Anticancer peptides mechanisms, simple and complex.

Peptide therapy has started since 1920s with the advent of insulin application, and now it has emerged as a new approach in treatment of diseases including cancer. Using anti-cancer peptides (ACPs) is a promising way of cancer therapy as ACPs are continuing to be approved and arrived at major pharmaceutical markets. Traditional cancer treatments face different problems like intensive adverse effects to patient's body, cell resistance to conventional chemical drugs and in some worse cases the occurrence of cell multidrug resistance (MDR) of cancerous tissues against chemotherapy. On the other hand, there are some benefits conceived for peptides usage in treatment of diseases specifically cancer, as these compounds present favorable characteristics such as smaller size, high activity, low immunogenicity, good biocompatibility in vivo, convenient and rapid way of synthesis, amenable to sequence modification and revision and there is no limitation for the type of cargo they carry. It is possible to achieve an optimum molecular and functional structure of peptides based on previous experience and bank of peptide motif data which may result in novel peptide design. Bioactive peptides are able to form pores in cell membrane and induce necrosis or apoptosis of abnormal cells. Moreover, recent researches have focused on the tumor recognizing peptide motifs with the ability to permeate to cancerous cells with the aim of cancer treatment at earlier stages. In this strategy the most important factors for addressing cancer are choosing peptides with easy accessibility to tumor cell without cytotoxicity effect towards normal cells. The peptides must also meet acceptable pharmacokinetic requirements. In this review, the characteristics of peptides and cancer cells are discussed. The various mechanisms of peptides' action proposed against cancer cells make the next part of discussion. It will be followed by giving information on peptides application, various methods of peptide designing along with introducing various databases. Future aspects of peptides for employing in area of cancer treatment come as conclusion at the end.

The Synthesis of Conjugated Peptides Containing Triazole and Quinolone-3-Carboxamide Moieties Designed as Anticancer Agents.

Background: Cancer is a major health concern in human populations worldwide, and due to its causes being multi-factorial, it is not easily curable. Many attempts have been made to tackle this disease in hopes of finding effective anticancer agents which are not harmful to healthy tissues. Peptides with several medicinal activities have been shown to be good candidates as anticancer agents to replace common classic anticancer drugs. Peptides in conjugation with either biologically active heterocyclic compounds or anticancer drugs may result in new molecules compiling the biological benefits of both individual compounds within a unit structure. Objective: In this study some triazole-peptide conjugates as well as ciprofloxacin-peptide conjugates were designed, synthesized, and their anticancer activities evaluated. A normal skin cell line, NIH3, was also employed to determine the safety profiles of these conjugates. Materials and Methods: Two peptides; YIGSR and LSGNK were synthesized by the solid phase peptide synthesis (SPPS) method using Wang resin. Cell viability was examined by employing the MTT assay. To determine the cytotoxicity of the triazole and ciprofloxacin conjugates, two human cancer cell lines were employed; HepG2 (human liver cancer cell line) and LNCaP (human prostatic carcinoma cell line). A human skin fibroblast cell line was also included for comparison. Results: MTT results showed that all the compounds could inhibit the viability of cancerous cells in a concentration- dependent manner. Conclusions: The results showed that these peptide conjugates are toxic against the aforementioned cancerous cells and thus may raise a hope for finding new anticancer agents made by such strategy in the near future.

Cancer Treatment by Caryophyllaceae-Type Cyclopeptides.

Cancer is one of the leading diseases, which, in the most cases, ends with death and, thus, continues to be a major concern in human beings worldwide. The conventional anticancer agents used in the clinic often face resistance among many cancer diseases. Moreover, heavy financial costs preclude patients from continuing treatment. Bioactive peptides, active in several diverse areas against man's health problems, such as infection, pain, hypertension, and so on, show the potential to be effective in cancer treatment and may offer promise as better candidates for combating cancer. Cyclopeptides, of natural or synthetic origin, have several advantages over other drug molecules with low toxicity and low immunogenicity, and they are easily amenable to several changes in their sequences. Given their many demanded homologues, they have created new hope of discovering better compounds with desired properties in the field of challenging cancer diseases. Caryophyllaceae-type cyclopeptides show several biological activities, including cancer cytotoxicity. These cyclopeptides have been discovered in several plant families but mainly are from the Caryophyllaceae family. In this review, a summary of biological activities found for these cyclopeptides is given; the focus is on the anticancer findings of these peptides. Among these cyclopeptides, information about Dianthins (including Longicalycinin A), isolated from different species of Caryophyllaceae, as well as their synthetic analogues is detailed. Finally, by comparing their structures and cytotoxic activities, finding the common figures of these kinds of cyclopeptides as well as their possible future place in the clinic for cancer treatment is put forward.

Design and Synthesis of Novel Triazole-based Peptide Analogues as Anticancer Agents.

Cancer disease is a great concern in the worldwide public health and current treatments do not give satisfactory results, so, developing novel therapeutic agents to combat cancer is highly demanded. Nowadays, anticancer peptides (ACPs) are becoming promising anticancer drug candidates. This is due to several advantages inherited in peptide molecules, such as being usually with small size, high activity, low immunogenicity, good biocompatibility, diversity of sequence, and more modification sites for functionalization. To get benefit of these merits, in this work, we synthesized a new series of triazole- based analogues with peptide scaffold by employing click chemistry and evaluated their anticancer activities against breast, colon cancer cell lines as well as fibroblast cells using MTT assay. Our results suggest that peptide scaffolds containing 1H-1, 2, 3-triazole ring group are toxic against colon and breast cancer cells viability, and this effect was more pronounced on MDA-MB-231 cells compared with MCF-7 breast cells. As a conclusion, these designed peptide analogues may be good and safe candidates as future anticancer agents.

