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Anticancer peptides (ACPs) modes of action may include disruption of plasma/ mitochondrial membranes (Sinthuvanich et al., 2012), necrosis, apoptosis (van Zoggel et al., 2012; Xu et al., 2013), mechanisms of mediated immunity (Wang et al., 2009c), membrane receptors involvement (Leuschner and Hansel, 2005), inhibition of DNA synthesis (Ourth, 2011) and anti-angiogenic effects (Koskimaki et al., 2009). Different ACPs can act by more than one mechanism simultaneously (Wang et al., 2009c; Xu et al., 2013).
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Antimicrobial peptides (AMPs) are part of the innate immune defense mechanism of many organisms. Although AMPs have been essentially studied and developed as potential alternatives for fighting infectious diseases, their use as anticancer peptides (ACPs) in cancer therapy either alone or in combination with other conventional drugs has been regarde...
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Citations
... Anticancer peptides (ACPs), typically consisting of 10-50 amino acids, are bioactive molecules that induce cytotoxicity against cancer cells by disrupting and penetrating cell or organelle membranes. Their selective cytotoxicity has been observed in various cancers, positioning them as potential novel antineoplastic agents [7]. One notable difference between tumor and healthy cells lies in the membrane's electrical properties. ...
... This indicates that ACPs primarily interact with cancer cells through electrostatic interactions with anionic phospholipids in the plasma membrane. This is a key mechanism through which ACPs disrupt membrane integrity, leading to the leakage of cellular contents [7,36]. composition (DPC) [34], and k-spaced amino acid pairs (CKSAAPs) [35] were employed to differentiate ACPs from non-ACPs. ...
... This indicates that ACPs primarily interact with cancer cells through electrostatic interactions with anionic phospholipids in the plasma membrane. This is a key mechanism through which ACPs disrupt membrane integrity, leading to the leakage of cellular contents [7,36]. Additionally, cysteine (C), an amino acid with both polar and hydrophobic properties, plays a critical role in protein structure and stability and is more frequently found in ACPs. ...
Anticancer peptides (ACPs) are bioactive compounds known for their selective cytotoxicity against tumor cells via various mechanisms. Recent studies have demonstrated that in silico machine learning methods are effective in predicting peptides with anticancer activity. In this study, we collected and analyzed over a thousand experimentally verified ACPs, specifically targeting peptides derived from natural sources. We developed a precise prediction model based on their sequence and structural features, and the model’s evaluation results suggest its strong predictive ability for anticancer activity. To enhance reliability, we integrated the results of this model with those from other available methods. In total, we identified 176 potential ACPs, some of which were synthesized and further evaluated using the MTT colorimetric assay. All of these putative ACPs exhibited significant anticancer effects and selective cytotoxicity against specific tumor cells. In summary, we present a strategy for identifying and characterizing natural peptides with selective cytotoxicity against cancer cells, which could serve as novel therapeutic agents. Our prediction model can effectively screen new molecules for potential anticancer activity, and the results from in vitro experiments provide compelling evidence of the candidates’ anticancer effects and selective cytotoxicity.
... Several preclinical studies have demonstrated the wide potential of natural and synthetically modified peptides as effective anticancer agents [10][11][12][13][14][15][16]. The proposed mechanisms of peptide action include the induction of apoptosis, promotion of necrotic cell death, inhibition of DNA replication, suppression of angiogenesis, and modulation of immunity mechanism [17,18]. ...
In recent yearsjajajj, peptide-based therapeutics have attracted increasing interest as a potential approach to cancer treatment. Peptides are characterized by high specificity and low cytotoxicity, but they cannot be considered universal drugs for all types of cancer. Of the numerous anticancer-reported peptides, both natural and synthetic, only a few have reached clinical applications. However, in most cases, the mechanism behind the anticancer activity of the peptide is not fully understood. For this reason, in this work, we investigated the effect of the novel peptide ∆M4, which has documented anticancer activity, on two human skin cancer cell lines. A novel approach to studying the potential induction of apoptosis by anticancer peptides is the use of protein microarrays. The results of the apoptosis protein study demonstrated that both cell types, skin malignant melanoma (A375) and epidermoid carcinoma (A431), exhibited markers associated with apoptosis and cellular response to oxidative stress. Additionally, ∆M4 induced concentration- and time-dependent moderate ROS production, triggering a defensive response from the cells, which showed decreased activation of cytoplasmic superoxide dismutase. However, the studied cells exhibited a differential response in catalase activity, with A375 cells showing greater resistance to the peptide action, possibly mediated by the Nrf2 pathway. Nevertheless, both cell types showed moderate activity of caspases 3/7, suggesting that they may undergo partial apoptosis, although another pathway of programmed death cannot be excluded. Extended analysis of the mechanisms of action of anticancer peptides may help determine their effectiveness in overcoming chemoresistance in cancerous cells.
