Search Results (827)

Chronic inflammation and cyclooxygenase (COX)-2–mediated prostanoid signaling contribute to melanoma progression, yet their modulation by natural products remains poorly defined. We examined the effects of dogwood fruit extracts—Japanese cornel (Cornus officinalis) and two European cultivars (‘Uholok’, ‘Yantarnyi’)—on temporal prostanoid dynamics in A375 (primary tumor–derived) and MeWo (metastasis-derived) mela-noma cells. Dynamic changes rather than static levels were modeled using GAMLSS or zero-inflated Gamma models to assess time, cell line, cornel type, and dose effects. Untreated A375 cells showed time-dependent increases in PGE₂, PGF_2α, thromboxane B₂, and 13,14-dihydro-PGE₁, consistent with inducible COX-2 activation, whereas MeWo cells maintained consistently high prostanoid levels, reflecting constitutive COX-2 expression. Cornus extracts modulated these trajectories in a cell- and dose-dependent manner. In A375, low concentrations allowed prostanoid accumulation, while higher doses flattened or reversed these increases; Japanese cornel produced the strongest inhibition, whereas European cultivars showed weaker or cultivar-specific effects. MeWo cells were less responsive, with significant changes emerging only at higher doses. PGD₂ and 6-keto-PGF_1α remained largely unchanged, indicating selective targeting of COX-2–dependent prostanoids. Extracts also reduced accumulation of downstream prostanoids, including 15-deoxy-Δ¹²,¹⁴-PGJ₂ and 13,14-dihydro-PGE₁, particularly in A375 cells. These differences highlight a stronger susceptibility of early-stage melanoma to phytochemical intervention and support cultivar-dependent bioactivity linked to phytochemical composition. In summary, Cornus extracts selectively attenuate time-dependent trajectories of tumor-promoting prostanoids—most effectively with Japanese cornel—while sparing homeostatic mediators, warranting further investigation on their potential for melanoma chemoprevention or adjunctive therapy. Full article

Cancer development arises from dynamic interactions between inherited susceptibility and modifiable environmental exposures, among which diet plays a central role. Carotenoids, lipophilic plant-derived pigments including lycopene, α-carotene, and β-carotene, and retinoids, the vitamin A derivatives that regulate gene transcription via retinoic acid receptors (RARs) and retinoid X receptors (RXRs), have been extensively investigated for their chemopreventive and therapeutic potential. This review aims to provide an integrated, mechanism-based synthesis of the roles of lycopene, α- and β-carotene, and retinoids in cancer chemoprevention and to clarify the conditions under which they are most likely to be effective. Beyond summarizing established antioxidant and nuclear-receptor mechanisms, we highlight as a novel emphasis the epigenetic actions of these compounds, including effects on DNA methylation, histone modification, and microRNA regulation, and we integrate these with the well-recognized divergence between dietary and high-dose supplement outcomes. Experimental evidence demonstrates that carotenoids modulate oxidative stress, inflammation, proliferation, apoptosis, angiogenesis, and metastasis through pathways such as Nrf2/ARE, NF-κB, STAT3, Akt/mTOR, MAPK, and Wnt/β-catenin. Lycopene, in particular, exhibits strong antioxidant capacity and multi-target signaling effects, while provitamin A carotenoids additionally influence retinoid-mediated transcriptional programs. Retinoids exert broader differentiation-inducing and antiproliferative effects through direct nuclear receptor signaling and represent one of the few successful differentiation therapies in oncology, most notably in acute promyelocytic leukemia. Epidemiologic studies generally associate higher dietary carotenoid intake with reduced risk of several malignancies, including prostate, breast, lung, colorectal, and gastric cancers. However, randomized trials of isolated high-dose supplementation, particularly β-carotene in smokers, have demonstrated null or harmful effects, highlighting a critical divergence between whole-food dietary patterns and pharmacologic supplementation. In conclusion, carotenoids and retinoids possess biologically plausible anticancer properties, yet their clinical utility remains context dependent. Future research should prioritize biomarker-guided, precision-based strategies, standardized formulations, and whole-food dietary approaches to clarify their role in cancer prevention and treatment. Full article

