Search Results (17,849)

Head and neck cancer (HNC) remains a major therapeutic challenge due to high recurrence rates, limited efficacy of current treatments, and the frequent emergence of therapeutic resistance. Curcumin and its analogs have gained increasing interest as adjuvant compounds capable of potentiating the efficacy of conventional anticancer strategies, including chemotherapy with cisplatin, paclitaxel, and 5-fluorouracil, as well as radiotherapy. This review summarizes preclinical and translational evidence investigating combination approaches involving curcumin-based compounds and standard therapies in HNC models, highlighting their synergistic effects on tumor growth inhibition, apoptosis induction, modulation of therapy resistance mechanisms, and mitigation of treatment-related toxicity. Strategies aimed at overcoming the pharmacokinetic limitations of curcumin, including nanoformulations, co-delivery systems, and targeted delivery platforms, are also discussed. By integrating current evidence, this review highlights the translational potential of curcumin and its analogs as adjuvant agents in multimodal HNC therapy, while identifying current gaps in clinical validation, and outlining future directions for improving therapeutic efficacy and safety. Full article

Background: This study evaluates transdermal delivery of tamoxifen (TXN) as an alternative to the oral route of administration in treating breast cancer, which is the leading cause of cancer-related death in women globally. Oral TXN, a Class II drug, is associated with first-pass metabolism and serious side effects, including secondary cancers. Objectives: To enhance transdermal delivery, lipid-based transethosomes (TRS) were formulated using three different 2⁴ factorial designs with various non-ionic surfactants, including Tween 20^®, Span 20^®, and Span 80^®. Methods: Optimized TRS formulations were incorporated into HPMC-based gels and characterized for morphology, drug content, pH, viscosity, spreadability, ex vivo skin penetration, and deposition. Additionally, cytotoxicity and stability were assessed. Results: All TXN-TRS gels were suitable for transdermal use; however, Span 20^®-based TRS gel demonstrated the highest skin penetration (40.3 ± 1.5 µg/cm²), representing a 127-fold enhancement rate compared with the non-ethosomal TXN gel. In line with the enhanced penetration profile, cellular studies on MCF-7 cells showed concentration-dependent cytotoxicity, reaching 91.24 ± 1.01% inhibition at 2% w/w after 72 h, with an IC₅₀ value of 0.85 ± 0.02% w/w. Stability testing showed all formulations were more stable under refrigeration than at dry room temperature storage, supporting their potential as preclinical transdermal tamoxifen delivery platforms. Conclusions: Span 20^®-based TXN transethosomal gel markedly enhanced skin penetration while maintaining potent cytotoxic activity, supporting its further preclinical evaluation as a promising transdermal alternative to oral tamoxifen. Full article

Kaposi’s Sarcoma Herpesvirus (KSHV), an enveloped double-stranded DNA virus, is the etiological agent of Kaposi’s Sarcoma (KS), an endothelial cell-based tumor. KSHV is a leading cause of infection-related cancers in sub-Saharan Africa and immunocompromised individuals worldwide. Therefore, it is vital to identify the underlying mechanisms of viral infection and transmission to effectively identify specific therapeutic strategies and combat the disease. Here, we demonstrate that KSHV rewires the host cell lipidome during lytic infection. Bulk lipidomic analysis shows significant changes in the abundance of neutral lipids and phospholipids during lytic infection. We further investigated fatty acid binding proteins (FABPs) to understand the underlying mechanisms that support KSHV pathogenesis. Using the doxycycline-inducible iSLK.BAC16 cell line, we find that FABP genes are differentially regulated by lytic KSHV infection compared to latent infection. We report that FABP4 is significantly upregulated during lytic infection. FABP4 knockdown using siRNA or inhibition of the FABP4 protein via treatment with a competitive inhibitor during lytic infection significantly reduces extracellular viral titers, indicating that FABP4 supports maximal infectious virion production. This study highlights the role of FABP4 as a host target that facilitates KSHV infection and pathogenesis. Full article

