Anticancer Activity Research Articles

Design, Synthesis, and Biological Evaluation of Some Novel Retinoid Derivatives

Background: As cancer stands as a significant global health concern, many heterocyclic compounds that are more effective in cancer cells than healthy cells are being investigated for their selective anticancer potentials. One such compound is fenretinide, a synthetic derivative of retinoic acid that has a broad spectrum of cytotoxic activity against primary tumor cells, cell lines, and/or xenografts of various cancers. In this context, bexarotene and its derivatives, synthesized from hybridization of the fenretinide, are expected to possess a potential anticancer activity. Objective: The objective of the present study was to investigate the synthesis of novel amid-derived and bexarotene-based compounds, as well as to assess their cytotoxic effects in different cancer cell lines. Methods: This study involved the synthesis of twelve novel retinoid derivatives (6-17) in a six-step process. The cytotoxic activities of these compounds were assessed against various cancer cell lines, such as A549 (human lung carcinoma), HeLa (human cervical cancer), MCF7 (human breast adenocarcinoma), and WiDr (human colon adenocarcinoma). The chemical structures of these compounds were elucidated through their elemental analysis, mass spectrometry (ESI+, ESI-), as well as 1H-NMR and 13C-NMR spectroscopic data. Results: The obtained cell toxicity results indicated that compounds 6, 8, 11, 12, 13, 14, and 17 were found to exhibit the strongest cytotoxic activity in above mentioned cancer cell lines. The IC50 values for active compounds, 11 and 12, were determined as 2.38μM and 2.29μM, respectively. Remarkably, these compounds displayed higher cytotoxic activity in the WiDr cell line related to positive control, camptothecin (CPT). Moreover, compounds 14 and 17 demonstrated very similar level of cytotoxic activity to CPT, indicating their potential for antitumoral applications upon further studies. Conclusion: While compounds 11, 12, 14, and 17 indicated a very comparable anticancer activity to CPT, compounds 6, 8, 11 and 12 showed more selective anticancer effect against cancer cells than noncancerous cells. In accordance with the findings of the present study, they can be evaluated as primary candidates for further studies, specifically as RXRα-targeted anticancer agents.

Synthesis, anticancer activity and mechanism of action of Fe(III) complexes.

To inhibit the growth and metastasis of triple-negative breast cancer (TNBC), two Fe(III) thiosemicarbazone complexes (Fe1 and Fe2) were designed and synthesized. The structures of the Fe(III) complexes were characterized by single crystal X-ray diffraction. The antiproliferative activity of Fe1 and Fe2 against four cancer lines (MDA-MB-231, T98G, HepG2, 143B) and human renal proximal tubular epithelial cell line (HK-2) was evaluated by MTT assay. Among all cells, Fe2 showed significant cytotoxicity to TNBC cells (MDA-MB-231), with an IC50 value of 12.38 μM. Furthermore, Fe2 showed less toxicity to HK-2 cells. The two Fe(III) complexes can produce excess of reactive oxygen species, decrease of mitochondrial membrane potential, and induce DNA damage, then lead to apoptosis of MDA-MB-231 cells. In addition, Fe1 and Fe2 can also inhibit migration and invasion of MDA-MB-231 cells. This study provides guidance for the development of metal complexes that inhibit the growth and metastasis of TNBC.

Synergistic Action of Rutin-Coated Zinc Oxide Nanoparticles: Targeting Biofilm Formation Receptors of Dental Pathogens and Modulating Apoptosis Genes for Enhanced Oral Anticancer Activity.