Xanthohumol (XN), a prenylated chalcone isolated from Humulus lupulus L., exhibits a wide range of biological activities, including antioxidant, anti-inflammatory, and chemopreventive effects. However, its therapeutic application is limited by poor aqueous solubility, low chemical stability, and rapid clearance from the systemic circulation. The present study aimed to develop and characterize a novel nano-sized drug-delivery system for XN that combines favourable colloidal stability, efficient encapsulation, sustained release, and reduced recognition by macrophages (“stealth-like” properties). To achieve this, XN-loaded cationic liposomes were coated with two marine polysaccharides, iota-carrageenan (CAR) and fucoidan (FUC), followed by Ca²⁺-mediated cross-linking. Liposomes were prepared by the ethanol injection method, and formulation parameters were optimized using a 2³ + 1 full factorial design. Surface modification and cross-linking conditions were further optimized through polyelectrolyte titration and a Taguchi L9 orthogonal array. The resulting nanocarriers were evaluated for particle size, polydispersity, ζ-potential, encapsulation efficiency, release behavior, and cellular uptake. Both coatings significantly prolonged XN release compared with uncoated liposomes, with CAR-coated vesicles providing the most sustained release (≈55% over 48 h). In RAW264.7 macrophages, 50 µg/mL CAR-coated liposomes reduced cellular uptake by approximately 74% following 1-h incubation relative to uncoated controls and maintained this reduction over 2 h whereas FUC-coated vesicles afforded only transient early evasion. The cross-linked iota-carrageenan coating thus represents a promising strategy for conferring stable “stealth-like” characteristics to XN-loaded liposomes intended for prolonged drug delivery. Full article

Breast cancer remains one of the leading causes of cancer-related mortality among women worldwide, highlighting the need for safer and more effective chemopreventive strategies. Although many phytochemicals can modulate key molecular processes involved in breast carcinogenesis, their chemopreventive potential largely depends on delivery strategies that preserve their biological activity and enable efficient accumulation at the target site. Protein-based nanocarriers have emerged as promising delivery systems capable of improving the protection, solubility, cellular uptake, targeted delivery, and controlled release of bioactive compounds in tumor tissues. This review summarizes recent advances in selected animal- and plant-derived protein nanocarriers used for the encapsulation and delivery of natural compounds in breast cancer chemoprevention. Particular attention is given to their physicochemical properties, encapsulation performance, release behavior, biological activity, targeting potential, and translational limitations. Furthermore, the mechanisms underlying the enhanced anticancer activity of encapsulated phytochemicals, including improved stability, receptor-mediated uptake, pH-responsive release, apoptosis induction, oxidative stress modulation, and inhibition of tumor growth and metastasis, are highlighted. Current challenges, including enzymatic degradation, formulation instability, immunogenicity concerns, manufacturing scalability, and limited clinical evidence, remain important barriers to translation. Overall, selected protein-based nanocarriers represent promising multifunctional platforms for improving the chemopreventive potential of natural compounds in breast cancer. Full article

Colorectal cancer (CRC) is a major global health threat, necessitating the development of functional foods with chemopreventive potential. This study aimed to evaluate the modulation of the anticancer activity of Hericium erinaceus with different iron forms (FeCl₃, FeSO₄, and FeHBED) as it modulates its anticancer activity against HT-29 cells. The extracts were subjected to simulated in vitro digestion and analyzed for cytotoxicity (MTT), antioxidant capacity (DPPH), and morphological changes, alongside high-throughput RT-qPCR profiling of 92 cancer-related genes. The results demonstrated that iron speciation is critical, with FeHBED-biofortified extracts exhibiting the most potent concentration-dependent cytotoxic and antiproliferative effects. Treated cells displayed apoptotic morphology, including chromatin condensation and cell shrinkage. Molecular analysis revealed significant downregulation of key oncogenes (HRAS, MYC), cell cycle regulators (CDK4), and migration markers (RHOA, ITGB1), whereas VEGFA was upregulated as a stress-induced response. In conclusion, biofortification with FeHBED significantly enhanced the anticancer potential of H. erinaceus by targeting specific proliferative and survival pathways. These findings highlight the potential of iron-biofortified mushrooms as a functional dietary component for colorectal cancer prevention. Full article

