Abstract
Targeted therapies of melanoma are of urgent need considering the resistance of this aggressive type of cancer to chemotherapeutics. The voltage-dependent anion channel 1 (VDAC1)-hexokinase-II (HK-II) complex is an emerging target for novel anticancer therapies based on induced mitochondria-mediated apoptosis. The low cell membrane permeability of the anticancer 12-mer peptide N-Ter (RDVFTKGYGFGL) derived from the N-terminal fragment of the VDAC1 protein impedes the intracellular targeting. Here, novel multiblock VDAC1-derived cationic amphiphilic peptides (referred to as Pal-N-Ter-TAT, pFL-N-Ter-TAT, and Pal-pFL-N-Ter-TAT) are designed with a self-assembly propensity and cell-penetrating properties. The created multiblock amphiphilic peptides of partial α-helical conformations form nanoparticles of ellipsoid-like shapes and are characterized by enhanced cellular uptake. The amphiphilic peptides can target mitochondria and dissociate the VDAC1-HK-II complex at the outer mitochondrial membrane, which result in mitochondria-mediated apoptosis. The latter is associated with decrease of the mitochondrial membrane potential, cytochrome c release, and changes of the expression levels of the apoptotic proteins in A375 melanoma cells. Importantly, the mitochondrial VDAC1-derived amphiphilic peptides have a comparable IC50 value for melanoma cells to a small-molecule drug, sorafenib, which has been previously used in clinical trials for melanoma. These results demonstrate the potential of the designed peptide constructs for efficient melanoma inhibition.
Highlights
Images showed that Pal-N-terminal of VDAC1 (N-Ter)-TAT formed ellipsoid-like assemblies with an average length of about 6 nm (Figure 2a). pFL-N-Ter-TAT formed ellipsoid-like assemblies with an average length of about 8 nm (Figure 2b), whereas Pal-pFL-N-Ter-TAT formed ellipsoid-like assemblies with an average length of about 12 nm (Figure 2c)
The results indicated that Pal-pFL-N-Ter-TAT displays strongest anticancer activity in the three cancer cell lines and has the strongest toxicity to melanoma A375 cells
Induction of apoptosis was achieved through protein–protein interaction inhibition using rationally designed amphiphilic peptide structures
Summary
VDAC1, located at the outer mitochondrial membrane (OMM), is a multi-functional barrel protein.[17,22] It regulates mitochondrial energy metabolism by transporting various ions, active substances, and metabolites into and out of the mitochondria.[23]. VDAC1 plays a key role in mitochondria-mediated apoptosis pathway via interactions with a variety of proteins with different functions (Figure 1).[23-24]. VDAC1 protein-protein interaction inhibition offers emergent opportunities for development of more efficient anti-cancer therapies
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