Oral diseases are often associated with bacterial and fungal pathogens such as Staphylococcus aureus, Streptococcus mutans, Enterococcus faecalis, and Candida albicans. This research explored a novel approach to addressing these pathogens by synthesizing zinc oxide nanoparticles (ZnO NPs) coated with rutin (RT), a plant-derived compound. The synthesized ZnO-RT NPs were comprehensively characterized using UV-Vis spectrophotometer, SEM, and EDAX techniques to confirm their structural composition. The antioxidant potential was assessed through free radical scavenging assays. Additionally, the antimicrobial activity of ZnO-RT NPs was evaluated using a zone of inhibition assay against oral pathogens. Molecular docking studies with the Autodock tool were performed to elucidate the interactions between RT and the receptors of oral pathogens. The findings demonstrated that ZnO-RT NPs exhibited robust free radical scavenging activity. Furthermore, they showed significant antimicrobial activity with a minimal inhibitory concentration of 40 μg/mL against oral pathogens. ZnO-RT NPs also displayed dose-dependent anticancer effects on human oral cancer cells at concentrations of 10, 20, 40, and 80 μg/mL. Mechanistic insights into the anticancer activity on KB cells revealed the upregulation of apoptotic genes. This study underscores the promising potential of ZnO-RT NPs for dental applications due to their strong antioxidant, anticancer, and antimicrobial properties. These nanoparticles offer a hopeful prospect for addressing oral pathogen challenges and enhancing overall oral health.

Combined treatment with Aronia berry extract and oligomeric proanthocyanidins exhibit a synergistic anticancer efficacy through LMNB1-AKT signaling pathways in colorectal cancer.

Colorectal cancer (CRC) is one of the most prevalent and highly recurrent malignancies worldwide and currently ranks as the second leading cause of cancer-related deaths. The high degree of morbidity and mortality associated with CRC is primarily attributed to the limited effectiveness of current therapeutic approaches and the emergence of chemoresistance to standard treatment modalities. Recent research indicates that several natural products, including Aronia berry extracts (ABE) and oligomeric proanthocyanidins (OPCs), might offer a safe, cost-effective, and multitargeted adjunctive role to cancer treatment. Herein, we hypothesized a combined treatment with ABE and OPCs could synergistically modulate multiple oncogenic pathways in CRC, thereby enhancing their anticancer activity. We initially conducted a series of in vitro experiments to assess the synergistic anticancer effects of ABE and OPCs on CRC cell lines. We demonstrate that these two compounds exhibited a superior synergistic anticancer potential versus individual treatments in enhancing the ability to inhibit cell viability, suppress colony formation, and induce apoptosis (p < 0.05). Consistent with our in vitro findings, we validated this combinatorial anticancer effect in tumor-derived 3D organoids (PDOs; p < 0.01). Using genome-wide transcriptomic profiling, we identified that a specific gene, LMNB1, associated with the cell apoptosis pathway, was found to play a crucial role in exhibiting anticancer effects with these two products. Furthermore, the combined treatment of ABE and OPCs significantly impacted the expression of key proteins involved in apoptosis, including suppressed expression levels of LMNB1 in CRC cell lines (p < 0.05), which resulted in inhibiting downstream AKT phosphorylation. In conclusion, our study provides novel evidence of the synergistic anticancer effects of ABE and OPCs in CRC cells, partially mediated through the regulation of apoptosis and the oncogene LMNB1 within the AKT signaling pathway. These findings have the potential to better appreciate the anticancer potential of natural products in CRC and help improve treatment outcomes in this malignancy.

Jellein-I-conjugated Gold nanoparticles: Insights into the Antibacterial, Antibiofilm Activity against MRSA, and Anticancer Properties

