Oral administration of ferulic acid or ethyl ferulate attenuates retinal damage in sodium iodate-induced retinal degeneration mice.

Epidemiological studies indicate that the daily intake of antioxidants from a traditional Asian diet reduces the risk of developing age-related macular degeneration. Many of the phytochemicals that are abundant in whole grains exhibit a wide variety of biological activity such as antioxidant, anti-inflammatory, and neuroprotective effects. Ferulic acid (FA) is a phenolic acid found in vegetables and grains that has therapeutic potential for diabetes mellitus, Alzheimer's disease, and other diseases.

A novel interleukin-13 receptor alpha 2-targeted hybrid peptide for effective glioblastoma therapy.

We previously designed and reported a novel class of drugs, namely hybrid peptides, which are chemically synthesized and composed of a targeted binding peptide and a lytic-type peptide containing cationic amino acid residues that cause cancer cell death. In the present study, we screened for peptides that bind to interleukin-13 receptor alpha 2 (IL-13Rα2) by using a T7 random peptide phage display library system and isolated several positive phage clones. The A2b11 peptide, which was one of the positive clones, was shown to bind to IL-13Rα2 protein by Biacore analysis and a binding assay using glioblastoma (GB) cell lines.

Bile Acid as an Effective Absorption Enhancer for Oral Delivery of Epidermal Growth Factor Receptor-Targeted Hybrid Peptide.

The aim of this study was to improve the oral absorption of epidermal growth factor receptor-targeted hybrid peptide using bile acid as an absorption enhancer. The oral formulation of this peptide was formed through electrostatic interactions between the cationic peptide and anionic bile acid. Comparative studies of in vitro cell permeability and in vivo antitumor effects of peptide and peptide/bile acid complex were performed in Caco-2 cells and in a xenograft mouse model of human gastric cancer.

Novel EGFR-targeted strategy with hybrid peptide against oesophageal squamous cell carcinoma.

Epidermal growth factor receptor (EGFR) is a key molecule in the pathophysiology of oesophageal squamous cell carcinoma (OSCC). However, EGFR-targeted agents such as anti-EGFR antibody or tyrosine kinase inhibitors for OSCC have not demonstrated any clinical benefits. Recently, a novel chemotherapeutic agent, EGFR(2R)-lytic hybrid peptide, a composite of EGFR-binding peptide and lytic peptide fragments, has been shown to exhibit a potent anti-tumour effect against cancers that express high EGFR levels.

Potent anti-tumor effects of EGFR-targeted hybrid peptide on mice bearing liver metastases.

In this study, we investigated the therapeutic efficacy of EGFR2R-lytic hybrid peptide for the treatment of liver metastasis from colon carcinoma. The cytotoxic activity of the hybrid peptide against luciferase-expressing human colon cancer (HCT-116-luc) cells was determined by the WST-8 assay. The experimental mouse model of liver metastases was generated by splenic injection of HCT-116-luc cells.

Enhancement of anti-tumor activity of hybrid peptide in conjugation with carboxymethyl dextran via disulfide linkers.

To improve the anti-tumor activity of EGFR2R-lytic hybrid peptide, we prepared peptide-modified dextran conjugates with the disulfide bonds between thiolated carboxymethyl dextran (CMD-Cys) and cysteine-conjugated peptide (EGFR2R-lytic-Cys). In vitro release studies showed that the peptide was released from the CMD-s-s-peptide conjugate in a concentration-dependent manner in the presence of glutathione (GSH, 2μM-2mM). The CMD-s-s-peptide conjugate exhibited a similar cytotoxic activity with free peptide alone against human pancreatic cancer BxPC-3 cells in vitro.

The membrane-lytic peptides K8L9 and melittin enter cancer cells via receptor endocytosis following subcytotoxic exposure.

We investigate the cell entry mechanism of the membrane-lytic peptides K8L9 and melittin in cancer cell lines. K8L9 and melittin interacted with the highly expressed endocytic receptors neuropilin-1, low-density lipoprotein-related protein receptor 1 (LRP1), and transferrin receptor. Silencing of these receptors by small interfering RNAs (siRNAs) attenuated the cytotoxic activity of K8L9 in four cancer cell lines.

Synergetic cytotoxic activity toward breast cancer cells enhanced by the combination of Antp-TPR hybrid peptide targeting Hsp90 and Hsp70-targeted peptide.

Background: Heat shock protein (Hsp) 90 and Hsp70 are indispensable for cell survival under conditions of stress. They bind to client proteins to assist in protein stabilization, translocation of polypeptides across the cell membrane, and recovery of proteins from aggregates in the cell. Therefore, these proteins have recently emerged as important targets in the treatment of cancer.

Targeting interleukin-4 receptor alpha by hybrid Peptide for novel biliary tract cancer therapy.

