Noxa and Mcl-1 expression influence the sensitivity to BH3-mimetics that target Bcl-xL in patient-derived glioma stem cells

Abstract

The recurrence of Glioblastoma is partly attributed to the highly resistant subpopulation of glioma stem cells. A novel therapeutic approach focuses on restoring apoptotic programs in these cancer stem cells, as they are often deregulated. BH3-mimetics, targeting anti-apoptotic Bcl-2 family members, are emerging as promising compounds to sensitize cancer cells to antineoplastic treatments. Herein, we determined that the most abundantly expressed anti-apoptotic Bcl-2 family members, Bcl-xL and Mcl-1, are the most relevant in regulating patient-derived glioma stem cell survival. We exposed these cells to routinely used chemotherapeutic drugs and BH3-mimetics (ABT-263, WEHI-539, and S63845). We observed that the combination of BH3-mimetics targeting Bcl-xL with chemotherapeutic agents caused a marked increase in cell death and that this sensitivity to Bcl-xL inhibition correlated with Noxa expression levels. Interestingly, whereas co-targeting Bcl-xL and Mcl-1 led to massive cell death in all tested cell lines, down-regulation of Noxa promoted cell survival only in cell lines expressing higher levels of this BH3-only. Therefore, in glioma stem cells, the efficacy of Bcl-xL inhibition is closely associated with Mcl-1 activity and Noxa expression. Hence, a potentially effective strategy would consist of combining Bcl-xL inhibitors with chemotherapeutic agents capable of inducing Noxa, taking advantage of this pro-apoptotic factor.

Glioma Stem Cells Are Sensitized to BCL-2 Family Inhibition by Compromising Histone Deacetylases

“…Histone deacetylase inhibitors (HDACi) promote caspase-dependent apoptosis by diverse mechanisms [59][60][61]. As with prior work, our study of MEKi combined with HDACi highlighted the reliance of GBM cells on BCL2 proteins [62][63][64][65][66][67]. One of the most striking results in our study was the marked increase in cell death in the presence of HDACi plus an MCL1 inhibitor.…”