Antimicrobial peptides (AMPs) and their conjugation with nanoparticles hold promise for targeting Methicillin-resistant Staphylococcus aureus (MRSA). In this study, Jellein-I peptide, with a cysteine at the C-terminus, was conjugated to gold nanoparticles (GNPs) to enhance its antibacterial, antibiofilm, and anticancer activities. The GNPs were synthesized and then conjugated to Jellein-I, forming Jellein-I-Cys-GNPs. The nanoparticles were characterized using UV-visible spectroscopy, transmission electron microscopy (TEM), dynamic light scattering (DLS), and Fourier transform infrared (FTIR) spectroscopy. UV-visible spectroscopy, DLS, and TEM confirmed the formation of GNPs with an average size of 5.5 nm. The UV–visible spectroscopy and FTIR results indicated the presence of peptide functional groups on the surface of the GNPs. To assess antibacterial activity, minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) assays were performed against MRSA strains. The conjugated Jellein-I exhibited lower MIC and MBC values (94 μM) compared to the free peptide (512 μM) against both clinical and standard MRSA strains. Additionally, GNP-conjugated Jellein-I demonstrated antibiofilm activity, inhibiting and removing biofilms while reducing metabolic activity by more than 82%, 44%, and 72%, respectively. Cell viability studies on rat dermal fibroblast (RDF) cells showed over 80% viability across all treatment concentrations. Furthermore, a clonogenic assay on the metastatic melanoma cell line (A375) demonstrated that GNP-conjugated Jellein-I had significantly better anticancer effects than the free peptide, even at a concentration as low as 9 μM. Our findings suggest that the conjugation of Jellein-I-Cys to GNPs could be a promising formulation for enhancing the antibacterial, antibiofilm, and anticancer activities of peptides. Further in vivo studies may establish this new nanoformulation as a potential therapeutic candidate for MRSA infections and cancer treatment.

L-Amino Acid Oxidase from Marine Bacterium: Purification, Characterization and Evaluation of its Anticancer and antioxidant activities

L-Amino Acid Oxidase from Marine Bacterium: Purification, Characterization and Evaluation of its Anticancer and antioxidant activities

Acute and sub-acute toxicity of ethanol leaf extract from Acrostichum aureum in rats

Acrostichum aureum L. (A.aureum) is a medicinal plant that has anti-cancer, anti-inflammatory, and anti-bacterial activities and has been widely used traditionally in the treatment of many diseases. However, there is a dearth of information on the plant's safety. The present investigation was carried out to evaluate the acute and sub-acute toxicity of ethanol leaf extract of A. aureum (ELAA) in female Sprague Dawley (SD) rats. Oral acute toxicity was studied in female SD rats administered a single dose of 5000 mg kg-1 body weight ELAA. The sub-acute toxicity evaluation was also conducted orally with 100, 200, 500, and 750 mg kg-1 body weight of ELAA for 28 days in female SD rats. The impact of sub-acute treatment on body weight, gross histology, relative organ weight, urinalysis, hematology, plasma biochemistry, and histopathology was assessed following treatment. The ELAA did not cause death or signs of toxicity after acute treatment. Similarly, all the parameters evaluated during acute and sub-acute administration of ELAA did not significantly differ from the control. Therefore, the median lethal dose (LD50) of the ethanol extract of Acrostichum aureum is greater than 5000 mg kg-1 body weight. Its oral sub-acute administration is also non-toxic and safe at the tested doses.

Short Fragmented Peptides from Pardachirus Marmoratus Exhibit Stronger Anticancer Activities in In Silico Residue Replacement and Analyses.

Cancer is a worldwide issue. It has been observed that conventional therapies face many problems, such as side effects and drug resistance. Recent research reportedly used marine-derived products to treat various diseases and explored their potential in treating cancers. This study aims to discover short-length anticancer peptides derived from pardaxin 6 through an in silico approach. Fragmented peptides ranging from 5 to 15 amino acids were derived from the pardaxin 6 parental peptide. These peptides were further replaced with one residue and, along with the original fragmented peptides, were predicted for their SVM scores and physicochemical properties. The top 5 derivative peptides were further examined for their toxicity, hemolytic probability, peptide structures, docking models, and energy scores using various web servers. The trend of in silico analysis outputs across 5 to 15 amino acid fragments was further analyzed. Results showed that when the amino acids were increased, SVM scores of the original fragmented peptides were also increased. Designed peptides had increased SVM scores, which was aligned with previous studies where the single residue replacement transformed the non-anticancer peptide into an anticancer agent. Moreover, in vitro studies validated that the designed peptides retained or enhanced anticancer effects against different cancer cell lines. Interestingly, a decreasing trend was observed in those fragmented derivative peptides. Single residue replacement in fragmented pardaxin 6 was found to produce stronger anticancer agents through in silico predictions. Through bioinformatics tools, fragmented peptides improved the efficiency of marine-derived drugs with higher efficacy and lower hemolytic effects in treating cancers.