Thanks to the rapid development of advanced analytical methods, researchers can now identify new, so far unknown applications for existing drugs. This expanding knowledge about the mechanisms of drug action, including interactions with various molecules and molecular pathways, not only enables more effective use of available therapies but also reduces both the time and cost of developing new therapeutic options. One of the proteins reported to interact with numerous drugs and chemicals is Translationally Controlled Tumor Protein (TCTP). Numerous studies have demonstrated that TCTP plays a crucial role in diverse biological processes, including cell growth, cell cycle regulation, cellular proliferation, allergic reactions, stress response, inhibition of apoptosis, calcium ion binding, interacting with microtubules and actin microfilaments, the progression of various cancers, and tumor reversion. Therefore, this review article aims to compile a list of drugs and substances shown to interact with TCTP and that, given TCTP’s numerous cellular functions, could be repurposed for other therapies. Full article

Approximately 30% of tumors contain an activating mutation in the oncogene KRAS, leading to increased cell proliferation that often promotes non-small cell lung cancers, colorectal adenocarcinomas, pancreatic ductal adenocarcinomas (PDAC), and other cancers. Among the most common point mutations in KRAS is G12D, an example of an oncogenic sequence present in tumor cells but not normal cells. We developed peptide nucleic acid (PNA) oligomers that selectively bind KRAS G12D sequences and fused them with novel cell-penetrating peptide flanking regions (CPP-PNA-G12D) then evaluated them. Electrophoretic mobility shift assays demonstrated in vitro binding to and selectivity for KRAS G12D over wild-type KRAS and KRAS G12C. Cells and nuclei were able to uptake CPP-PNA-G12D at high efficiency as shown by fluorescent microscopy and flow cytometry. Cell viability assays showed a striking dose-response effect in on-target cells expressing KRAS G12D, while relatively sparing off-target cells expressing KRAS G12C. CPP-PNA-G12D constructs were effective against a panel of PDAC cell lines and in female Balb/c mice bearing patient-derived xenografts. These results show promise for an enhanced PNA-delivery peptide conjugate strategy as a potential therapeutic strategy to selectively target KRAS mutant cancer cells, with the potential to expand this technology to additional cancer-derived mutant oncogenes. Full article

Cancer remains one of the leading causes of morbidity and mortality worldwide, highlighting the need for safe and effective therapeutic strategies targeting multiple oncogenic pathways. Cinnamon (Cinnamomum spp.) contains several bioactive phytochemicals with reported antioxidant and anticancer properties; however, their potential interactions with key cancer-associated signaling proteins have not been comprehensively investigated. In this study, an integrated computational and preliminary experimental approach was employed to evaluate four major cinnamon phytochemicals, namely e-cinnamaldehyde, eugenol, p-cymene, and cinnamic acid. Consensus molecular docking was performed using AutoDock Vina (v1.2.7), Smina (v2020.12.10), and GNINA (v1.3.3) against phosphoinositide 3-kinase (PI3K), nuclear factor kappa B (NF-κB), and mammalian target of rapamycin (mTOR). Docking analyses were complemented by protein-ligand interaction profiling, pharmacokinetic and toxicity prediction (ADMET), and a 100 ns molecular dynamics simulation with MM/GBSA binding free-energy analysis of the selected mTOR-p-cymene complex. In addition, the antioxidant activity and cytotoxic effects of a crude methanolic cinnamon bark extract were evaluated using in vitro antioxidant assays and MTT assays against HCT-116 and HT-29 colorectal cancer cell lines. Consensus docking predicted that all four phytochemicals were capable of interacting with the selected protein targets, although the predicted binding profiles varied among the compounds. Eugenol showed comparatively more favorable predicted interactions with PI3K, p-cymene produced the lowest predicted docking score for NF-κB, and cinnamic acid displayed a comparatively consistent predicted multitarget binding profile across PI3K, NF-κB, and mTOR. ADMET analysis suggested that all compounds satisfied major drug-likeness criteria and exhibited predicted oral bioavailability, although potential cytochrome P450 interactions and hepatotoxicity were predicted for some compounds. Molecular dynamics simulation indicated that the selected mTOR-p-cymene complex maintained a stable binding pose throughout the simulation, while MM/GBSA analysis yielded a modest binding free-energy estimate (ΔG_bind = −4.70 ± 8.20 kcal/mol), which should be interpreted cautiously because of the observed energetic variability. The crude methanolic cinnamon bark extract exhibited antioxidant activity and reduced the viability of HCT-116 and HT-29 colorectal cancer cells in a concentration-dependent manner. Collectively, these findings provide computational predictions of potential interactions between selected cinnamon-derived phytochemicals and cancer-associated signaling proteins and are consistent with the preliminary observation that the crude cinnamon extract exhibits antioxidant activity and cytotoxic effects in colorectal cancer cell lines. However, the computational analyses do not establish direct inhibition of the PI3K/NF-κB/mTOR signaling pathway, and the biological assays were performed using a crude extract rather than isolated phytochemicals. Therefore, further studies using purified compounds, biochemical target validation, pathway-specific cellular analyses, and in vivo models are required to determine whether the predicted protein-ligand interactions contribute to the observed biological activity. Full article

