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Down-regulating Proteolysis to Enhance Anticancer Activity of Peptide Nanofibers.

ABSTRACT: Nanofibers of short peptides are emerging as a promising type of agents for inhibiting cancer cells. But the proteolysis of peptides decreases the anticancer efficacy of the peptide nanofibers. Here we show that decreasing the activity of proteasomes enhance the activity of peptide nanofibers for inhibiting cancer cells. Based on the structure of galactin-3, we designed a heptapeptide, which self-assembles to form nanofibers. The nanofibers of the heptapeptide exhibit moderate cytotoxicity to three representative cancer cell lines (HeLa, MCF-7, and HepG2), largely due to the proteolysis of the peptides. Using a clinically approved proteasome inhibitor, bortezomib, to treat the cancer cells significantly decreases the proteolysis of the peptides and enhances the activity of the peptide nanofibers for inhibiting the cancer cells. This work illustrates a promising approach for enhancing the anticancer efficacy of peptide nanofibers by modulating intracellular protein degradation machinery, as well as provides insights for understanding the cytotoxicity of aberrant protein or peptide aggregates in complicated cellular environment.

SUBMITTER: Li J

PROVIDER: S-EPMC6242746 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Down-regulating Proteolysis to Enhance Anticancer Activity of Peptide Nanofibers.

Li Jie J Du Xuewen X Powell Devon J DJ Zhou Rong R Shi Junfeng J He Hongjian H Feng Zhaoqianqi Z Xu Bing B

Chemistry, an Asian journal 20180724 22

Nanofibers of short peptides are emerging as a promising type of agents for inhibiting cancer cells. But the proteolysis of peptides decreases the anticancer efficacy of the peptide nanofibers. Here we show that decreasing the activity of proteasomes enhance the activity of peptide nanofibers for inhibiting cancer cells. Based on the structure of galactin-3, we designed a heptapeptide, which self-assembles to form nanofibers. The nanofibers of the heptapeptide exhibit moderate cytotoxicity to th ...[more]

PMID: 29897657

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Project description:Drug resistance is a major cause of the inefficacy of conventional cancer therapies, and often accompanied by severe side effects. Thus, there is an urgent need to develop novel drugs with low cytotoxicity, high selectivity and minimal acquired chemical resistance. Peptide-based drugs (less than 0.5 kDa) have emerged as a potential approach to address these issues due to their high specificity and potent anticancer activity. In this study, we developed a support vector machine model (SVM) to detect the potential anticancer properties of novel peptides by scanning the American University in Cairo (AUC) Red Sea metagenomics library. We identified a novel 37-mer antimicrobial peptide through SVM pipeline analysis and characterized its anticancer potential through in silico cross-examination. The peptide sequence was further modified to enhance its anticancer activity, analyzed for gene ontology, and subsequently synthesized. To evaluate the anticancer properties of the modified 37-mer peptide, we assessed its effect on the viability and morphology of SNU449, HepG2, SKOV3, and HeLa cells, using an MTT assay. Additionally, we evaluated the migration capabilities of SNU449 and SKOV3 cells using a scratch-wound healing assay. The targeted selectivity of the modified peptide was examined by evaluating its hemolytic activity on human erythrocytes. Treatment with the peptide significantly reduced cell viability and had a critical impact on the morphology of hepatocellular carcinoma (SNU449 and HepG2), and ovarian cancer (SKOV3) cells, with a marginal effect on cervical cancer cell lines (HeLa). The viability of a human fibroblast cell line (1Br-hTERT) was also significantly reduced by peptide treatment, as were the proliferation and migration abilities of SNU449 and SKOV3 cells. The annexin V assay revealed programmed cell death (apoptosis) as one of the potential cellular death pathways in SNU449 cells upon peptide treatment. Finally, the peptide exhibited antimicrobial effects on both gram-positive and gram-negative bacterial strains. The findings presented here suggest the potential of our novel peptide as a potent anticancer and antimicrobial agent.

Project description:Cancer associated drug resistance is a major cause for cancer aggravation, particularly as conventional therapies have presented limited efficiency, low specificity, resulting in long term deleterious side effects. Peptide based drugs have emerged as potential alternative cancer treatment tools due to their selectivity, ease of design and synthesis, safety profile, and low cost of manufacturing. In this study, we utilized the Red Sea metagenomics database, generated during AUC/KAUST Red Sea microbiome project, to derive a viable anticancer peptide (ACP). We generated a set of peptide hits from our library that shared similar composition to ACPs. A peptide with a homeodomain was selected, modified to improve its anticancer properties, verified to maintain high anticancer properties, and processed for further in-silico prediction of structure and function. The peptide's anticancer properties were then assessed in vitro on osteosarcoma U2OS cells, through cytotoxicity assay (MTT assay), scratch-wound healing assay, apoptosis/necrosis detection assay (Annexin/PI assay), RNA expression analysis of Caspase 3, KI67 and Survivin, and protein expression of PARP1. L929 mouse fibroblasts were also assessed for cytotoxicity treatment. In addition, the antimicrobial activity of the peptide was also examined on E coli and S. aureus, as sample representative species of the human bacterial microbiome, by examining viability, disk diffusion, morphological assessment, and hemolytic analysis. We observed a dose dependent cytotoxic response from peptide treatment of U2OS, with a higher tolerance in L929s. Wound closure was debilitated in cells exposed to the peptide, while annexin fluorescent imaging suggested peptide treatment caused apoptosis as a major mode of cell death. Caspase 3 gene expression was not altered, while KI67 and Survivin were both downregulated in peptide treated cells. Additionally, PARP-1 protein analysis showed a decrease in expression with peptide exposure. The peptide exhibited minimal antimicrobial activity on critical human microbiome species E. coli and S. aureus, with a low inhibition rate, maintenance of structural morphology and minimal hemolytic impact. These findings suggest our novel peptide displayed preliminary ACP properties against U2OS cells, through limited specificity, while triggering apoptosis as a primary mode of cell death and while having minimal impact on the microbiological species E. coli and S. aureus.

Dataset Information

Down-regulating Proteolysis to Enhance Anticancer Activity of Peptide Nanofibers.

Publications

Down-regulating Proteolysis to Enhance Anticancer Activity of Peptide Nanofibers.

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