Conjugation of Doxorubicin and Carbon-based-nanostructures for Drug Delivery against HT-29 Colon Cancer Cells.

A drug delivery system is the method or process of administering a pharmaceutical compound to achieve a therapeutic effect in humans or animals. Such systems release the drugs at specific amounts in a specific site. The carbon based-nanomaterials have been actively used as drug carriers to treat various cancer. This study aimed to evaluate the cytotoxic effects of DOX-GO, DOX-OMC and DOXCNT in colon cancer cells (HT29). We reported platforms based on graphene oxide (GO), ordered mesoporous carbon (OMC) and carbon nanotubes (CNT) to conjugate with doxorubicin (DOX). The conjugation of DOX with carbon nanomaterial was investigated by UV-Vis spectroscopy, field emission scanning electron microscope (FE-SEM) and cyclic voltammetry (CV) methods. We showed that graphene oxide was a highly efficient matrix. Efficient loading of DOX, 89%, 78%, and 73.5% at pH 7.0 was seen onto GO, OMC and CNT, respectively. Upon pH 4. 0 after 15 h, 69%, 61% and 61% of DOX could be released from the DOX-GO, DOX-OMC and DOX-CNT, respectively, which illustrated the significant benefits of the developed approach for carbon nanomaterial applications. In vitro cytotoxicity analysis showed greater cytotoxicity of DOX/GO, DOX/OMC and DOX/CNT in comparison with GO, OMC and CNT against HT29 colon cancer cells with cell viability of 22%, 40% and 44% after 48 h for DOX-GO, DOX-OMC and DOX-CNT, respectively. The nanohybrids based on DOX-carbon nanomaterial, because of their unique physical and chemical properties, will remarkably enhance the anti-cancer activity.

Thymol as adjuvant in oncology: molecular mechanisms, therapeutic potentials, and prospects for integration in cancer management.

Cancer remains a global health challenge, prompting a search for effective treatments with fewer side effects. Thymol, a natural monoterpenoid phenol derived primarily from thyme (Thymus vulgaris) and other plants in the Lamiaceae family, is known for its diverse biological activities. It emerges as a promising candidate in cancer prevention and therapy. This study aims to consolidate current research on thymol's anticancer effects, elucidating its mechanisms and potential to enhance standard chemotherapy, and to identify gaps for future research. A comprehensive review was conducted using databases like PubMed/MedLine, Google Scholar, and ScienceDirect, focusing on studies from the last 6years. All cancer types were included, assessing thymol's impact in both cell-based (in vitro) and animal (in vivo) studies. Thymol has been shown to induce programmed cell death (apoptosis), halt the cell division cycle (cell cycle arrest), and inhibit cancer spread (metastasis) through modulation of critical signaling pathways, including phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), extracellular signal-regulated kinase (ERK), mechanistic target of rapamycin (mTOR), and Wnt/β-catenin. It also enhances the efficacy of 5-fluorouracil (5-FU) in colorectal cancer treatments. Thymol's broad-spectrum anticancer activities and non-toxic profile to normal cells underscore its potential as an adjunct in cancer therapy. Further clinical trials are essential to fully understand its therapeutic benefits and integration into existing treatment protocols.

Discovery of pyrrolo[2,3-d]pyrimidin-4-one derivative YCH3124 as a potent USP7 inhibitor for cancer therapy

USP7 is one of the most studied deubiquitinating enzymes, which is involved in the regulation of multiple cell signaling pathways and has been shown to be associated with the occurrence and progression of a variety of cancers. Inhibitors targeting USP7 have been studied by several teams, but most of them lack selectivity and have low activities. Herein, we reported a serious of pyrrole[2,3-d]pyrimidin-4-one derivatives through scaffold hopping of recently reported 4-hydroxypiperidine compounds. The representative compound Z33 (YCH3124) exhibited highly potent USP7 inhibition activity as well as anti-proliferative activity against four kinds of cancer cell lines. Further study revealed that YCH3124 effectively inhibited the downstream USP7 pathway and resulted in the accumulation of both p53 and p21 in a dose-dependent manner. Notably, YCH3124 disrupted cell cycle progression through restricting G1 phase and induced significant apoptosis in CHP-212 cells. In summary, our efforts provided a series of novel pyrrole[2,3-d]pyrimidin-4-one analogs as potent USP7 inhibitors with excellent anti-cancer activity.

