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Cancer is a disease advanced via surplus angiogenesis. The development of new anti-angiogenic therapeutic agents with more efficacy and fewer side effects is still quite necessary. Conventional therapies saving the life of many cancer patients but due to drug resistance and lack of specificity utilizing these methods is faced with limits. Recently,...
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... Angiogenesis has been investigated for several years in several aspects, most notably its morphological characteristics, as determined by MRI, and its biological aspects, as determined by biomarker assays [9,10]. Researchers are interested in this phenomenon because it plays a substantial role in all tumoral processes and represents a new therapeutic avenue, as various compounds with anti-angiogenic properties are presently proposed as cancer treatments [7,[11][12][13]. Many studies have proven the critical roles of Growth Factors in angiogenesis; nevertheless, the molecular processes underlying these roles, as well as how these mechanisms might be targeted in lung cancer therapy, are still to be fully understood. ...
Simple Summary
Growth factors promote angiogenesis, which is a critical process in the development of tumors. One of the therapeutic techniques being investigated in the treatment of cancer is the inhibition of angiogenesis through the inhibition of growth factors. This article aims to summarize the mechanisms by which growth factors influence the unfavorable evolution of lung cancers via angiogenesis as well as the therapeutic approaches that have been developed or are currently being developed in order to provide a foundation for researchers to investigate this question further and for practitioners to discuss therapeutic strategies when confronted with a lung cancer patient.
Abstract
Research has shown the role of growth factors in lung cancer angiogenesis. Angiogenesis promotes lung cancer progression by stimulating tumor growth, enhancing tumor invasion, contributing to metastasis, and modifying immune system responses within the tumor microenvironment. As a result, new treatment techniques based on the anti-angiogenic characteristics of compounds have been developed. These compounds selectively block the growth factors themselves, their receptors, or the downstream signaling pathways activated by these growth factors. The EGF and VEGF families are the primary targets in this approach, and several studies are being conducted to propose anti-angiogenic drugs that are increasingly suitable for the treatment of lung cancer, either as monotherapy or as combined therapy. The efficacy of the results are encouraging, but caution must be placed on the higher risk of toxicity, outlining the importance of personalized follow-up in the management of these patients.
... Angiogenesis has been investigated for several years in several aspects, most notably its morphological characteristics, as determined by MRI, and its biological aspects, as determined by 2 biomarker assays [5,6]. Researchers are interested in this phenomenon because it plays a substantial role in all tumoral processes and represents a new therapeutic avenue, as various compounds with anti-angiogenic properties are presently proposed as cancer treatments [7][8][9][10]. Many studies have proven the critical roles of Growth Factors in angiogenesis; nevertheless, the molecular processes underlying these roles, as well as how these mechanisms might be targeted in lung cancer therapy, are still to be fully understood. ...
Research has shown the role of growth factors in lung cancer angiogenesis. Angiogenesis promotes lung cancer progression by stimulating tumor growth, enhancing tumor invasion, contributing to metastasis, and modifying immune system responses within the tumor microenvironment. As a result, new treatment techniques based on the anti-angiogenic characteristics of compounds have been developed. These compounds selectively block the growth factors themselves, their receptors, or the downstream signaling pathways activated by these growth factors. The EGF and VEGF families are the primary targets in this approach, and several studies are being conducted to propose anti-angiogenic drugs that are increasingly suitable for the treatment of lung cancer, either as monotherapy or as combined therapy. The efficacy results are encouraging, but a caution must be placed on the higher risk of toxicity, outlining the importance of personalized follow-up in the management of these patients.
... Tumor growth is often accompanied by promoting the formation of new blood vessels from existing ones through high expression of pro-angiogenic factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF), which induce tumor proliferation and metastasis (Lugano et al. 2020;Shoari et al. 2021). CIGB-300, a peptide inhibitor, limited NSCLC angiogenesis by inhibiting casein kinase 2 (CK2) and therefore decreased vascular response to angiogenesis. ...
... Another ACP, F4 (CNPEDCLYPVSHAHQR) derived from collagen XIX, was found to inhibit VEGFinduced pseudo-tube formation on Matrigel in a mouse melanoma model via α5β1 and αvβ3 integrin interaction, thus inhibiting tumor cell angiogenesis and migration (Oudart et al. 2021). Briefly, due to low toxicity, high specificity, and high penetrating rate of anti-angiogenic ACPs, they could be considered as new therapeutic agents for cancer patients (Shoari et al. 2021). ...
Background
Cancer, being a complex disease, presents a major challenge for the scientific and medical communities. Peptide therapeutics have played a significant role in different medical practices, including cancer treatment.
Method
This review provides an overview of the current situation and potential development prospects of anticancer peptides (ACPs), with a particular focus on peptide vaccines and peptide-drug conjugates for cancer treatment.