It is known that the interleukin-4 receptor α (IL-4R α ) is highly expressed on the surface of various human solid tumors. We previously designed novel IL-4R α -lytic hybrid peptide composed of binding peptide to IL-4R α and cell-lytic peptide and reported that the designed IL-4R α -lytic hybrid peptide exhibited cytotoxic and antitumor activity both in vitro and in vivo against the human pancreatic cancer cells expressing IL-4R α . Here, we evaluated the antitumor activity of the IL-4R α -lytic hybrid peptide as a novel molecular targeted therapy for human biliary tract cancer (BTC).

Local drug delivery to a human pancreatic tumor via a newly designed multiple injectable needle.

Endoscopic ultrasound-guided fine needle injection (EUS-FNI) has been proposed as a novel technique for local delivery of antitumor agents to refractory tumors, including pancreatic cancer. However, the present outcome of this strategy remains insufficient, and further improvements as well as novel agents and injection devices are required. The aim of the study was to determine the feasibility of a newly designed 'multiple injectable needle' (MIN) for EUS-FNI and the resulting improvements in the drug distribution to the tumor in comparison with straight-type needles.

Combination of hybrid peptide with biodegradable gelatin hydrogel for controlled release and enhancement of anti-tumor activity in vivo.

We previously reported that the EGFR2R-lytic hybrid peptide has cytotoxic and anti-tumor activities both in vitro and in vivo. In this study, to improve the peptide pharmacokinetics and its anti-tumor activity after intravenous injection, we prepared biodegradable gelatin hydrogel nanoparticles as the delivery system of peptide. The complex is formed through the electrostatic interaction between the cationic peptide and anionic gelatin.

Entry of a cationic lytic-type peptide into the cytoplasm via endocytosis-dependent and -independent pathways in human glioma U251 cells.

Cationic lytic-type peptides have been studied for clinical application in various infections and cancers. This study aimed to determine the functions of our specially designed lytic peptide. To investigate the functional mechanism at the cell membrane level, we used giant unilayer vesicles (GUVs) mimicking cell membranes.

Localization of the anti-cancer peptide EGFR-lytic hybrid peptide in human pancreatic cancer BxPC-3 cells by immunocytochemistry.

Cationic lytic-type peptides have been studied for clinical application in various infections and cancers, but their functional cellular mechanisms remain unclear. We generated anti-cancer epithelial growth factor receptor (EGFR)-lytic hybrid peptide, a 32-amino-acid peptide composed of an EGFR-binding sequence and lytic sequence. In this study, we investigated the distribution of EGFR-lytic hybrid peptide in BxPC-3 human pancreatic cancer cells by an immunocytochemical (ICC) method.

Interleukin-4 receptor α-based hybrid peptide effectively induces antitumor activity in head and neck squamous cell carcinoma.

Interleukin-4 receptor α (IL-4Rα) is highly expressed on the surface of various human solid tumors including head and neck squamous cell carcinoma (HNSCC). We designed a novel IL-4Rα-lytic hybrid peptide composed of a binding peptide to IL-4Rα and a cell-lytic peptide. In the present study, we evaluated the antitumor activity of the IL-4Rα-lytic hybrid peptide as a novel molecular-targeted therapy in HNSCC.

HER2-targeted hybrid peptide that blocks HER2 tyrosine kinase disintegrates cancer cell membrane and inhibits tumor growth in vivo.

HER2 is a transmembrane oncoprotein encoded by the HER2/neu gene and is overexpressed in approximately 20% to 30% of breast cancers. We have recently designed a novel class of drug, the hybrid peptide, which is chemically synthesized and is composed of a target-binding peptide and a lytic peptide containing cationic-rich amino acid components that disintegrate the cell membrane, leading to cancer cell death via membrane lysis. In this study, we designed a HER2-binding peptide linked to this novel lytic peptide, which we termed the HER2-lytic hybrid peptide and assessed the cytotoxic activity of this hybrid peptide in vitro and in vivo.

Immunogenicity and toxicity of transferrin receptor-targeted hybrid peptide as a potent anticancer agent.

Purpose: Transferrin receptor (TfR) is a cell membrane-associated glycoprotein involved in the cellular uptake of iron and the regulation of cell growth. Recent studies have shown elevated expression levels of TfR on cancer cells compared with normal cells. We previously designed a TfR-lytic hybrid peptide, which combines the TfR-binding peptide and a lytic peptide, and reported that it bound specifically to TfR and selectively killed cancer cells.

Molecular mechanism of cytotoxicity induced by Hsp90-targeted Antp-TPR hybrid peptide in glioblastoma cells.

Background: Heat-shock protein 90 (Hsp90) is vital to cell survival under conditions of stress, and binds client proteins to assist in protein stabilization, translocation of polypeptides across cell membranes, and recovery of proteins from aggregates. Therefore, Hsp90 has emerged as an important target for the treatment of cancer. We previously reported that novel Antp-TPR hybrid peptide, which can inhibit the interaction of Hsp90 with the TPR2A domain of Hop, induces selective cytotoxic activity to discriminate between normal and cancer cells both in vitro and in vivo.