Pt(IV) Complexes with Biologically Active and Physicochemical Properties Modifier Ligands

: The octahedral Pt(IV) complexes contain either inert or biologically active ligands where the nature of these axial ligands provides additional stability and synergistic biological activity. There are many literature reports from each of the classes mentioning the varied nature of these axial ligands. The targeting, as well as the non-targeting nature of these moieties, exerts additive or synergistic effects of anticancer activity of Pt(II) moieties. Herein, we have discussed the effects of these axially oriented ligands, changes in the non-leaving am(m)ine groups, and changes in the leaving groups on the biological activity. In this review, we have discussed the axial ligands with a focus on the nature of the ligands and alterations in biological activities.

Essential Oil of Hyptis suaveolens (L.) Poit: A comprehensive study of its chemical and biological properties for therapeutic and industrial applications

The essential oil from the leaves of Hyptis suaveolens was extracted through steam distillation, yielding an average of 0.08% with a density of 0.8. The chemical composition was determined using Gas Chromatography (GC) and Gas Chromatography-Mass Spectrometry (GC-MS), identifying 24 compounds, predominantly sesquiterpenes. Antimicrobial activity tests were conducted using the microdilution method to evaluate the efficacy of the oil against 14 bacterial strains. The essential oil was mainly composed of β-Caryophyllene (33.9%), Germacrene D (25.4%), α-Humulene (8.3%), and Germacrene B (8.2%). Antibacterial tests revealed bactericidal activity against most of the tested strains, with Minimum Inhibitory Concentration (MIC) values ranging from 0.3 to 12.2 mg/mL and slightly higher Minimum Bactericidal Concentrations (MBC). The essential oil of Hyptis suaveolens shows significant antibacterial activity, making it a potential preservative agent for the food industry. Further studies on its antifungal, anticancer activities, and other physical parameters such as refractive index are suggested to explore its full potential.

Gamma irradiation green synthesis of (polyacrylamide/chitosan/silver nanoparticles) hydrogel nanocomposites and their using as antifungal against Candida albicans and anti-cancer modulator

Silver nanoparticles-loaded hydrogel nanocomposites are exploited for medicinal and pharmaceutical applications. Hydrogel nanocomposites were prepared from acrylamide (Am), chitosan (CS) and AgNO3 utilizing gamma rays. Diverse variables were applied in preparation of silver nanoparticles-laoded hydrogel nanocomposites of (PAm/CS)-AgNPs such as influence of radiation dose and influnece of CS concentration. Diverse techniques were utilized to characterize hydrogel nanocomposites; Fourier transform infrared spectroscopy (FTIR), thermal gravimetric analysis (TGA), X-ray diffraction (XRD), Transmission electron microscopy (TEM), energy dispersive X-ray (EDX) and scanning electron microscopy (SEM). Results confirmed formation of silver nanoparticles-loaded hydrogel nanocomposites of (PAm/CS)-AgNPs. Antifungal activity of (PAm/CS)-AgNPs hydrogel nanocomposites on viability of C. albicans was esitmated. Results displayed the efficient microbial inhibition activity of treatment against C. albicans compared to control. Furthermore, (PAm/CS)-AgNPs hydrogel nanocomposite against cervical cancer HeLa cell line was investigated. Cytotoxicity of (PAm/CS)-AgNPs hydrogel nanocomposites on prior cancer cell line empolyed to prohibition of cell growth assesssed by MTT test. HeLa cancer cell is treated by (PAm/CS)-AgNPs for 48 h exposed a potential apoptotic activity by noticeable up-regulation of p53 gene expression. Moreover, anticancer activity was investigated by down-regulation of platelet-based growth variable receptor beta (PDGFR-β), Bcl2, Cathepsine, and MMP-2 gene expression. antioxidant activity was investigated and results showed antioxidant activity of (PAm/CS) hydrogel and (PAm/CS)-AgNPs hydrogel nanocomposite are 87.8% and 62.9%, respectively.