Background: Apoptosis is a fundamental process for maintaining tissue homeostasis, and its dysregulation is closely linked to the development of numerous diseases, including colorectal cancer. In recent years, dietary polyphenols have gained interest due to their antioxidant, pro-apoptotic, and chemopreventive properties. Artichoke (Cynara scolymus L.) by-products are rich source of hydroxycinnamic acids and flavonoids, making them promising source of bioactive compounds. Methods: In this study we evaluated the cytotoxic and pro-apoptotic activity of four aqueous extracts obtained from artichoke bract by-products, including one commercial hybrid (CAPB) and three local Apulian varieties (BriB, VaMB, LMTB), in human colorectal adenocarcinoma cell lines (Caco-2 and HT29). The extracts were characterized according to their total polyphenol content and phenolic profile. Results: The selected artichoke by-product extracts exhibited significant cytotoxic effects both in a concentration- and time-dependent manner, with concentrations ≥ 2 mg/mL significantly reducing cell viability and nearly abolishing it at 4 mg/mL after 48 h. Moreover, treatment with the extracts modulated the expression of apoptosis-related proteins, characterized by an increase in pro-apoptotic markers (Bax, caspase-9, caspase-3) and a decrease in the anti-apoptotic protein Bcl-2, suggesting activation of the mitochondrial apoptotic pathway. In particular, the BriB extract was able to induce an apoptosis rate higher than 80% in Caco-2 cells and achieved comparable rates in HT29 cells at concentrations of 2–3 mg/mL. Conclusions: Overall, these findings demonstrate that artichoke by-product extracts exert significant pro-apoptotic effects in colorectal cancer cells and highlight their potential as sustainable sources of bioactive compounds for nutraceutical or adjuvant anticancer applications. Full article

N-nitrosamines and acrylamide are food mutagens classified as “probably carcinogenic to humans (Group 2A)” by the International Agency for Research on Cancer (IARC) from evidence of carcinogenicity. One of the main objectives of food safety is to reduce the presence of these substances in food. Therefore, the present study aimed to evaluate the effect of the addition of propolis, royal jelly or a combination of both bee products (2–10%) to chestnut and thyme honey on their protective properties against food mutagen-induced genotoxicity. DNA damage was evaluated by the alkaline comet assay. N-nitrosamines (N-nitrosodimethylamine (NDMA) and N-nitrosopyrrolidine (NPYR)) and acrylamide (AA) induced genotoxicity in human hepatoma HepG2 cells. All tested samples at all concentrations used (0.1–10 µg/mL) decreased genotoxic effects of the three food mutagens. The protective effects of honey samples and mixtures towards DNA damage induced by food mutagens were in the following order: NDMA > AA > NPYR, being more effective against NDMA compared to AA and NPYR. The mixtures of chestnut honey with 10% propolis, or 10% royal jelly, and 10% propolis showed a greater protective effect against NDMA, NPYR and AA compared to the honey sample alone. This protective activity may be attributable to the phenolic compound content and antioxidant capacity exhibited by the analyzed samples. Overall, the results suggest that thyme and chestnut honey supplemented with bee-derived products could represent potential natural chemopreventive candidates against food-borne mutagens. Full article