Results
ACPs can be used directly as cytotoxic agents (molecularly targeted peptides) or can act as carriers (guiding missile) of chemotherapeutic agents and radionuclides by specifically targeting cancer cells. More than 60 natural and synthetic cationic peptides are approved in the USA and other major markets for the treatment of cancer and other diseases. Compared to traditional cancer treatments, peptides exhibit anticancer activity with high specificity and the ability to rapidly kill target cancer cells. ACP's target and kill cancer cells via different mechanisms, including membrane disruption, pore formation, induction of apoptosis, necrosis, autophagy, and regulation of the immune system. Modified peptides have been developed as carriers for drugs, vaccines, and peptide–drug conjugates, which have been evaluated in various phases of clinical trials for the treatment of different types of solid and leukemia cancer.
Conclusions
This review highlights the potential of ACPs as a promising therapeutic option for cancer treatment, particularly through the use of peptide vaccines and peptide–drug conjugates. Despite the limitations of peptides, such as poor metabolic stability and low bioavailability, modified peptides show promise in addressing these challenges.
Graphical abstract
Various mechanism of action of anticancer peptides. Modes of action against cancer cells including: inducing apoptosis by cytochrome c release, direct cell membrane lysis (necrosis), inhibiting angiogenesis, inducing autophagy-mediated cell death and immune cell regulation.
... For example, VEGF is one of the most influential modulators of angiogenesis. Thus, inhibiting its interaction with the VEGF receptor-1 (VEGFR1) through antagonistic peptides is a promising anti-angiogenic therapy (Shoari et al. 2021). A cyclic pentapeptide (DWLPK) derived from the glycoprotein prosaposin (PSAP) sequence was developed and tested in patient-derived ovarian cancer xenografts. ...
Conventional cancer therapies cause severe side effects. Peptide-based therapy as a complementary option in cancer treatment reports promising results due to its multifunctionality, selectivity, and safety. The aim of this study was to describe the multiple roles peptides have acquired in cancer therapy, the engineering approaches utilized to enhance peptide efficacy, and to evaluate the status and trends of publications related to anticancer peptides. Information related to the roles of peptides in anticancer therapy and to the engineering strategies to improve their efficacy was curated. The digital libraries PubMed, ScienceDirect, and SpringrLink, were consulted for the bibliometric analysis. Anticancer peptides may act through multiple pathways to eliminate tumor cells. Engineering strategies have been successfully implemented to overcome the low bioavailability of peptides, allowing them to improve their efficacy. The bibliometric analysis allowed the visualization of the importance anticancer peptides have gained in cancer therapy in the past two decades.
... Peptides are less immunogenic, and lower doses of peptides are required for solid tumors. Expressing antibodies in eukaryotic systems is more costly, and due to their large size and high molecular weight, they cannot penetrate the target tissue [174]. Therefore, developing novel anticancer agents, such as ACPs, is in great demand due to low side effects and high selectivity and penetration [1]. ...
Complex pathological diseases, such as cancer, infection, and Alzheimer’s, need to be targeted by multipronged curative. Various omics technologies, with a high rate of data generation, demand artificial intelligence to translate these data into druggable targets. In this study, 82 marine venomous animal species were retrieved, and 3505 cryptic cell-penetrating peptides (CPPs) were identified in their toxins. A total of 279 safe peptides were further analyzed for antimicrobial, anticancer, and immunomodulatory characteristics. Protease-resistant CPPs with endosomal-escape ability in Hydrophis hardwickii, nuclear-localizing peptides in Scorpaena plumieri, and mitochondrial-targeting peptides from Synanceia horrida were suitable for compartmental drug delivery. A broad-spectrum S. horrida-derived antimicrobial peptide with a high binding-affinity to bacterial membranes was an antigen-presenting cell (APC) stimulator that primes cytokine release and naïve T-cell maturation simultaneously. While antibiofilm and wound-healing peptides were detected in Synanceia verrucosa, APC epitopes as universal adjuvants for antiviral vaccination were in Pterois volitans and Conus monile. Conus pennaceus-derived anticancer peptides showed antiangiogenic and IL-2-inducing properties with moderate BBB-permeation and were defined to be a tumor-homing peptide (THP) with the ability to inhibit programmed death ligand-1 (PDL-1). Isoforms of RGD-containing peptides with innate antiangiogenic characteristics were in Conus tessulatus for tumor targeting. Inhibitors of neuropilin-1 in C. pennaceus are proposed for imaging probes or therapeutic delivery. A Conus betulinus cryptic peptide, with BBB-permeation, mitochondrial-targeting, and antioxidant capacity, was a stimulator of anti-inflammatory cytokines and non-inducer of proinflammation proposed for Alzheimer’s. Conclusively, we have considered the dynamic interaction of cells, their microenvironment, and proportional-orchestrating-host- immune pathways by multi-target-directed CPPs resembling single-molecule polypharmacology. This strategy might fill the therapeutic gap in complex resistant disorders and increase the candidates’ clinical-translation chance.
