Chronic lymphocytic leukemia (CLL) remains an incurable disease requiring innovative new approaches to improve therapeutic outcome. Here, a new strategy for inducing cell death in CLL, involving the mitochondrial protein VDAC1, is presented. VDAC1 mediate the metabolic cross-talk between mitochondrion and the rest of the cell thus has a fundamental role in cell energy metabolism. VDAC1 also plays a key role in mitochondria-mediated apoptosis, interacting with anti-apoptotic proteins. We previously demonstrated that a VDAC1-based cell-penetrating peptide, Antp-LP4, prevented the interaction of anti-apoptotic proteins with VDAC1, and their anti-apoptotic effects. Here, we demonstrate that the Antp-LP4 preferentially induced cell death of CLL patient-derived cells. The cell death-inducing competence of the Antp-LP4 correlated well with the amount of CD5+/CD19+-expressing cells, further illustrating the selectivity of the peptide towards CLL cancer cells. The mode of action of the peptide involves decreasing energy production and inducing apoptosis. Over 27 versions of cell-penetrating VDAC1-based peptides were designed and screened to identify the most stable, short, and apoptosis-inducing peptides towards CLL-derived lymphocytes. This comprehensive screen identified three optimized peptides suitable for in vivo studies. This study thus reveals the potential of VDAC1-based peptides for the development of an innovative and effective anti-CLL therapy.