Oldenlandia diffusa(Willd.) Roxb. Essential Oil from Assam, India: GC-MS Analysis and Anticancer Activity

In this study essential oil from Oldenlandia diffusa (aerial parts) was extracted using hydrodistillation method. Characterization of the essential oil was done by using GC-MS analysis and identified 71 compounds. Pentacosane (13.29%), hexacosane (11.59%), tetracosane (11.18%), heptacosane (9.76%),tricosane (6.90%), phytol (5.71%), hexatriacontane (4.87%) and isophytol (4.69%) were the major compounds constituting the oil. Further, cytotoxicity of the extracted oil was observed against PA1 (Ovarian), MIAPaCa-2 (Pancreatic), A549 (Lung), MCF7 (Breast), HeLa (Cervical), HepG2 (Liver), PC-3 (Prostatic), MDA-MB-231 (Breast) cell lines. The oil exhibited dose and time dependent inhibition effects against the cancer cell lines. Best inhibition activity was observed against PA1, HeLa and PC-3 cancer cell lines. The IC50 values ranged from 24.19±0.837 - 3.12±0.126 µg/mL in PA1 cells, 51.87±3.104 - 28.95±0.76 µg/mL in HeLa cells and 52.92±1.233 - 14.62±0.465 µg/mL in PC-3 cells at 24, 48 and 72h. From the experiments, it was clear that essential oil of Oldenlandia diffusa should be further explored as an anticancer agent for developing medicinal drug.

Evaluation of Xanthone and Cinnamoylbenzene as Anticancer Agents for Breast Cancer Cell Lines through In Vitro and In Silico Assays

Breast cancer is a severe global disease for women as the number of deaths increases annually. Therefore, attempts to find new anticancer agents are critical and inevitable. In this work, we report the investigation on the anticancer activity of xanthone and cinnamoylbenzene compounds against two breast cancer cell lines, i.e., T47D and MCF-7, through experimental in vitro and theoretical in silico assays. Xanthone and cinnamoylbenzene exhibit anticancer activity with a half-maximal inhibitory concentration (IC50) of 136.7–194.3 and 235.8–262.4 µg/mL against T47D and MCF-7 cancer cells, respectively. Cinnamoylbenzene generates less cytotoxicity to normal Vero cells with a selectivity index of 1.095–2.102. The molecular docking studies agree with the experimental data in which cinnamoylbenzene is more active against T47D with an IC50 of 136.7 µg/mL due to Topoisomerase II inhibition through π-π stacked interactions with Adenine12 and Guanine13 nitrogen bases. Meanwhile, xanthone is more active against MCF-7 with an IC50 of 235.8 µg/mL due to EGFR inhibition through van der Waals interaction and hydrogen bond with Glutamic acid767 and Methionine769 amino acid residues, respectively. Additionally, the pharmacokinetic parameters of xanthone and cinnamoylbenzene are predicted through absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis, and they show better suitability than doxorubicin as the commercial anticancer drug.