Natural compounds are increasingly explored as complementary strategies to enhance the effectiveness of chemotherapy and reduce toxicity. Among these are isothiocyanates (ITCs), bioactive metabolites derived from glucosinolates in cruciferous vegetables, which have gained substantial attention for their chemopreventive and antileukemic potential. ITCs exert diverse biological effects driven by the high reactivity of the –NCS group, enabling covalent modification of key cellular proteins and modulation of signaling pathways. Well-studied representatives, including sulforaphane (SFN), allyl isothiocyanate (AITC), 6-(methylsulfinyl)hexyl isothiocyanate (6-MITC), benzyl isothiocyanate (BITC), and phenethyl isothiocyanate (PEITC), exhibit diverse antileukemic activities, including cytotoxic, pro-apoptotic, differentiation-inducing, and cell-cycle-modulating effects. Although individual compounds differ in their relative potency and predominant biological responses, their activities are generally mediated through multiple interconnected mechanisms including oxidative stress modulation, mitochondrial dysfunction, regulation of apoptosis-related proteins, and interference with key signaling pathways. In addition to apoptosis, several ITCs have also been reported to induce autophagy, ferroptosis, or cellular differentiation in leukemic cells. Taken together, the existing evidence highlights ITCs as promising candidates for leukemia chemoprevention or therapy, acting through multi-targeted mechanisms that may complement conventional treatment strategies. Further studies are needed to clarify their selectivity, mechanistic diversity, and translational potential. Full article

Cutaneous squamous cell carcinoma (cSCC) is one of the most common non-melanoma skin cancers worldwide. Although surgery and adjuvant therapies are often effective, the treatment of high-risk or advanced lesions remains challenging due to recurrence, resistance, toxicity, and limited long-term control. Natural compounds have, therefore, gained interest as multi-target agents for cancer prevention and treatment. This systematic review aimed to evaluate the antitumoral activity of natural compounds against cSCC. A systematic literature search was conducted following PRISMA 2020 guidelines. Sixty studies met the inclusion criteria and were analyzed using a conservative, mechanism-based classification framework. The included studies evaluated purified compounds, crude extracts, essential oils, formulations, and combination treatments. Despite chemical diversity, antitumoral activity converged on defined biological processes, including apoptosis, non-apoptotic regulated cell death, redox modulation, oncogenic signaling inhibition, cell-cycle arrest, epigenetic regulation, photodynamic ROS generation, and chemopreventive or immune-mediated mechanisms. Mechanistic specificity was higher among purified compounds, while complex extracts showed broader, context-dependent effects. Several agents demonstrated consistent in vitro and in vivo activity, which supports their translational relevance. Natural compounds target shared biological vulnerabilities in cSCC through mechanistically convergent pathways. The framework presented here supports mechanism-guided prioritization and may facilitate the translation of promising compounds into clinically relevant strategies. Full article

Skin cancer presents a significant global health burden with rising incidence. The side effects of current therapies and the emergence of drug resistance necessitate the exploration of alternative and complementary strategies. Natural products, with their long history of use in treating skin disorders, have emerged as a promising source of novel therapeutic agents. This review comprehensively elucidates the potential efficacy of natural bioactive compounds in both preventing and treating skin cancer. We summarize the molecular mechanisms through which key natural bioactive compounds exert their anti-skin cancer effects, including induction of apoptosis, inhibition of proliferation and metastasis, anti-inflammatory and antioxidant activities, DNA damage repair, and photoprotection. Furthermore, we discuss the biological barriers relevant to skin cancer therapy using natural bioactive compounds and link them to corresponding delivery strategies, while identifying key translational challenges. In conclusion, natural bioactive compounds offer a multi-targeted and synergistic approach against skin carcinogenesis, holding substantial promise as sources of adjuvant therapies and chemopreventive agents to improve patient outcomes. Full article