PARP1/2 inhibitors have received FDA approval for pancreatic cancer harboring BRCA1/2 mutations and homologous recombination (HR) deficiency; however, their limited indications restrict their broader clinical application. Previous studies have demonstrated that PARP7, a member of the PARP family, enhances tumor sensitivity to PARP1/2 inhibition. However, the mechanisms underlying their synergistic effects in pancreatic cancer remain unclear. Herein, we found that combined inhibition of PARP1/2 and PARP7 using Olaparib and XYL-1 significantly inhibited the proliferation of SW1990 and CFPAC cells compared with either single agent. Furthermore, XYL-1 and Olaparib cooperatively caused DNA damage and induced cell apoptosis in SW1990 cells. Consistently, combined treatment with XYL-1 and Olaparib significantly suppressed SW1990 tumor growth compared with single-agent treatment in mouse xenograft models, accompanied by elevated levels of phosphorylated H2AX in tumor tissues. Notably, bioinformatic analyses and mechanistic studies identified SCD1 and BRCA1 as key mediators of the synergistic antitumor effects of XYL-1 and Olaparib. More importantly, the combination of XYL-1 and Olaparib synergistically downregulated the expression of SCD1 and BRCA1, thereby impairing the HR-mediated DNA repair pathway. Collectively, these findings suggest that dual targeting of PARP7 and PARP1/2 may represent a promising therapeutic strategy for BRCA-proficient pancreatic cancer. Full article

Background/Objectives: The development of multifunctional small molecules capable of simultaneously addressing cancer progression and antimicrobial resistance represents an important challenge in medicinal chemistry. This study aimed to design, synthesize, and biologically evaluate a series of novel morpholine-based nitrogen-rich heterocyclic hybrids as potential anticancer and antibacterial agents, supported by computational investigations. Methods: Twelve morpholine-derived nitrogen-enriched heterocyclic hybrids incorporating pyran, triazine, pyrimidinone, and sulfur-containing scaffolds were synthesized and fully characterized using IR, ¹H NMR, ¹³C NMR, mass spectrometry, and elemental analysis. Their antiproliferative activities were evaluated against MCF-7 and HCT-116 cancer cell lines. The most active compounds were further investigated through kinase inhibition assays, cell cycle analysis, apoptosis, mitochondrial membrane potential, intracellular ROS determination, and apoptosis-related gene expression. Antibacterial, antibiofilm, antioxidant, and computational studies, including molecular docking, molecular dynamics simulations, MM-GBSA/MM-PBSA binding free-energy calculations, DFT calculations, and ADMET prediction, were also performed. Results: Compounds 3, 10, and 12 exhibited the highest antiproliferative activity, with compound 10 emerging as the lead candidate. It potently inhibited EGFR, PI3K, and mTOR, with IC₅₀ values of 0.086 ± 0.003, 0.107 ± 0.005, and 0.223 ± 0.008 μM, respectively. Mechanistic investigations revealed G₂/M arrest in MCF-7 cells and G₀/G₁ arrest in HCT-116 cells, accompanied by apoptosis rates of 32.66% and 37.12%; mitochondrial membrane depolarization; a 3.55-fold increase in intracellular ROS; upregulation of caspase-3, caspase-9, and Bax; and downregulation of Bcl-2, supporting activation of the intrinsic apoptotic pathway. Compound 10 also displayed the broadest antibacterial spectrum, surpassed ciprofloxacin against several tested isolates, exhibited MIC values of 5–20 μg/mL, achieved 42.80% inhibition of Pseudomonas aeruginosa biofilm formation, and showed the strongest antioxidant activity in DPPH and ABTS assays. Computational analyses supported the experimental findings by predicting stable interactions with EGFR and Staphylococcus aureus DNA gyrase, together with favorable MM-GBSA/MM-PBSA binding free energies of −23.44 and −24.99 ± 2.71 kcal/mol, respectively. Conclusions: The present findings identify compound 10 as a promising multifunctional lead with potent anticancer, antibacterial, antibiofilm, antioxidant, and multitarget kinase inhibitory activities. The combined biochemical, cellular, and computational findings support the proposed involvement of the EGFR/PI3K/mTOR signaling pathway in its antiproliferative activity and identify DNA gyrase as a potential antibacterial target. Nevertheless, the present study is limited to in vitro biological evaluation and computational investigations. Therefore, further in vivo efficacy studies, pharmacokinetic profiling, toxicity assessment, and experimental validation of the proposed molecular targets are warranted before considering preclinical development. Full article