Metal-based organic complexes with anticancer activity

Metal-based organic complexes with anticancer activity

Cinnamon – A Competent Drug: A Review on Extraction, Analysis and Anticancer Action

AbstractCinnamon, an Indigenous species, is extensively used as a folk medicine in India, China, and other parts of the world due to its therapeutic potential inherited via the latent chemical composition. The vital component presented is cinnamaldehyde, along with cinnamic acid and cinnamate, which contributes to being an anti‐inflammatory, antimicrobial, antidiabetic, and anticancer agent together with the capability to control neurological syndromes like Alzheimer's and even Parkinson's diseases. Given the importance of the anticarcinogenic properties of cinnamon on various cell strains concerning the curable effect, this review focuses on evaluating different extraction methods like steam distillation, Soxhlet extraction, microwave‐assisted extraction, and more, in addition to a summary of new technologies like gas chromatography, HPLC, DART‐MS, and NMR, etc. which paved the way in characterizing the chemical composition of cinnamon. Cinnamaldehyde showed its apoptosis through various mechanistic pathways on an adequate number of cell lines and antineoplastic potential on specific multifaceted cancerous cells, which advocates for continued research and investment in this vital area of drug discovery and suggestions for future scope.

In‐Silico Design of Novel Indole‐Selenide Derivatives as Potential P‐Glycoprotein Inhibitors Against Multi‐Drug Resistance in MCF‐7/ADR Cells: 2D‐QSAR, Molecular Docking, and Dynamics Simulations

AbstractIn this work, a set of thirty‐one novel indole‐selenide derivatives (C1–C31), reported recently as P‐glycoprotein inhibitors against multi‐drug resistance in MCF‐7/ADR cells, have been computationally investigated for the first time by in‐silico approaches, combining 2D‐quantitative structure‐activity relationship based virtual screening (2D‐QSAR‐VS) model, molecular docking, and dynamics simulations. The in‐silico study aims to design new potent molecules with higher anticancer inhibitory activity than observed with in‐vitro assays. The 2D‐QSAR model is built using multiple linear regression (MLR) techniques, and cross‐validated by internal and external parameters, applicability domain (AD) analysis, and Y‐randomization tests, corroborating the Golbreikh and Tropsha criteria. Subsequently, virtual screening was performed on the generated database, considering higher pIC50 values than the most effective in‐vivo C27 inhibitor. Subsequently, molecular docking and dynamics simulations were applied on the selected higher‐scoring ligands showing the best interactions with the PHE643, TYR745, and PRO571 amino acids of the P‐gp receptor (7 A6E), predicting dynamically stable complexes at the time‐scale of 200 ns. The in‐silico outcomes indicate that the selected new ligands have shown promising inhibitory activity for future anti‐cancer therapies, with perspective validating by in‐vitro and in‐vivo studies.

GD2 in Breast Cancer: A Potential Biomarker and Therapeutic Target.

Expression of disialoganglioside GD2 in normal tissues is primarily limited to the central nervous system, peripheral sensory nerve fibers, dermal melanocytes, lymphocytes, and mesenchymal stem cells. Its widespread overexpression in various cancer types allows it to be classified as a tumor-associated antigen with potential diagnostic and therapeutic implications. This article reviews the synthesis pathways of GD2 and its role in cancer cell adhesion, proliferation, and metastasis with a focus on breast cancer. GD2 appears to be overexpressed on the outer membrane of most breast cancer cells and breast cancer stem cells (BCSCs) and is closely linked to epithelial-mesenchymal transition (EMT). GD3 synthase (GD3S) is considered to be the rate-determining step in GD2 synthesis. Clinical studies indicate that GD2 expression is increased in 35-70% of breast cancer samples, with higher levels in triple-negative breast cancer (TNBC). This overexpression correlates with more aggressive tumor features and worse prognosis. Therapeutic targeting of GD2 with monoclonal antibodies (moABs) like dinutuximab and naxitamab has demonstrated anti-cancer activity in preclinical cancer models and human clinical trials against high-risk neuroblastoma reducing tumor growth and enhancing survival. GD2-specific chimeric antigen receptor (CAR) T-cell therapy and GD3S inhibition present other promising therapeutic strategies to improve clinical outcomes. Furthermore, GD2-targeted vaccines are currently being investigated in cancer therapy. This narrative review article underscores the critical role of GD2 in breast cancer pathogenesis and highlights the promising therapeutic opportunities it offers. It advocates for the initiation of clinical trials to further explore the potential of GD2-targeted treatment in combination with standard breast cancer therapies.