VDAC1-Based Peptides as a Potential Therapeutics for Glioblastoma

Glioblastoma multiforme (GBM), a common primary brain malignancy characterized by high morbidity, relapse rate and mortality, is highly invasive, proliferative, and resistant to chemo- and radiotherapies and for which effective therapeutic options are lacking. GBMs undergo metabolic reprograming and develop cell survival strategies, involving anti-apoptotic defense mechanisms, hallmarks of numerous cancers. As such, tumor metabolism and apoptosis resistance are emerging avenues for cancer therapy. The outer mitochondrial membrane protein voltage-dependent anion channel 1 (VDAC1) is a central player in cell energy metabolism and assumes a key role in mitochondria-mediated apoptosis.

Here, we demonstrate that VDAC1-based cell-penetrating peptides induce cell death in several brain cancer-derived cell lines, including GBM and GBM-derived stem cells. The mode of action of the VDAC1-based peptides involved induction of mitochondria-mediated apoptosis and impairment of energy and metabolic homeostasis. In a xenograft glioblastoma mouse model, VDAC1-based peptides, markedly inhibited tumor growth and induce apoptosis. Strikingly, peptide-treated tumors showed down-regulation of the glucose transporter, glycolytic enzymes and VDAC1 expression. In contrast, the levels of apoptotic proteins, such as p53 cytochrome c and caspases, increased. Moreover, peptide tumor treatment induced dramatic decreases in cell proliferation and eliminated stem cells. These findings show that VDAC1-based peptides dramatically inhibit cancer cell growth and tumor development, eliminate cancer stem cells and trigger apoptosis, raising the possibility of a more effective pipeline of anti-glioblastoma drugs designed to overcome GBM stemness, invasiveness and relapse.