... 8,9 In addition, many peptides have been constructed and tested as antiangiogenic therapeutic agents targeting various antigens linked to angiogenesis. 10 These include the HRH peptide with in vitro and in vivo angiogenesis inhibition, 11 the TM peptide for breast cancer treatment, 12 and cilengitide for ocular melanoma and adenoid cystic cancer treatment. 13 A previously published study by Miettinen et al. detected VEGFR-2 as a typical marker of some types of vascular tumors, nominally in angiosarcoma and Kaposi sarcoma with the consistent expression of VEGFR-2, and also in other mesenchymal and epithelial tumors with its limited expression. ...
... 9,17 Therefore, the search for new tools to detect VEGFR-1/-2-positive cancer lesions is currently an important scientific challenge. 10 The goal of the present study was to prepare VEGFR-targeting peptide imaging agents potentially useful for PET diagnostics. ...
As angiogenesis plays a key role in tumor growth and metastasis, the angiogenic process has attracted scientific interest as a target for diagnostic and therapeutic agents. Factors influencing angiogenesis include the vascular endothelial growth factor (VEGF) family and the two associated receptor types (VEGFR-1 and VEGFR-2). VEGFR-1/-2 detection and quantification in cancer lesions are essential for tumor process management. As a result of the advantageous pharmacokinetics and image contrast, peptides radiolabeled with PET emitters have become interesting tools for the visualization of VEGFR-1/-2-positive tumors. In this study, we prepared 68Ga-labeled peptides containing 15 (peptide 1) and 23 (peptide 2) amino acids as new PET tracers for tumor angiogenic process imaging.
Methods:
The peptides were conjugated with NODAGA-tris(t-Bu ester) and subsequently radiolabeled with [68Ga]Ga-chloride. The prepared [68Ga]Ga-NODAGA-peptide 1 and [68Ga]Ga-NODAGA-peptide 2 were tested for radiochemical purity and saline/plasma stability. Consequently, the binding affinity toward VEGFRs was assessed in vitro on human glioblastoma and kidney carcinoma cells. The found peptide receptor affinity was compared with the calculated values in the PROtein binDIng enerGY prediction (PRODIGY) server. Finally, the biodistribution study was performed on BALB/c female mice to reveal the basic pharmacokinetic behavior of radiopeptides.
Results:
The in vitro affinity testing of [68Ga]Ga-NODAGA-peptides 1 and 2 showed retained receptor binding as characterized by equilibrium dissociation constant (KD) values in the range of 0.5-1.2 μM and inhibitory concentration 50% (IC50) values in the range of 3.0-5.6 μM. Better binding properties of peptide 2 to VEGFR-1/-2 were found in the PRODIGY server. The biodistribution study on mice showed remarkable accumulation of both peptides in the kidneys and urinary bladder with a short half-life after intravenous application. The in vitro plasma stability of [68Ga]Ga-NODAGA-peptide 2 was superior to that of [68Ga]Ga-NODAGA-peptide 1.
Conclusions:
The obtained results demonstrated a high radiolabeling yield with no need for purification and preserved binding potency of 68Ga-labeled peptides 1 and 2 toward VEGFRs in cancer cells. The peptide-receptor protein interaction assessed in protein-peptide docking determined the strongest interaction of peptide 2 with domain 2 of VEGFR-2 in addition to a more acceptable plasma stability (t1/2 = 120 min) than that for peptide 1. We found both radiolabeled peptides very potent in their receptor binding, which makes them suitable imaging agents. The rapid transition of the radiopeptides into the urinary tract indicates suitable pharmacokinetic characteristics.
... Several anti-angiogenic drugs have been approved by FDA and numerous are in clinical trials including endogenous angiogenesis inhibitors (Jászai and Schmidt 2019;Teleanu et al. 2020). Because of the advantages of peptides to antibodies, recombinant proteins, and small molecules, various research has been performed to obtain potent antiangiogenic peptides (Chamani et al. 2015(Chamani et al. , 2016Shoari et al. 2021). Peptides can be easily synthesized, are cost-effective, have high specificity, and have low immunogenicity and toxicity (Marqus et al. 2017). ...
