Targeting intrinsic apoptosis and other forms of cell death by BH3-mimetics in glioblastoma

Abstract

Introduction: Novel approaches to treat malignant brain tumors are necessary since these neoplasms still display an unfavorable prognosis. Areas covered: In this review, the authors summarize and analyze recent preclinical data that suggest that targeting intrinsic apoptosis may be a suitable strategy for the treatment of malignant gliomas. They focus on the anti-apoptotic Bcl-2 family members of proteins and the recent drug developments in that field with a special focus on BH3-mimetics. With the discovery of BH3-mimetics that interfere with anti-apoptotic Bcl-2 family members in the low nanomolar range significant excitement has been generated towards these class of inhibitors, such as ABT-737, ABT-263 and the most recent successor, ABT-199 which is most advanced with respect to clinical application. The authors discuss the more recent selective inhibitors of Bcl-xL and Mcl-1. Concerning Mcl-1, these novel classes of inhibitors have the potential to impact malignant gliomas since these tumors reveal increased levels of Mcl-1. Expert opinion: The recent development of certain small molecules raises significant hope that intrinsic apoptosis might soon be efficiently targetable for malignancies of the central nervous system. That being said, additional studies are necessary to determine which of the BH3-mimetics might be most suitable.

Activation of LXR β inhibits tumor respiration and is synthetically lethal with Bcl‐ xL inhibition

“…These observations (GSEA findings) led us to hypothesize that LXR agonists synergize with BH3 mimetics (ABT263). Therefore, we conducted cellular viability assays with dose–responses of each drug, followed by drug combination treatment and synergy analysis based on the Chou–Talalay method, which enables the calculation of normalized isobolograms (median‐effect equation) (Chou, ; Karpel‐Massler et al , 2017c; Merino et al , ). Selected conditions of the single and combination treatments are provided and statistically compared (Fig G–N and Appendix Fig ).…”

“…Our study fills this gap at least partially by providing a mechanism and through that a novel efficacious combination therapy, involving GW3965 and LXR623. Because Bcl-2 family members are central regulators of cell death in malignant tumors (Preuss et al, 2013;Souers et al, 2013;Chan et al, 2015;Faber et al, 2015;Hata et al, 2015;Johnson-Farley et al, 2015;Elgendy et al, 2016;Karpel-Massler et al, 2017c), we hypothesized that LXR agonists have an impact on their expression. While certain members of this family are more relevant in hematological malignancies, others maintain a pivotal role in solid tumors.…”

“…Aside from metabolism, tumor cells maintain a deregulated cell death machinery and have lost the ability to die in a physiological manner. This feature is linked to resistance to apoptosis, a form of cell death that is largely regulated by the pro‐ and anti‐apoptotic Bcl‐2 family members (Lagadec et al , ; Souers et al , ; Chen et al , ; Kiprianova et al , ; Karpel‐Massler et al , 2017c). Classical anti‐apoptotic members are Mcl‐1, Bcl‐2, and Bcl‐xL.…”

“…Representing the most relevant feature in this context is undoubtedly aerobic glycolysis, a paradoxical phenomenon that tumor cells bypass oxidative metabolism by converting glucose via pyruvate to lactate (Locasale et al, 2011;Masui et al, 2013;Viale et al, 2014;Pacold et al, 2016;Li et al, 2017). However, recent evidence shows that some tumor cells depend on oxidative phosphorylation as well and indeed there are several cancer cell lines that have a high dependency on cellular respiration to maintain their survival (Dranoff et al, 1985;Qing et al, family members (Lagadec et al, 2008;Souers et al, 2013;Chen et al, 2014;Kiprianova et al, 2015;Karpel-Massler et al, 2017c). Classical anti-apoptotic members are Mcl-1, Bcl-2, and Bcl-xL.…”

Bcl‐2/Bcl‐xL inhibition predominantly synergistically enhances the anti‐neoplastic activity of a low‐dose CUSP9 repurposed drug regime against glioblastoma

“…In cancer, anti-apoptotic Bcl-2 family proteins such as Bcl-2, Mcl-1, and Bcl-xL are frequently overexpressed, which shifts the cellular homeostasis towards an anti-apoptotic cellular phenotype facilitating the survival of cancer cells. BH3 mimetics like ABT263 (navitoclax) interfere with the function of anti-apoptotic Bcl-2 family proteins Bcl-2 and Bcl-xL by inhibiting the sequestration of pro-apoptotic multi-domain effector proteins BAX and BAK which leads to pore formation in the outer mitochondrial membrane and to restoration of a pro-apoptotic cellular phenotype (Karpel-Massler, Ishida, Zhang, Halatsch, et al, 2017;Tse et al, 2008). Moreover, BH3 mimetics induce a displacement of BH3-only proteins such as NOXA, BAD, or Bim from anti-apoptotic Bcl-2 family proteins to further promote apoptosis (Kale, Osterlund, & Andrews, 2018).…”