Galectin-3-mediated processes are important during many aspects of cancer progression, but they are not well understood. Galectin-3 is present extracellularly, and because of its carbohydrate recognition domain (CRD) and unstructured N-terminal domain (NTD), galectin-3 undergoes multimerization, which influences events such as carbohydrate-controlled cell–cell interactions. Investigations reported herein using an in vitro wound-healing assay show that exogenous galectin-3 inhibits cancer cellular migration. Since the addition of the galectin-3 CRD without the NTD does not arrest cellular migration, we attribute the effect of full-length galectin-3 on migration to the extracellular interactions between multimeric, full-length galectin-3 and extracellular receptors. In this publication, lactose-functionalized dendrimers serve as multivalent binding partners for galectin-3 and are used to mitigate extracellular multivalent galectin/carbohydrate interactions. The addition of lactose-functionalized dendrimers provides significant restoration of cellular migration in the presence of exogenous galectin-3 without increasing cellular viability. Thus, although galectin-3/protein interactions within the cell are known to increase both cellular migration and viability, cell surface galectin-3/carbohydrate interactions have the opposite impact and decrease cellular migration. Full article

Imidazolium salt derivatives (IMSDs) represent a structurally diverse class of compounds that has attracted increasing interest as a source of novel anticancer agents due to their tunable chemical architecture and broad spectrum of biological activities. This review summarizes current advances in the development of organic imidazolium derivatives and metal–N-heterocyclic carbene (NHC) complexes, with particular emphasis on their structure–activity relationships (SARs), mechanisms of action, and therapeutic potential. Numerous IMSDs exhibit significant antiproliferative activity against a wide range of cancer cell lines through multiple mechanisms, including DNA damage, reactive oxygen species generation, mitochondrial dysfunction, thioredoxin reductase inhibition, cell-cycle arrest, and apoptosis induction. Among the reported compounds, Au(I)-, Pt(II)-, and Ag(I)-NHC complexes consistently demonstrate the highest cytotoxic potency, whereas hybrid derivatives incorporating pharmacologically active moieties, such as lithocholic acid, have been investigated as potential approaches to improving selectivity and multitarget activity. Current SAR analyses indicate that metal coordination, bulky aromatic substituents, molecular hybridization, and balanced lipophilicity are key determinants of enhanced biological activity. Despite these encouraging findings, most available evidence is limited to in vitro studies, while comprehensive in vivo evaluation, pharmacokinetic characterization, and systematic toxicological assessment remain insufficient. Consequently, the clinical relevance of these compounds has yet to be established. Future research should focus on rational structural optimization, standardized preclinical evaluation, combination therapies, and advanced drug delivery strategies, including nanomedicine, to facilitate the translation of IMSDs into clinically useful anticancer agents. Full article