Cytotoxic activity to acute myeloid leukemia cells by Antp-TPR hybrid peptide targeting Hsp90.

We previously reported that Antp-TPR hybrid peptide inhibited the interaction of Hsp90 with TPR2A and had selective cytotoxic activity discriminating between normal and cancer cells to induce cancer cell death. In this study, we investigated the cytotoxic activity of Antp-TPR peptide toward acute myeloid leukemia (AML) cells. It was demonstrated that Antp-TPR peptide induced AML cell death in cell lines such as U937, K562, THP-1, and HL-60 via activation of caspases 3 and 7, and disruption of mitochondrial membrane potential.

Targeting interleukin-4 receptor α with hybrid peptide for effective cancer therapy.

Interleukin-4 receptor α (IL-4Rα) chain is highly expressed on the surface of various human solid tumors. We designed a novel hybrid peptide termed IL-4Rα-lytic peptide that targets the IL-4Rα chain. The IL-4Rα-lytic peptide contains a target moiety to bind to IL-4Rα and a cellular toxic lytic peptide that selectively kills cancer cells.

Semaphorin 3A lytic hybrid peptide binding to neuropilin-1 as a novel anti-cancer agent in pancreatic cancer.

We previously reported that novel targeted "hybrid peptide" in which epidermal growth factor receptor (EGFR) binding peptide was conjugated with lytic-type peptide had selective cytotoxic activity to EGFR expressing cancer cells. In this study, we have generated a novel type hybrid peptide, semaphorin 3A lytic (Sema3A-lytic), which is composed of two functional amino acid domains: a sequence derived from Sema3A that binds to neuropilin-1 (NRP1) and a cytotoxic lytic peptide. We found that this hybrid peptide had cytotoxic activity against NRP1-positive pancreatic cancer cell lines such as BxPC-3 and Panc-1, whereas the peptide did not affect the viability of normal cells in vitro.

A novel transferrin receptor-targeted hybrid peptide disintegrates cancer cell membrane to induce rapid killing of cancer cells.

Background: Transferrin receptor (TfR) is a cell membrane-associated glycoprotein involved in the cellular uptake of iron and the regulation of cell growth. Recent studies have shown the elevated expression levels of TfR on cancer cells compared with normal cells. The elevated expression levels of this receptor in malignancies, which is the accessible extracellular protein, can be a fascinating target for the treatment of cancer.

A single replacement of histidine to arginine in EGFR-lytic hybrid peptide demonstrates the improved anticancer activity.

We previously reported that novel targeted "hybrid peptide" in which epidermal growth factor receptor (EGFR) binding peptide was conjugated with lytic-type peptide had selective cytotoxic activity to EGFR expressing cancer cell lines, and in vivo analysis revealed that this EGFR-lytic peptide displayed significant antitumor activity in a xenograft model of human breast cancer which was resistant to tyrosine kinase inhibitor drugs. As an attempt to improve the selective anticancer activity of EGFR-lytic peptide, we modified the EGFR-binding peptide through introducing the mutation of amino acid according to biophysical analysis by biomolecular interaction and circular dichroism (CD) spectra. When cytotoxic activity of EGFR-lytic or EGFR(2R)-lytic hybrid peptides was investigated in various human cancer and normal cell lines, it was demonstrated that EGFR(2R)-lytic, in which second histidine (H) of EGFR-binding peptide was replaced to arginine (R) had 1.

Characterization of antilytic peptide antibody: application for the detection of lytic-based hybrid peptide in serum samples.

We previously reported that a novel targeted drug termed hybrid epidermal growth factor receptor (EGFR)-lytic peptide, made by chemical conjugation of targeted binding peptide and cell-killing, lytic-peptide components, has selective cytotoxic activity that allows it to discriminate between normal and cancer cells. In addition, in vivo analysis revealed that this hybrid peptide displays significant antitumor activity in a xenograft model of human breast and pancreatic cancer in mice. Here, we characterized antilytic peptide antibody, which was raised from rabbit serum using the antigen of lytic peptide conjugated with keyhole limpet hemocyanin.

Designed hybrid TPR peptide targeting Hsp90 as a novel anticancer agent.

Background: Despite an ever-improving understanding of the molecular biology of cancer, the treatment of most cancers has not changed dramatically in the past three decades and drugs that do not discriminate between tumor cells and normal tissues remain the mainstays of anticancer therapy. Since Hsp90 is typically involved in cell proliferation and survival, this is thought to play a key role in cancer, and Hsp90 has attracted considerable interest in recent years as a potential therapeutic target.

Methods: We focused on the interaction of Hsp90 with its cofactor protein p60/Hop, and engineered a cell-permeable peptidomimetic, termed "hybrid Antp-TPR peptide", modeled on the binding interface between the molecular chaperone Hsp90 and the TPR2A domain of Hop.