1 research outputs found
Selective induction of cancer cell death by VDAC1âbased peptides and their potential use in cancer therapy
Mitochondrial VDAC1 mediates cross talk between the mitochondria and other parts of the cell by transporting anions, cations, ATP, Ca2+, and metabolites and serves as a key player in apoptosis. As such, VDAC1 is involved in two important hallmarks of cancer development, namely energy and metabolic reprograming and apoptotic cell death evasion. We previously developed cellâpenetrating VDAC1âderived peptides that interact with hexokinase (HK), Bclâ2, and BclâxL to prevent the antiâapoptotic activities of these proteins and induce cancer cell death, with a focus on leukemia and glioblastoma. In this study, we demonstrated the sensitivity of a panel of genetically characterized cancer cell lines, differing in origin and carried mutations, to VDAC1âbased peptideâinduced apoptosis. Noncancerous cell lines were less affected by the peptides. Furthermore, we constructed additional VDAC1âbased peptides with the aim of improving targeting, selectivity, and cellular stability, including RâTfâDâLP4, containing the transferrin receptor internalization sequence (Tf) that allows targeting of the peptide to cancer cells, known to overexpress the transferrin receptor. The mode of action of the VDAC1âbased peptides involves HK detachment, interfering with the action of antiâapoptotic proteins, and thus activating multiple routes leading to an impairment of cell energy and metabolism homeostasis and the induction of apoptosis. Finally, in xenograft glioblastoma, lung, and breast cancer mouse models, RâTfâDâLP4 inhibited tumor growth while inducing massive cancer cell death, including of cancer stem cells. Thus, VDAC1âbased peptides offer an innovative new conceptual framework for cancer therapy