphatase osteosarcoma; brusatol; Nrf2; EB1089; hypoxia; growth; differentiation; alkaline phosphatase

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MDPI and ACS Style

Stephens, E.; Greenhough, A.; Mansell, J.P. The Nrf2 Inhibitor Brusatol Promotes Human Osteosarcoma (MG63) Growth and Blocks EB1089-Induced Differentiation. Int. J. Mol. Sci. 2025, 26, 9675. https://doi.org/10.3390/ijms26199675

AMA Style

Stephens E, Greenhough A, Mansell JP. The Nrf2 Inhibitor Brusatol Promotes Human Osteosarcoma (MG63) Growth and Blocks EB1089-Induced Differentiation. International Journal of Molecular Sciences. 2025; 26(19):9675. https://doi.org/10.3390/ijms26199675

Chicago/Turabian Style

Stephens, Emily, Alexander Greenhough, and Jason P. Mansell. 2025. "The Nrf2 Inhibitor Brusatol Promotes Human Osteosarcoma (MG63) Growth and Blocks EB1089-Induced Differentiation" International Journal of Molecular Sciences 26, no. 19: 9675. https://doi.org/10.3390/ijms26199675

APA Style

Stephens, E., Greenhough, A., & Mansell, J. P. (2025). The Nrf2 Inhibitor Brusatol Promotes Human Osteosarcoma (MG63) Growth and Blocks EB1089-Induced Differentiation. International Journal of Molecular Sciences, 26(19), 9675. https://doi.org/10.3390/ijms26199675

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