Canstatin, the NC1 domain of the α2 chain of collagen IV, prevents tumor growth through angiogenesis inhibition and apoptosis induction. N-terminal 1–89 amino acid fragment of canstatin induces apoptosis much higher than the C-terminal fragment. Recently, we demonstrated that the amino acids 78–86 of canstatin, so-called Cans, have more anti-migration, anti-tube formation, and anti-tumor activities than other collagen IV derived peptides. Here, we evaluated HUVEC, MCF10A, and L929 cell viability, the percentage of apoptotic cells by Annexin V-FITC/PI staining, caspase-3 activity, Bcl-2, and caspase-8 gene expression using RT-qPCR in endothelial cells, and Bax and Bcl-2 expression in tumors by immunohistochemistry to investigate the apoptotic effect of Cans. Results showed that the peptide reduced the percentage of viable HUVE cells with EC50 of 21 μM and was not toxic for normal cell lines. 30 and 50 μM of Cans induced 34.6% and 50.7% early and late apoptosis in HUVECs compared to 16.5% in control. In addition, caspase-3 activity was amplified up to threefold compared to the untreated cells. Cans down-regulated Bcl-2 and caspase-8 gene expression. This result may show that this peptide acts through the intrinsic pathway and cannot affect the extrinsic pathway of apoptosis. However, this hypothesis requires more investigation. Besides, Bcl-2 reduction and Bax elevation in tumor sections indicated that this peptide could stimulate apoptosis in vivo. In conclusion, we showed that the short canstatin peptide induces apoptosis in endothelial and tumor cells as one of its anti-angiogenic and anti-tumor mechanisms.
... Despite common cancer treatments, recurrence of SCLC is a challenge and no one has yet been able to prevent a recurrence of SCLC (3). 429 Considering the disadvantages of conventional therapies, complementary therapies such as molecular targeting therapy, anti-angiogenesis therapy, immunotherapy, apoptosis regulation, signal transduction therapy, and nucleic acid-based therapy have attracted the interest of researchers (4,5). ...
Abstract
Background and purpose: The lack of a new effective treatment for small cell lung cancer (SCLC) is an
unresolved problem. Due to the new identification of delta-like ligand 3 (DLL3) and its high expression in
SCLC patients, the use of DLL3 in target therapy can be effective. The use of bacterial toxins belonging to
the ADP-ribosyl transferase toxins family and human enzymes to remove cancerous cells has been effective
in the structure of immunotoxins. In this study, single-chain fragment variable of rovalpituzumab antibody
fused to granzyme B (Rova-GrB) and PltA of typhoid toxin (Rova-Typh) as immunotoxins were designed, and
bioinformatics analysis was done.
Experimental approach: In silico analysis including the physicochemical properties, evaluation of the
secondary and tertiary structure, refinement and validation of 3D models, and docking were performed.
Immunotoxin genes were cloned and expressed in the Escherichia coli BL21 (DE3) host, purified,
subsequently confirmed by western blotting and their secondary structure was evaluated by the circular
dichroism method.
Findings/Results: The bioinformatics analysis showed that Rova-GrB and Rova-Typh had hydrophilic
properties, their codon optimization parameters were standard, validation parameters were improved after
immunotoxin refinement, and docking analysis showed that the binding domain of immunotoxins could bind
the N-terminal region of DLL3. immunotoxins had high expression and after purification under denaturing
condition by Ni-NTA column, the immunotoxins were dialyzed against PBS buffer.
Conclusion and implications: The immunotoxins had the right structure and can be produced in a prokaryotic
host. The recombinant immunotoxins against DLL3 can be promising therapeutic agents for SCLC cancer.
Keywords: DLL3; In silico design; Rovalpituzumab; SCLC.
... Other novel anti-angiogenic strategies include the exploitation of miRNAs-elucidating their role in angiogenesis and evaluating novel miRNA-mediated immunotherapies [164] . Advances in miRNA targeting and delivery strategies, such as the use of nanoparticles or cell-derived membrane vesicles for therapeutic miRNA delivery, may provide miRNA-based therapeutics as anti-angiogenic treatments. ...
Cancer is a group of diseases with significant morbidity and mortality. In cancer cells, where energy requirements are exceptionally high, angiogenesis, which is the sprouting of new blood vessels from pre-existing ones, is an important process for tumour survival and progression. Hence, extensive research in recent years focuses on the discovery of new anticancer drugs that target angiogenesis. Several methodologies have been developed preclinically, including the inhibition of pro-angiogenic factors and their receptors via micromolecular agents or monoclonal antibodies and the inhibition of other compensatory pathways beyond the traditional angiogenic ones. The purpose of the literature review is to present new anticancer drugs that target the process of angiogenesis and have been under preclinical or clinical investigation during the last five years. Many new anticancer drugs targeting angiogenesis are identified in the literature. The results of the in vitro and in vivo evaluation of these drugs show that, apart from inhibiting angiogenesis, they also affect cancer cell proliferation and tumour growth. Recent clinical studies show that these drugs increase the overall or disease-free survival of patients, even those with persistent, chemotherapy-resistant and metastatic types of cancer, although treatment-related side effects are not uncommon. Drugs that target the process of angiogenesis are likely to be the future of anticancer therapy, especially in cases where more traditional treatments do not produce the desired results and where combination regimens of anti-angiogenic agents with standard chemotherapeutics increase patient survival.