Background: Cardiotoxicity remains a major concern in breast cancer management, with implications for prognosis and quality of life. Natural compounds have shown chemopreventive potential while preserving cardiac safety. This study evaluated the cardiac effects of a Santolina chamaecyparissus aqueous extract (SCE), characterized by high levels of 1,3-O-dicaffeoylquinic acid and myricetin-O-glucuronide, in female Wistar rats subjected to N-methyl-N-nitrosourea (MNU)-induced mammary carcinogenesis. Methods: Twenty-eight animals were assigned to four groups (n = 7/group): control (CTRL), MNU-induced (IND), SCE-supplemented (SCE), and MNU-induced SCE-supplemented (SCE+IND). SCE was administered in water (120 µg/mL) for 20 weeks, and MNU was injected intraperitoneally (50 mg/kg) at 50 days of age. At the end of the experiment, body and heart weights were recorded, creatine kinase MB (CK-MB) concentrations assessed, and echocardiography performed to evaluate cardiac structure and function. Results: Final body and relative heart weights did not differ among groups. CK-MB was lower in SCE-supplemented groups compared with CTRL and IND (p < 0.05). IND animals exhibited a hyperdynamic functional profile accompanied by impaired ventricular filling, which was attenuated in SCE+IND animals (p < 0.05). Cardiac structural parameters were largely preserved with SCE, despite an increased left ventricular mass (p < 0.05). Conclusions: SCE did not induce adverse cardiac effects and partially mitigated early carcinogenesis-associated cardiac alterations under the tested conditions, supporting its cardiac safety as a potential phenolic-rich chemopreventive strategy. Full article

Head and neck squamous cell carcinoma (HNSCC) remains an immunosuppressive and metabolically dysregulated malignancy, contributing to tumor progression and resistance to conventional therapies. Natural compounds offer a unique multi-target opportunity to address these challenges, with berry-derived phytochemicals emerging as particularly promising candidates. Preclinical evidence demonstrates that these compounds modulate dendritic cell activation, macrophage polarization, regulatory T cell function, and cytokine signaling, restoring immune balance while simultaneously regulating tumor metabolism and reducing chronic inflammation. Beyond these immunometabolic effects, berry-derived compounds influence glucocorticoid signaling at the endocrine–immune interface, alleviating additional immunosuppressive pressures within the tumor microenvironment. Early clinical studies support the feasibility of standardized berry-derived formulations as adjunctive agents. In patients with oral premalignant lesions and HNSCC, black-raspberry-based interventions including topical gels and oral troches, have demonstrated favorable safety profiles, measurable tissue uptake of bioactive phytochemicals, modulation of proliferation and inflammation-associated biomarkers (e.g., Ki-67, COX-2, and NF-κB), and partial histologic regression in a subset of lesions. Collectively, these pleiotropic actions highlight chemopreventive potential and provide a mechanistic rationale for combinatorial strategies with immune checkpoint inhibitors targeting PD-1/PD-L1 and CTLA-4. Opportunities for both local and systemic delivery may further enhance therapeutic efficacy. Integrating these natural compounds into precision chemoprevention and immunotherapy paradigms could inform rational drug discovery, biomarker-driven patient stratification, and combination therapy design. This review highlights the convergent immunologic, metabolic, and endocrine-targeted mechanisms of berry-derived phytochemicals in HNSCC and emphasizes their translational potential as integrative modulators of antitumor immunity. Full article