... Contrarily, the finding mentioned by Al-Madboly et al. that enterocin (LNS18) produced from E. thilandicus had an IC50 value of 15.643 μM against HepG2 (Al-Madboly et al. 2020) without any significant cytotoxic effects on normal fibroblast cells (BJ ATCC® CRL-2522™) (Al-Madboly et al. 2020). This can be supported by the previous study, which showed the activity due to structural properties of target cancer cells without affecting normal cells, such as hydrophobicity, the positively charged amino acid numbers, and the capacity to develop amphipathic structures (Gaspar et al. 2013). ...
In our study, the secretome of the clinical isolate Enterococcus faecalis HY7 displayed antibacterial activity against the vancomycin-resistant Enterococcus faecalis V853. These bacteriocin-like substances showed thermal stability at a wide range of temperatures up to 121 °C, while proteinase K treatment resulted in a total loss of their activity. PCR-based screening for bacteriocin biosynthetic genes revealed that Enterococcus faecalis HY7 harbored multiple enterocin-producing genes, including ent A, avc A, and as-48. The production kinetics demonstrated the highest levels of bacteriocins production at 16 h, whereas the activity was diminished after 32 h of microbial growth. Notably, the partially purified bacteriocins exhibited anti-proliferative activity on the colon cancer cells, Caco2, with an IC50 value of 172.8 μg/mL. Remarkably, the nanoencapsulation of our bacteriocins in liposome showed a fourfold increase in its anti-vancomycin-resistant Enterococcus activity, which is the first report of liposome encapsulation with anti-vancomycin resistant Enterococcus bacteriocin.
... Commonly, anticancer peptides (ACPs) are characterised by their small size containing fewer than 50 amino acids. They usually exhibit a cationic nature [54], and their antiproliferative effects are typically performed via attaching to negatively charged phosphatidylserines that are uncovered on the surfaces of cancer cells [51,52]. Indeed, a significant number of ACPs are derived from antimicrobial peptides (AMPs). ...
... As a result, both AMPs and ACPs share similar characteristics, including cationic properties, often containing basic and hydrophobic residues. This similarity underscores the potential dual functionality of these peptides in both antimicrobial and anticancer activities [54,55]. ...
... While the membrane-lytic mode of action is predominant among ACPs, some have demonstrated alternative mechanisms such as the induction of apoptosis through the disruption of mitochondrial membranes. The selective toxicity of many ACPs against cancer cells is often linked to variations in lipid content and other components within the biological membranes of normal versus cancer cells [54,55]. ...
Peptides with antimicrobial activity or protease inhibitory activity are potential candidates to supplement traditional antibiotics or cancer chemotherapies. However, the potential of many peptides are limited by drawbacks such as cytotoxicity or susceptibility to hydrolysis. Therefore, strategies to modify the structure of promising peptides may represent an effective approach for developing more promising clinical candidates. In this study, the mature peptide OSTI−1949, a Kunitz-type inhibitor from Odorrana schmackeri, and four designed analogues were successfully synthesised. In contrast to the parent peptide, the analogues showed impressive multi-functionality including antimicrobial, anticancer, and trypsin inhibitory activities. In terms of safety, there were no obvious changes observed in the haemolytic activity at the highest tested concentration, and the analogue OSTI−2461 showed an increase in activity against cancer cell lines without cytotoxicity to normal cells (HaCaT). In summary, through structural modification of a natural Kunitz-type peptide, the biological activity of analogues was improved whilst retaining low cytotoxicity. The strategy of helicity enhancement by forming an artificial α-helix and ß-sheet structure provides a promising way to develop original bioactive peptides for clinical therapeutics.