Background/Objectives: Metformin is a prominent candidate for cancer drug repurposing, backed by preclinical and epidemiological evidence showing reduced cancer incidence in diabetic patients. Its pleiotropic effects include AMPK activation, protein synthesis inhibition, and metabolic alterations. This review integrates global preclinical data via a comprehensive tabular overview alongside a cross-analysis of specific investigations of hamster fibrosarcoma. Since head-to-head comparisons of metformin-based combinations on hamster fibrosarcoma remain limited, this work performs an integrated cross-study evaluation to establish a clear comparative hierarchy of various repurposed adjuvants combined with metformin. Methods: A literature review and cross-study re-analysis of peer-reviewed preclinical studies were conducted, focusing on in vivo therapeutic outcomes within the BHK-21/C13-induced hamster fibrosarcoma model. Treatment regimens from distinct primary studies were evaluated side-by-side using tumor endpoint data expressed as a percentage of control mean (± SD). Only statistically significant pairwise differences (p < 0.05) determined the comparative hierarchy. Results: Integrated analysis identified disulfiram and diclofenac as the most promising adjuvants among compared metformin combinations, showing the highest statistical significance across all evaluated endpoints. The statistical ranking of the metformin-based combinations followed a descending order: disulfiram, diclofenac, nitroglycerin, itraconazole, and caffeine. Conclusions: By synthesizing previously fragmented primary data into a unified comparative framework, these findings provide a strong, consolidated preclinical rationale for metformin-based combination strategies. The established hierarchy of adjuvant potency resolves structural ambiguity and supports further translational and clinical investigation to evaluate their therapeutic potential in fibrosarcoma and other malignancies. Full article

Background: Colorectal cancers (CRCs) harboring the BRAFV600E (V600E) mutation exhibit aggressive clinical behavior and chemotherapy resistance, yet the underlying mechanisms remain poorly understood. Ferroptosis, which is driven by iron-dependent lipid peroxidation, has emerged as a potential therapeutic vulnerability. This study aimed to explore whether the NF-κB/Lipocalin 2 (LCN2) pathway modulates cisplatin sensitivity through Fenton-reaction-induced ferroptosis in BRAFV600E-overexpressing CRC cells. Methods: BRAF mutation status and the expression of LCN2, PTGS2, and cleaved caspase3 were examined in clinical CRC specimens by immunohistochemistry. The correlations between ferroptosis and apoptosis markers and 5-year survival rate were evaluated in TCGA datasets. CRC cells with LCN2 knockdown/knockout or BRAF/V600E/LCN2 overexpression were established to assess the proliferation, lipid metabolism, iron levels, and NF-κB/LCN2 signaling under cisplatin treatment. In vivo studies were employed with BALB/c xenograft models. Results: V600E-mutant clinical specimens exhibit significantly reduced expression of the ferroptosis marker PTGS2, and the iron metabolism regulators LCN2. Within a KRAS-mutant cellular model, V600E overexpression attenuated cisplatin-induced ferroptosis through suppression of the NF-κB/LCN2 signaling axis, leading to impairment of Fenton-reaction-mediated lipid peroxidation. Restoration of LCN2 expression re-sensitized V600E-overexpressing cells to cisplatin both in vitro and in vivo. Interestingly, inhibition of apoptosis contributes to the resistance of cisplatin induced ferroptosis in V600E overexpression cells, implying a crosstalk between ferroptosis and apoptosis within the therapeutic resistance. Conclusions: Our findings show that the NF-κB/LCN2 axis drives Fenton-reaction-induced ferroptosis to promote the vulnerability of V600E overexpression CRC cells within a KRAS-mutant background to cisplatin. LCN2 restoration partially overcomes V600E overexpression resistance both in vitro and in vivo, suggesting LCN2 as a promising therapeutic target. The crosstalk between ferroptosis and apoptosis may offer potential strategies to overcome chemotherapy resistance of this high-risk CRC subtype. Full article