Design, Synthesis and Biological Evaluation of Ciprofloxacin- Peptide Conjugates as Anticancer Agents.

Cancer has emerged as a leading cause of death throughout the world. Peptides are a novel class of anticancer agents that can specifically target cancer cells with low toxicity to normal tissues and thus, offer new opportunities for future cancer treatment. On the other hand, Ciprofloxacin, an antibiotic, also known to its anticancer property for enabling cell cycle arrest and creating double strand breaks in nucleic acid can trigger apoptosis of cancer cells. Thus, joining anticancer peptides with Ciprofloxacin may be good idea to get benefit of the both compounds' properties and therefore gives better anticancer agents. The aim of this study was to synthesize Ciprofloxacin- cytotoxic peptide conjugates and to investigate the anticancer activity of the resultant compounds. The conjugates were prepared by solid phase peptide synthesis technique using Fmoc strategy. Anticancer activity of these compounds was examined on three cancer cell lines, HT-29, MCF-7, MDA-MB-231 as well as skin fibroblast cells as a control, employing MTT test. Our results showed that the cytotoxic activity of the synthesized compounds against cancer cells was raised considerably without producing a high toxicity on normal cells. Moreover, Ciprofloxacin-peptide conjugates showed selectivity against different kinds of breast cancer cells, especially on those with triple negative receptors. Therefore, it can be suggested that the strategy of making Ciprofloxacin- peptide conjugates as cytotoxic agents with safety profiles on the normal cells, rise promise to find better chemotherapeutic candidates to combat cancer.

Design, Synthesis and Biological Evaluation of Novel Peptide-Like Analogues as Selective COX-2 Inhibitors.

A new series of peptide-like derivatives containing different aromatic amino acids and possessing pharmacophores of COX-2 inhibitors as SO2Me or N3 attached to the para position of an end phenyl ring was synthesized for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. The synthetic reactions were based on the solid phase peptide synthesis method using Wang resin. One of the analogues, i.e., compound 2d, as the representative of these series was recognized as the most effective and the highest selective COX-2 inhibitor with IC50 value of 0.08 µM and COX-2 selectivity index of 351.2, among the other synthesized compounds. Molecular docking study was operated to determine possible binding models of compound 2d to COX-2 enzyme. The study showed that the p-azido-phenyl fragment of 2d occupied inside the secondary COX-2 binding site (Arg513, and His90). The structure-activity relationships acquired disclosed that compound 2d with 4-(azido phenyl) group as pharmacophore and histidine as amino acid gives the essential geometry to provide inhibition of the COX-2 enzyme with high selectivity. Compound 2d can be a good candidate for the development of new hits of COX-2 inhibitors.

L-Asparaginase Activity in Cell Lysates and Culture Media of Halophilic Bacterial Isolates.

The objective of this study was to isolate halophilic bacteria with the ability to produce intracellular or extracellular L-asparaginase. A total number of 120 halophilic bacteria were isolated from 17 different saline habitats of Iran including salt lakes, wetlands, brine springs and deserts. Among these, 68 were able to grow in the presence of 1.5 M NaCl and 52 demonstrated the ability to grow in the selection medium containing 3.5 M NaCl. None of the isolates appeared to produce appreciable amounts of extracellular L-asparaginase. Among the isolates that produced intracellular L-asparaginase, 5 moderate and 1 extreme halophiles were selected for further study based on their observed activity level. The moderately halophilic isolates were shown to belong to the genus Halomonas while the extreme halophile was identified as a member of the genus Aidingimonas.

Search for Proteins in the Liquid Extract of Edible Mushroom, Agaricusbisporus, and Studying their Antibacterial Effects.

The edible mushrooms (basidomycetes) have high nutritional value, promote the immune system, and as a source of natural antimicrobial substances have been used to cure bacterial infections since ancient times.Various kinds of proteins with several biological activities are produced by mushrooms. In this research, in order to evaluate antibacterial activity of edible mushrooms, we isolated proteins of Agaricus bisporus and examined their effects on gr + and gr- bacteria. Protein extract of the mushroom was first discriminated by homogenation of the chopped fruiting bodies in tris buffer with pH 7.3 and then centrifuged. The Protein concentration was determined by Bradford method. Gel filtration of the proteins was performed by Sephadex G-100 using UV spectrophotometer as detector.Three fractions were collected and their purity level were defined by SDS-PAGE . In order to reach to a more purification level, isolated proteins from the G-100 column were fractionated by the DEAE ion exchange column. Antibacterial activity of total extact proteins as well as protein fractions was evaluated by the method of microdilution against gr+ and gr- bacteria. This study showed that the isolated proteins from the mushroom, Agaricus bisporus fruiting bodies were effective against Staphylococcus aureus and MRSA. The proteins of edible mushrooms like Agaricus bisporus, maybe viewed as a natural source of antibacterial agents.