Antimicrobial peptide moricin induces ROS mediated caspase-dependent apoptosis in human triple-negative breast cancer via suppression of notch pathway (original) (raw)
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Research Square (Research Square), 2024
Introduction: Microcins are Antimicrobial peptides (AMPs) with low molecular weight, which are produced by Enterobacterales and have broad-spectrum antibacterial activity. They can selectively replace common cancer treatments in cancer cells with less side effects and higher effectiveness. Given the aforementioned context, the present study endeavors to examine the antitumor activity of microcins isolated from of the Enterobacterales. Material and Methods In total, 120 Enterobacterales isolates were examined after identi cation. Subsequently, the bacteria were subjected to an agar diffusion test to assess their antibacterial e cacy. Positive isolates were further examined for the presence of Mccj25 using PCR. The cytotoxic effects of isolates harboring the microcin gene were explored using quantitative real-time PCR (RT-qPCR) and the MTT test on breast cancer cells. Additionally, the expression levels of BCL2 and STAT3 genes were evaluated, and apoptosis was quanti ed using ow cytometry. The repair rate of normal cells was determined using a scratch assay. Results The ndings obtained from the phenotypic and biochemical assays have duly veri ed and established the categorization of the Enterobacterales. After conducting the agar diffusion test, a total of 25 isolates of Escherichia coli and Klebsiella pneumoniae displaying inhibition zones were chosen as suitable specimens possessing AMPs. Urinary E. coli was identi ed as isolate 83. The analysis conducted on the expression of the Mccj25 gene within the aforementioned isolates indicated that isolate 83 exhibited signi cant expression of the Mccj25 gene. Conclusion The extract obtained from this isolate on the breast cancer cell line exhibited the most signi cant degree of toxicity after precisely 48 h. Furthermore, the treatment of breast cancer cells with isolate 83 showed that the rate of apoptosis was about 86%, and the expression of BCL2 and STAT3 genes decreased. Moreover, it potentiated the reparative ability of normal broblast cells. They resulted in growth suppression of breast cancer cells and elicited an escalated rate of cellular demise via the apoptosis pathway. the use of medicinal drugs with fewer side effects has received considerable attention in recent years. Antimicrobial peptides (AMPs) are a class of anti-cancer peptides. AMPs have a wide range of antibacterial, antiviral, antifungal, and anticancer properties, and are part of the intrinsic resistance to microorganisms [3]. AMPs, members of the class of anticancer peptides, are among these substances. AMPs have a wide range of antibacterial, antiviral, antifungal, and anticancer properties and are part of the intrinsic resistance reaction to microorganisms [3]. Numerous studies have reported the use of AMPs against cancer cells, including breast, lung, lymphoma, leukemia, and myeloma cells [4].. E. coli bacteriocins are divided into colicins (25-80 kDa) and microcins (1-10 kDa) based on their molecular weight [5, 6]. Microcins possess an advantage over colicins as they do not pose lethality to the strains that produce them. [7]. There are two types of microcins. Class I microcins have a molecular mass of less than 5 kDa and are highly post-translationally modi ed, which include microcin B17 (MccB17), MccJ25, MccC7/C51, and MccD93. In contrast, class II peptide microcins are larger (5-10 kDa) and are further divided into two subclasses, IIa and IIb. Accordingly, subclass IIa does not require post-translational modi cations, but can contain disul de bonds, including the plasmid-mediated microcins MccL, MccV, and MccS, and siderophore bacteriocins, known as class IIb microcins, including MccE492, MccM, MccI47, and MccH47 [8]. The signi cance of utilizing microcins as possible alternatives to antibiotics is attributable to the absence of bacterial resistance to these AMPs [9]. In addition to their antimicrobial properties, microcins have antitumor functions and can act through various mechanisms such as apoptosis, necrosis, and pore creation in the target cell membrane, thereby inhibiting angiogenesis and activating the immune system against cancer cells [10]. Recently, researchers have exhibited signi cant interest in the potential use of microcins for cancer treatment because of their selective nature, which results in higher