Background/Objectives: Aspirin-based colorectal cancer (CRC) chemoprevention remains a promising yet individually variable strategy. As a proof-of-concept toward future personalized chemoprevention frameworks, we aimed to develop and validate machine learning (ML) models capable of distinguishing aspirin-exposed from placebo-exposed participants based on their plasma metabolomic signatures, thereby characterizing the metabolomic footprint of aspirin administration rather than directly predicting clinical chemoprevention benefit. Methods: Training was performed on the Aspirin/Folate Polyp Prevention Study (AFPPS) dataset ST001422 (n = 300) and external validation on ST001423 (n = 223). After multi-method consensus feature selection, reducing 19,433 features to 300, sixteen ML and deep learning (DL) architectures were benchmarked under nested cross-validation. Model interpretability was assessed using SHapley Additive exPlanations (SHAP) and Local Interpretable Model-agnostic Explanations (LIME) analyses. Results: GBM_sklearn achieved the highest cross-validation Precision–Recall AUC (PR-AUC) of 0.945, while ensemble stacking (Stack_LGB) offered superior calibration (Brier = 0.117). DL models consistently underperformed traditional ML (PR-AUC: 0.673–0.843 vs. 0.881–0.945), attributable to limited sample size. SHAP and LIME analyses independently identified m/z 196.0604 (C18, RT 89.4 s) as the top metabolic biomarker, consistent with aspirin-induced glycerophospholipid pathway alterations. External validation performance degraded substantially (PR-AUC: 0.945 → 0.711), attributable to inter-study analytical batch effects. Conclusions: This framework demonstrates the feasibility of metabolomics-driven personalized chemoprevention. Although the high feature-to-sample ratio (300:300) and the substantial drop between internal and external performance indicate that the cross-validation estimates likely include dataset-specific noise in addition to the true biological signal. While highlighting batch harmonization and aggressive feature reduction (e.g., LASSO/RFE-based selection of 10–20 high-impact metabolites) as a prerequisite for clinical translation. Full article

Head and neck cancers (HNCs) represent a major global health burden and remain associated with substantial morbidity and limited therapeutic options, particularly in advanced or recurrent disease. Increasing interest has focused on naturally derived bioactive compounds with potential chemopreventive and therapeutic properties. Sulforaphane, a dietary xenobiotic isothiocyanate derived from glucoraphanin in cruciferous vegetables, has attracted attention due to its ability to modulate redox balance, epigenetic regulation, and multiple oncogenic signaling pathways. This manuscript reviews current evidence regarding the biological effects of sulforaphane in HNCs. Particular attention is given to the molecular mechanisms underlying its modulation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, a key regulator of cellular antioxidant and detoxification responses that can be activated by sulforaphane. Several studies indicate that sulforaphane can inhibit tumor growth through several mechanisms beyond Nrf2 activation, including induction of apoptosis, cell cycle arrest, epigenetic modulation, and suppression of oncogenic signaling pathways. In addition, sulforaphane has been shown to enhance the efficacy of conventional treatments, including chemotherapy, radiotherapy, and photodynamic therapy. Overall, the literature suggests that sulforaphane may represent a promising chemopreventive or therapeutic adjunct in HNC, although further clinical investigation is required to clarify its translational potential. Full article

Nicotinamide (NAM), the amide form of vitamin B3, has gained increasing attention in dermatology due to its potential role in both skin aging and non-melanoma skin cancer (NMSC) prevention. This review summarizes the biological rationale and current clinical evidence supporting the use of NAM and other NAD⁺ precursors in photoaging and cutaneous carcinogenesis. Chronic ultraviolet exposure induces DNA damage, oxidative stress, inflammation, immune dysregulation, and extracellular matrix remodeling, linking photoaged skin to increased susceptibility to actinic keratoses (AKs), squamous cell carcinoma (SCCs), and basal cell carcinoma (BCCs). Through the NAD⁺ salvage pathway, NAM contributes to the maintenance of intracellular NAD⁺ pools, thereby influencing energy metabolism, DNA repair, mitochondrial function, redox homeostasis, and the activity of NAD⁺-dependent enzymes. Preclinical studies indicate that NAM enhances DNA repair, reduces oxidative stress and inflammatory signaling, supports autophagy and mitophagy, and improves epidermal barrier function and extracellular matrix integrity. Clinically, the strongest evidence for anti-aging effects concerns topical NAM, which consistently improves wrinkles, texture irregularities, pigmentation, and barrier function. Oral NAM has demonstrated chemopreventive activity in high-risk patients with previous NMSC, particularly by reducing the incidence of new SCCs and AKs during active treatment. However, despite a strong mechanistic rationale, current evidence remains heterogeneous, and additional long-term, skin-focused clinical trials are needed to better define efficacy, safety, optimal dosing strategies, and patient selection. Full article