... Peptides attract increasing attention as potential pharmaceuticals due to specific biochemical and therapeutic advantages over smallmolecule drugs and proteins [8,9]. In oncology, relevant results have been achieved with anticancer peptides (ACPs) as therapeutic agents [10]. Our commitment to developing effective and nontoxic molecules to tackle TNBC has resulted in the discovery of vCPP2319, an ACP with high activity and selectivity towards TNBC cells and a low toxicity for noncancerous cells [11,12]. ...
Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by the absence of commonly targeted receptors. Unspecific chemotherapy is currently the main therapeutic option, with poor results. Another major challenge is the frequent appearance of brain metastasis (BM) associated with a significant decrease in patient overall survival. The treatment of BM is even more challenging due to the presence of the blood-brain barrier (BBB). Here, we present a dual-acting peptide (PepH3-vCPP2319) designed to tackle TNBC/BM, in which a TNBC-specific anticancer peptide (ACP) motif (vCPP2319) is joined to a BBB peptide shuttle (BBBpS) motif (PepH3). PepH3-vCPP2319 demonstrated selectivity and efficiency in eliminating TNBC both in mono-layers (IC 50 ≈5.0 µM) and in spheroids (IC 50 ≈25.0 µM), with no stringent toxicity toward noncancerous cell lines and red blood cells (RBCs). PepH3-vCPP2319 was also able to cross the BBB in vitro and penetrate the brain in vivo, and was stable in serum with a half-life above 120 min. Tumor cell-peptide interaction is fast, with quick peptide internalization via clathrin-mediated endocytosis without membrane disruption. Upon internalization, the peptide is detected in the nucleus and the cytoplasm, indicating a multi-targeted mechanism of action that ultimately induces irreversible cell damage and apoptosis. In conclusion, we have designed a dual-acting peptide capable of brain penetration and TNBC cell elimination, thus expanding the drug arsenal to fight this BC subtype and its BM.
... The intricacy and diversity of cancer pose Thirumurthy Madhavan thiru.murthyunom@gmail.com Honglae Sohn hsohn@chosun.ac.kr effective anticancer drugs is a long and expensive process [5]. ...
Cancer, being the second leading cause of death globally. So, the development of effective anticancer treatments is crucial in the field of medicine. Anticancer peptides (ACPs) have shown promising therapeutic potential in cancer treatment compared to traditional methods. However, the process of identifying ACPs through experimental means is often time-intensive and expensive. To overcome this issue, we employed a machine learning-based approach for the first time to develop an anticancer model using small molecules. Anticancer small molecules (ACSMs) are compounds that have been developed to target and inhibit cancer cells. In this study, we used 10,000 compounds to develop the machine learning models using five algorithms such as, Random Forest (RF), Light gradient boosting machine (LightGBM), K-nearest neighbors (KNN), Decision tree (DT) and Extreme Gradient Boosting (XGB). The developed models were evaluated using the test set and top three models were identified (RF, LightGBM and XGB). Furthermore, to validate the predictive performance of our models, we have performed external validation using an FDA approved anticancer compounds/drugs. Following this analysis, we found that our LightGBM model correctly predicted 9 compounds as active. However, RF and XGB exhibited some limitations by predicting 8 and 7 compounds as active out of 10, respectively. These results demonstrate that, when compared to RF and XGB, the LightGBM model showcase robust prediction capabilities, achieving a superior accuracy of 79% with an AUC of 0.88. These findings provide promising insights into the potential of our approach for predicting anticancer small molecules, highlighting the role of machine learning in advancing cancer treatment research.
... Anticancer peptides (ACPs) exert their cytotoxic activities in a similar mechanism to AMPs as they share similar biophysical properties attributed to their analogous synthesis origins and their targeting of relatively negative charged tumor and bacterial cells [7]. The ability for ACPs to selectively target cancer cells is still being elucidated and researchers seek to understand the mechanistic actions by which cancer cellular death is actuated. ...