e cacy and minimal adverse effects. [9, 10]. MccJ25 is a 21-amino acid peptide produced by some Enterobacterales, especially E. coli, and has a stable structure to avoid degradation by proteases in the digestive tract [8]. MccJ25 has antimicrobial activity and as a membrane-active peptide, it causes the death of eukaryotic cells by destroying cytochrome c [11, 12]. Against this background, in the current study, we examined how breast cancer cells respond to isolated MccJ25 from E. coli. 2. Materials and Methods 2.1. isolate collection, culture, and identi cation E. coli were isolated and con rmed from urine samples obtained from private laboratories. In brief, 120 Enterobacterales isolates were cultured on blood agar and eosin methylene blue at 35°C for 18-24 h. Next, E. coli isolates were identi ed and isolated using different phenotypic characteristics and biochemical tests, including Voges Proskauer (VP)
CancerGram: An Effective Classifier for Differentiating Anticancer from Antimicrobial Peptides
Pharmaceutics
Antimicrobial peptides (AMPs) constitute a diverse group of bioactive molecules that provide multicellular organisms with protection against microorganisms, and microorganisms with weaponry for competition. Some AMPs can target cancer cells; thus, they are called anticancer peptides (ACPs). Due to their small size, positive charge, hydrophobicity and amphipathicity, AMPs and ACPs interact with negatively charged components of biological membranes. AMPs preferentially permeabilize microbial membranes, but ACPs additionally target mitochondrial and plasma membranes of cancer cells. The preference towards mitochondrial membranes is explained by their membrane potential, membrane composition resulting from α-proteobacterial origin and the fact that mitochondrial targeting signals could have evolved from AMPs. Taking into account the therapeutic potential of ACPs and millions of deaths due to cancer annually, it is of vital importance to find new cationic peptides that selectively destro...
Marine drugs, 2018
Osteosarcoma (OS) is a common malignant bone cancer. The relatively high density of a person's bone structure means low permeability for drugs, and so finding drugs that can be more effective is important and should not be delayed. MSPs are marine antimicrobial peptides (AMP) and natural compounds extracted from Nile tilapia (). MSP-4 is a part of the AMPs series, with the advantage of having a molecular weight of about 2.7-kDa and anticancer effects, although the responsible anticancer mechanism is not very clear. The goal of this study is to determine the workings of the mechanism associated with apoptosis resulting from MSP-4 in osteosarcoma MG63 cells. The study showed that MSP-4 significantly induced apoptosis in MG63 cells, with Western blot indicating that MSP-4 induced this apoptosis through an intrinsic pathway and an extrinsic pathway. Thus, a pretreatment system with a particular inhibitor of Z-IETD-FMK (caspase-8 inhibitor) and Z-LEHD-FMK (caspase-9 inhibitor) signif...
ApInAPDB: a database of apoptosis-inducing anticancer peptides
Scientific Reports, 2022
ApInAPDB (Apoptosis-Inducing Anticancer Peptides Database) consists of 818 apoptosis-inducing anticancer peptides which are manually collected from research articles. The database provides scholars with peptide related information such as function, binding target and affinity, IC50 and etc. In addition, GRAVY (grand average of hydropathy), net charge at pH 7, hydrophobicity and other physicochemical properties are calculated and presented. Another category of information are structural information includes 3D modeling, secondary structure prediction and descriptors for QSAR (quantitative structure-activity relationship) modeling. In order to facilitate the browsing process, three types of user-friendly searching tools are provided: top categories browser, simple search and advanced search. Overall ApInAPDB as the first database presenting apoptosis-inducing anticancer peptides can be useful in the field of peptide design and especially cancer therapy. Researchers can freely access the database at http:// bioinf. modar es. ac. ir/ softw are/ ApInA PDB/. Cancer, one of the most serious public health problems on a global scale 1 , has significant treatment challenges including multidrug resistance and a lack of tumor-specific therapies with minimal side effects 2. Peptide-based therapy is a new strategy in cancer treatment 3. Anticancer peptides (ACPs) possess some advantages like short sequence (less than 50 amino acids) 4 , easy synthesis and modification, cost-effectiveness, biocompatibility, specific targeting, and low intrinsic toxicity 4-6 that makes them promising as anticancer therapeutics 2. ACPs have been categorized based on structure and activity. The structural categories include α-helical, β-sheet, random coil, and cyclic peptides. Since α-helical and β-sheet conformations have their advantages and disadvantages in anticancer peptide performance 7 , secondary structure prediction plays an important role in anticancer peptide design. Although the anticancer mechanism of ACPs is not thoroughly understood 4 , they are generally divided into four groups based on their activities I) cell membrane disruption; II) apoptosis-inducing; III) anti-angiogenesis peptides, and IV) immune regulation 7. Among these bioactivities, the apoptosis pathway is considered the most successful treatment in non-surgical cancer therapies because it induces minimal inflammation and damage into the treated tissues 8,9 , highlighting the potential of apoptosis-inducing peptides 10. The BCL-2 family is the main proteins that regulate the intrinsic apoptosis pathway while TNFR, FAS (CD95), and DR3/WSL are involved in extrinsic apoptosis 11. Peptide-based cancer therapy can target both apoptosis pathways 12,13. However, the origin of apoptosis-inducing anticancer peptides is not confined to analogues of the BCL-2 family. Numerous peptides such as human second mitochondria-derived activator of caspase (SMAC) peptides, venom-derived peptides and also antimicrobial peptides have been discovered with apoptosis induction effects on cancerous cells 14-16. Despite significant interest in peptide-based cancer therapy, there are limited anticancer peptide databases like CancerPPD 4 (anticancer peptides and proteins database), and to our knowledge, no database specifically includes apoptosis-inducing peptides. Here we have established ApInAPDB (Apoptosis-Inducing Anticancer Peptides Database) as a comprehensive database that is dedicated to apoptosis-inducing peptides and their analogues regardless of their degree of effectiveness. The information available in the database, taken from the literature, includes binding target, function, and their effectiveness reported as IC50, binding affinity or spot array. This database also presents additional information such as amino acid composition, hydrophobicity, charge and also prediction of secondary structure using different algorithms. All properties calculated for each
Asian Journal of Pharmaceutical and Clinical Research, 2017
Objective: Apoptosis is an important cellular process that causes the death of damaged cells. Its malfunction can lead to cancer development and poor response to conventional chemotherapy. Cellular proteins from the B-cell lymphoma 2 (BCL-2) family are crucial for apoptosis. Breast cancer is the most commonly diagnosed cancer among women worldwide. The aim of this work was to design using in silico docking antimycin A3, antimycin analogs, and its aromatic segments as inhibitors of Bcl-xl and Mcl-1.Methods: In silico molecular docking approach has been utilized to find the potential anticancer from antimycin A3 analogs and its aromatic segments. Antimycin A3 analogs and its aromatic segments were modeled into three-dimensional (3D) structures using Marvin Sketch. Based on Protein Data Bank, 3ZLN for Bcl-xl, and 5IEZ for Mcl-1 were selected as apoptosis protein marker from BCL-2 family. Geometry optimization and minimization of energy 3D structure of antimycin A3 analogs and segment...
Jurnal Natural
Breast cancer is one type of cancer with the highest incidence suffered by women. Doxorubicin is a chemotherapy that is often used as the main chemotherapy and combination chemotherapy, but the use of doxorubicin is often complained of side effects that cause auto resistance. Combination with chemopreventives from natural ingredients has become an option to increase therapeutic response and to minimize side effects and resistance to chemotherapy use. This study aims to screen several active compounds of the phenolic-flavonoid group contained in Moringa leaves (Moringa oleifera, Lam) against NFκβ receptors in silico using a molecular docking technique. The material in the form of “Canonical smiles” data is quercetin, quercetin-3 glycoside (Q3G), rutin, kaempferol, myricetin, isorhamnetin, deoxyelephantopin and doxorubicin which were downloaded from www.pubchem.org and converted to 3D structures using MOE software. While the 3D structure of the receptor (1VKX) was downloaded from www....
