Self-assembly of mitochondria-specific peptide amphiphiles amplifying lung cancer cell death through targeting the VDAC1-hexokinase-II complex

• Published in: Journal of materials chemistry. B, Materials for biology and medicine Materials for biology and medicine, 2019-07, Vol.7 (3), p.476-4716
• Main Authors: Liu, Dan, Angelova, Angelina, Liu, Jianwen, Garamus, Vasil M, Angelov, Borislav, Zhang, Xinlei, Li, Yawen, Feger, Guillaume, Li, Na, Zou, Aihua
• Format: Article
• Language: English
• Subjects: Amino acid sequence; Amplification; Apoptosis; Assemblies; Biocompatibility; Biological activity; Cancer; Cell death; Chemical Sciences; Circular dichroism; Confocal microscopy; Cryoforming; Cytotoxicity; Dichroism; Hexokinase; Ion channels; Life Sciences; Lipids; Lung cancer; Medication; Medicinal Chemistry; Microscopy; Mitochondria; N-Terminus; Non-small cell lung carcinoma; Peptides; Pharmaceutical sciences; Self-assembly; Small angle X ray scattering; Spectroscopy; Synthetic peptides; Toxicity; X-ray scattering
• ISSN: 2050-750X; 2050-7518
• DOI: 10.1039/c9tb00629j

Mitochondria-targeting peptides represent an emergent tool for cancer inhibition. Here supramolecular assemblies of novel amphiphilic cell-penetrating peptides for targeting cancer cell mitochondria are reported. The employed strategy aims at amplifying the apoptotic stimuli by weakening the mitochondrial VDAC1 (voltage-dependent anion channel-1)-hexokinase-II (HK-II) interaction. Peptide engineering is performed with the N-terminus of the HK-II protein, which binds to VDAC1. First, a designed positively charged segment (pKV) is anchored to the specific 15 amino acid sequence (MIASHLLAYFFTELN) to yield a cell-penetrating peptide (pHK-pKV). Second, a lipid chain (Pal) is conjugated to the N-terminus of pHK-pKV in order to enhance the intracellular delivery of the HK-II scaffold. The self-assembly properties of these two synthetic peptides are investigated by synchrotron small-angle X-ray scattering (BioSAXS) and cryogenic transmission electron (cryo-TEM) imaging, which evidence the formation of nanoassemblies of ellipsoid-like shapes. Circular dichroism (CD) spectroscopy demonstrates the induction of partial α-helical structures in the amphiphilic peptides. Confocal microscopy reveals the specific mitochondrial location of Pal-pHK-pKV assemblies in human non-small cell lung cancer (NSCLC) A549 cells. The cytotoxicity and apoptotic studies indicate the enhanced bioactivity of Pal-pHK-pKV self-assembled reservoirs, which cause massive A549 cell death with regard to pHK-pKV. Of significance, Pal-pHK-pKV treatment of non-cancerous NCM460 cells resulted in substantially lower cytotoxicity. The results demonstrate the potential of self-assembled lipo-peptide (HK-II-derived) conjugates as a promising strategy in cancer therapy. Novel cell-penetrating peptides self-assemble into ellipsoid-shape nanostructures which amplified the apoptotic stimuli by weakening the VDAC1-HK-II interaction.