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

TL;DR

Brusatol, an Nrf2 inhibitor, unexpectedly promotes growth of human osteosarcoma cells and blocks their differentiation, suggesting it may not be a suitable treatment for this cancer.

Contribution

This study reveals that Brusatol promotes osteosarcoma cell growth and inhibits differentiation, contrary to its reported anti-cancer effects in other cancers.

Findings

Brusatol increased MG63 cell growth by 1.7-fold under normoxic conditions.

Brusatol blocked MG63 differentiation induced by EB1089 and lysophosphatidic acid by 2.8-fold.

Nrf2 activation with dimethyl fumarate did not reverse Brusatol's effects on MG63 cells.

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.

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