Cancer prevention through dietary intervention utilizing bioactive natural compounds has garnered significant attention due to the therapeutic limitations of conventional cancer treatments. These plant-derived active compounds, including polyphenols, terpenoids, organosulfur compounds, bioactive peptides, and alkaloids, possess potent anticancer properties. This systemic review addresses a critical gap in the scientific literature by elucidating the precise multitargeted oncogenic regulatory mechanisms of these molecules. A comprehensive methodology was employed, involving a systematic literature search across major electronic databases (including PubMed, Web of Science, Embase, and SCOPUS) to identify relevant original peer-reviewed studies. The evidence gathered demonstrates that these active compounds deliver significant health benefits and protect cells by modulating crucial molecular targets involved in cell cycle regulation, apoptosis, oncogenic signaling, epigenetic control, angiogenesis, oxidative stress, and inflammation. Specifically, they operate via multi-targeted cascades, such as inhibiting the PI3K/Akt, NF-κB, and STAT3 pathways. To provide a clear structural overview, these active compounds are categorized comprehensively based on their botanical and structural origins, including spices, fruits, and rhizomes. However, despite their promising bioactivities, these compounds have not yet been fully translated into clinical therapy due to challenges such as low bioavailability, rapid metabolism, limited systematic exposure, and a lack of convincing evidence from large-scale clinical trials. Although most current evidence remains rooted in in vitro and experimental animal models, clinical validation through high-quality trials is still required. Ultimately, this review underscores the potential of these active compounds and highlights how advances in formulation and nano delivery strategies offer promising solutions for effective cancer prevention. Full article

Adenosine deaminase acting on RNA 1 (ADAR1) is a critical regulator of innate immune signaling and a pan-cancer therapeutic target. Through catalyzing adenosine-to-inosine (A-to-I) editing and editing-independent mechanisms, ADAR1 suppresses activation of dsRNA sensing pathways, including protein kinase R (PKR), melanoma differentiation-associated protein 5 (MDA5), and oligodenylate-synthetase (OAS) signaling, that are critical for maintaining cellular tolerance to endogenous RNAs. In a subset of tumors characterized by elevated interferon-stimulated gene (ISG) expression and dsRNA stress, this function creates a dependency on ADAR1 for survival, establishing a therapeutic vulnerability that can be exploited to induce viral mimicry in cancer cells and enhance anti-tumor immune responses. Here, we review the emerging landscape of ADAR1 modulators, organizing reported compounds into mechanistic classes including nucleoside analogs, catalytic inhibitors, Zα domain modulators, RNA substrate engagement inhibitors, indirect pathway regulators, and PROTACs. We evaluate molecules within these classes with a focus on their mechanisms of action and experimental validation. We further discuss the challenges associated with distinguishing direct inhibition of ADAR1 activity from broader effects on RNA metabolism and innate immune activation. Finally, we highlight the therapeutic potential of ADAR1 targeting defined cancer subsets and examine combination strategies that leverage ADAR1 inhibition for improved sensitivity to current cancer therapeutics. Overall, this review outlines key considerations for the development of selective therapies targeting ADAR1. Full article

Drug resistance arising during cancer development and progression remains a major challenge in the treatment of epidermal growth factor receptor (EGFR)-driven tumors, particularly those harboring the clinically relevant T790M/L858R double mutation. In this study, we developed an integrated computational workflow combining explainable machine learning, virtual screening, molecular dynamics simulations, and binding free-energy calculations to identify novel inhibitors of this drug-resistant EGFR variant. An XGBoost regression model was trained using scaffold-aware cross-validation, Bayesian hyperparameter optimization, and sequential feature selection, resulting in a compact model based on 16 molecular descriptors. The model demonstrated robust predictive performance on external validation data, while SHAP analysis identified descriptors related to the local electronic environment, fragment distribution, and molecular topology as the primary contributors to activity prediction. The optimized model was subsequently applied to screen compounds from the Enamine REAL database. Top-ranked candidates were evaluated using explicit-solvent molecular dynamics simulations and MM/GBSA binding free-energy calculations. Several compounds formed stable protein–ligand complexes and maintained key interactions with residues known to be important for EGFR inhibition, including Lys745, Met790, and Leu718. These results demonstrate that the proposed workflow can efficiently prioritize computational candidates of drug-resistant EGFR mutants and may support the development of new therapeutic strategies for overcoming resistance in EGFR-driven cancers. Full article