PeerJ
A previous study has shown that synthetic antimicrobial peptides (AMPs) derived from Anabas testudineus (ATMP1) could in-vitro inhibit the progression of breast cancer cell lines. In this study, we are interested in studying altered versions of previous synthetic AMPs to gain some insight into the peptides functions. The AMPs were altered and subjected to bioinformatics prediction using four databases (ADP3, CAMP-R3, AMPfun, and ANTICP) to select the highest anticancer activity. The bioinformatics in silico analysis led to the selection of two AMPs, which are ATMP5 (THPPTTTTTTTTTTTYTAAPATTT) and ATMP6 (THPPTTTTTTTTTTTTTAAPARTT). The in silico analysis predicted that ATMP5 and ATMP6 have anticancer activity and lead to cell death. The ATMP5 and ATMP6 were submitted to deep learning databases (ToxIBTL and ToxinPred2) to predict the toxicity of the peptides and to (AllerTOP & AllergenFP) check the allergenicity. The results of databases indicated that AMPs are non-toxic to normal human...
Anticancer Activity of Bacterial Proteins and Peptides
Pharmaceutics, 2018
Despite much progress in the diagnosis and treatment of cancer, tumour diseases constitute one of the main reasons of deaths worldwide. The side effects of chemotherapy and drug resistance of some cancer types belong to the significant current therapeutic problems. Hence, searching for new anticancer substances and medicines are very important. Among them, bacterial proteins and peptides are a promising group of bioactive compounds and potential anticancer drugs. Some of them, including anticancer antibiotics (actinomycin D, bleomycin, doxorubicin, mitomycin C) and diphtheria toxin, are already used in the cancer treatment, while other substances are in clinical trials (e.g., p28, arginine deiminase ADI) or tested in in vitro research. This review shows the current literature data regarding the anticancer activity of proteins and peptides originated from bacteria: antibiotics, bacteriocins, enzymes, nonribosomal peptides (NRPs), toxins and others such as azurin, p28, Entap and Pep27anal2. The special attention was paid to the still poorly understood active substances obtained from the marine sediment bacteria. In total, 37 chemical compounds or groups of compounds with antitumor properties have been described in the present article.
An inverse docking approach for identifying new potential anti-cancer targets
Journal of Molecular Graphics and Modelling, 2011
Inverse docking is a relatively new technique that has been used to identify potential receptor targets of small molecules. Our docking software package MDock is well suited for such an application as it is both computationally efficient, yet simultaneously shows adequate results in binding affinity predictions and enrichment tests. As a validation study, we present the first stage results of an inverse-docking study which seeks to identify potential direct targets of PRIMA-1. PRIMA-1 is well known for its ability to restore mutant p53's tumor suppressor function, leading to apoptosis in several types of cancer cells. For this reason, we believe that potential direct targets of PRIMA-1 identified in silico should be experimentally screened for their ability to inhibit cancer cell growth. The highest-ranked human protein of our PRIMA-1 docking results is oxidosqualene cyclase (OSC), which is part of the cholesterol synthetic pathway. The results of two followup experiments which treat OSC as a possible anti-cancer target are promising. We show that both PRIMA-1 and Ro 48-8071, a known potent OSC inhibitor, significantly reduce the viability of BT-474 breast cancer cells relative to normal mammary cells. In addition, like PRIMA-1, we find that Ro 48-8071 results in increased binding of mutant p53 to DNA in BT-474 cells (which highly express p53). For the first time, Ro 48-8071 is shown as a potent agent in killing human breast cancer cells. The potential of OSC as a new target for developing anticancer therapies is worth further investigation.
Genomics & Informatics
Moringa oleifera is nowadays raising as the most preferred medicinal plant, as every part of the moringa plant has potential bioactive compounds which can be used as herbal medicines. Some bioactive compounds of M. oleifera possess potential anti-cancer properties which interact with the apoptosis protein p53 in cancer cell lines of oral squamous cell carcinoma. This research work focuses on the interaction among the selected bioactive compounds derived from M. oleifera with targeted apoptosis protein p53 from the apoptosis pathway to check whether the bioactive compound will induce apoptosis after the mutation in p53. To check the toxicity and drug-likeness of the selected bioactive compound derived from M. oleifera based on Lipinski’s Rule of Five. Detailed analysis of the 3D structure of apoptosis protein p53. To analyze protein’s active site by CASTp 3.0 server. Molecular docking and binding affinity were analyzed between protein p53 with selected bioactive compounds in order to...