... Thus, our findings with PARP-1 are promising, however require further validation through the assessment of associated MMEJ repair proteins such as BRCA, FEN1, and XRCC1 [57,58]. Additionally, other peptides were found to mediate the cytotoxic effect in a caspase dependent manner at certain concentrations, and in a caspase independent manner with a change in these concentrations [7,43,59]. Therefore, expression analysis should encompass multiple dose dependent responses and exposure periods, for different cancer cell lines. ...
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.
... As a result, cyclopeptides have better pharmacological qualities overall and provide more stability against the activity of proteolytic enzymes, which prolongs their bioavailability. According to earlier studies, it was possible to successfully synthesize macrocyclic peptide derivatives chemically and produce compounds with strong antibacterial, anti-inflammatory, and anti-cancer effects [22,23]. ...
... A new direction for cancer treatment has been opened by determining ACPs because they have cationic properties that can easily target cancer-affected cells without interacting with normal cells [11]. However, ACPs have some potential drawbacks in the drug development process, i.e., high production costs and low stability [12]; despite this, they have some unique merits. ACPs are biological substances that naturally exist in a living organism; hence, they are more harmless than synthetic drugs and have better efficacy [13]. ...
Bioinformatics and genomics are driving a healthcare revolution, particularly in the domain of drug discovery for anticancer peptides (ACPs). The integration of artificial intelligence (AI) has transformed healthcare, enabling personalized and immersive patient care experiences. These advanced technologies, coupled with the power of bioinformatics and genomic data, facilitate groundbreaking developments. The precise prediction of ACPs from complex biological sequences remains an ongoing challenge in the genomic area. Currently, conventional approaches such as chemotherapy, target therapy, radiotherapy, and surgery are widely used for cancer treatment. However, these methods fail to completely eradicate neoplastic cells or cancer stem cells and damage healthy tissues, resulting in morbidity and even mortality. To control such diseases, oncologists and drug designers highly desire to develop new preventive techniques with more efficiency and minor side effects. Therefore, this research provides an optimized computational-based framework for discriminating against ACPs. In addition, the proposed approach intelligently integrates four peptide encoding methods, namely amino acid occurrence analysis (AAOA), dipeptide occurrence analysis (DOA), tripeptide occurrence analysis (TOA), and enhanced pseudo amino acid composition (EPseAAC). To overcome the issue of bias and reduce true error, the synthetic minority oversampling technique (SMOTE) is applied to balance the samples against each class. The empirical results over two datasets, where the accuracy of the proposed model on the benchmark dataset is 97.56% and on the independent dataset is 95.00%, verify the effectiveness of our ensemble learning mechanism and show remarkable performance when compared with state-of-the-art (SOTA) methods. In addition, the application of metaverse technology in healthcare holds promise for transformative innovations, potentially enhancing patient experiences and providing novel solutions in the realm of preventive techniques and patient care.
... The advances in HDPs/AMPs with anticancer activity have been summarized in several review papers, which either focus on the tumorsuppressor mechanisms (membranolytic or non-membranolytic mode), factors affecting the anticancer activities, or the application in different tumor types [15,18,19,29,[34][35][36][37][38][39][40]. Furthermore, Yang and Pan et al. recently summarized the application and prospects of AMPs-mimicking synthetic macromolecules and other peptidomimetics in combating cancer/microbial infection, respectively [32,41]. ...
Traditional cancer therapy methods, especially those directed against specific intracellular targets or signaling pathways, are not powerful enough to overcome tumor heterogeneity and therapeutic resistance. Oncolytic peptides that can induce membrane lysis-mediated cancer cell death and subsequent anticancer immune responses , has provided a new paradigm for cancer therapy. However, the clinical application of oncolytic peptides is always limited by some factors such as unsatisfactory bio-distribution, poor stability, and off-target toxicity. To overcome these limitations, oncolytic polymers stand out as prospective therapeutic materials owing to their high stability, chemical versatility, and scalable production capacity, which has the potential to drive a revolution in cancer treatment. This review provides an overview of the mechanism and structure-activity relationship of oncolytic peptides. Then the oncolytic peptides-mediated combination therapy and the nano-delivery strategies for oncolytic peptides are summarized. Emphatically, the current research progress of oncolytic polymers has been highlighted. Lastly, the challenges and prospects in the development of oncolytic polymers are discussed.
