Combined attenuation of anti-apoptotic Bcl-2 family members Bcl-xL and Mcl-1 activities distinctively sensitize patient-derived glioma stem cells to conventional chemotherapy in a cell line specific manner.

VERA, MARIANA BELÉN; NOGUEIRAS, GERMÁN IGNACIO; MORRIS HANON, OLIVIA; SEVLEVER, GUSTAVO EMILIO; SCASSA, MARÍA ELIDA; VIDELA RICHARDSON, GUILLERMO AGUSTÍN

Congreso; LXIV Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2019

High-grade gliomas are the most prevalent and malignantprimary braintumors (Fig. 1), and glioblastoma multiforme (GBM), a GradeIV-DiffuseGlioma, is one of the most aggressive and lethal humancancers. They display a hierarchical arrangement in which a minorsubpopulation of self-renewing, highly tumorigenic glioma stem cells (GSCs)contribute to tumor initiation. These cells are responsible, at least in part,to the high chemo-resistance of high-grade gliomas, which is often due toderegulated apoptosis. A new therapeutic approach currently attractingattentionconsists in therestoration ofapoptotic programs in GSCs.B-cell lymphoma 2 (Bcl-2) family members regulate apoptoticprograms. This family consists of threesubgroups based on function and sequence homology: thepro-survival or anti-apoptotic Bcl-2-like proteins(Bcl-2, Bcl-xL, Bcl-w, Mcl-1 and Bfl-1), the pro-apoptoticmulti-domain factors (Bax, Bak and Bok) and the single domain BH3-only proteins (Bim, Puma, Bid, Bad, Bik,Bmf, Noxa, and Hrk). Antagonism of anti-apoptotic Bcl-2 members through BH3-mimetics is emerging asa novel anti-cancer therapy. These inhibitors bind to anti-apoptotic factors, leading to the release ofactivator BH3-only proteins, which in turn mayactivate Bax and/or Bak directly, culminating inmitochondrial outer membrane poreformation.Recently, we found that the expression levels of thepro-apoptotic BH3-only Noxa determine the sensitivityof patient-derived GSCs to Bcl-xL inhibition. We observedthat cells displaying low levels of Noxa are lesssensitive to BH3 mimetics targeting Bcl-xL (ABT-263 orWEHI-539). Given that Noxa preferentiallyneutralizes Mcl-1, it is conceivable that pharmacologicalinhibition of Bcl-xL, together with the endogenousactivity of Noxa, leads to theinhibition of thesetwo keyanti-apoptotic factors in certain GSCs.