Search Results (1,447)

Background: Former and current smokers in lung cancer screening remain at elevated risk for lung cancer despite smoking cessation. We and others have shown that curcumin (CUR) exhibits anti-inflammatory and antiproliferative effects but is limited by poor bioavailability. However, since CUR is lipophilic, co-administration with ω-3 FAs represents a mechanistically rational strategy to enhance delivery and target complementary pathways, including signal transducer and activator of transcription 3 (STAT3) and the transcription factor NF-κB (NF-κB) signaling for lung cancer chemoprevention. Methods: We conducted a randomized, single-blind, placebo-controlled Phase II pilot study evaluating CUR combined with ω-3 FAs in high-risk former and current smokers with CT-detected pulmonary nodules. Participants received intervention agents with active-dose groups (low dose = 3; high dose = 9) or a placebo (n = 7) for 6 months. Primary endpoints included radiologic changes in nodule size, number, and density. Secondary endpoints included safety, adherence to the study agent and exploratory biomarker analyses. Correlation analyses of imaging-derived metrics were performed to assess relationships among LDCT parameters. Results: Nineteen participants were enrolled (intervention, n = 12; placebo, n = 7). Eighteen (11 intervention, 7 placebo) subjects completed post-intervention imaging. One subject was unable to complete follow-up and study-related procedures. Data from the treatment arms were pooled for analysis and comparison with the placebo arm. No statistically significant between-group differences were observed in primary imaging endpoints. The intervention was well tolerated, with predominantly grade 1 adverse events. Exploratory analyses demonstrated consistent positive correlations among established imaging biomarkers, with clustering of size-based metrics (mean diameter, volume, sum of longest diameters) and density-based parameters. Multidimensional scaling supported this structure, indicating internal coherence among imaging-derived endpoints. Conclusions: Although no statistically significant treatment effect on the image biomarkers was observed, this pilot study demonstrates feasibility challenges and identifies coherent imaging biomarkers that may serve as intermediate endpoints in early-phase chemoprevention trials. These results support further investigation of strategies utilizing agent combinations with enhanced bioavailability and safety and refinement of trial design in high-risk lung cancer patient populations. Full article

Background/Objectives: Skin cancer is a major health concern worldwide and has led to the quest for safer and more effective topical chemopreventive agents. In this study, the in vivo efficacy of a hydrogel formulation containing kaempferol and ferulic acid-loaded nanoparticles was evaluated for the management of DMBA-croton oil-induced skin cancer in Swiss albino mice. Methods: Drug-loaded nanoparticles prepared via nanoprecipitation were incorporated into hyaluronic acid to obtain single-drug (FAPG, KMPG) and dual-drug-loaded (FKMG) hydrogel formulations. Skin tumors were induced via DMBA as an initiator followed by croton oil as a promoter, with tumor onset observed after a similar latency period of approximately 5–6 weeks in all carcinogen-exposed groups. Treatment was initiated after week 6 and continued until week 16. Results: The gel formulation had a skin-compatible pH and the desired rheological and spreadability properties. The dual drug-loaded hydrogel formulation had a more controlled and prolonged release profile. Compared with the negative and vehicle control groups, the FKMG-treated group presented a marked reduction in tumor incidence and tumor burden, along with improved body weight gain. Biochemical analysis revealed the restoration of antioxidant and enzyme activity in treated animals, particularly in animals treated with FKMG. Histopathological examination revealed near-normal skin architecture in FKMG-treated mice, indicating strong protective effects. Additionally, significant downregulation of TNF-α and IL-6 suggested effective suppression of tumor-promoting inflammatory pathways. Conclusions: Overall, the FKMG formulation exhibited superior chemopreventive efficacy compared with the FAPG and KMPG treatments, highlighting its potential as a promising topical therapeutic strategy against chemically induced skin carcinogenesis. Full article

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

Cervical cancer (CxCa) remains a major global gynecological malignancy causally linked to high-risk human papillomavirus (HPV) infection. However, HPV alone is insufficient for carcinogenesis; sex hormones and their receptors serve as essential cofactors. This review aims to synthesize current knowledge on the role of cervical histoarchitecture and hormonal microenvironments in ectocervical squamous cell carcinoma (SCC), and to explore how receptor-mediated signals contribute to malignant transformation and metastatic spread. The review examines the expression patterns of estrogen receptor α (ERα) and progesterone receptor (PR) in the uterine cervix, which is a hormone-responsive tissue. It discusses how these receptors fluctuate throughout the menstrual cycle and evaluates evidence from HPV-transgenic mouse models and human tissue analyses. The findings converge on a compelling model: stromal ERα drives pro-carcinogenic paracrine signaling, epithelial PR suppresses neoplastic transformation, and stromal PRB confers antimetastatic protection. These insights highlight the complex interplay between hormonal signals and SCC development in the ectocervix. Future therapeutic exploitation of these mechanistic insights—including selective estrogen receptor modulators, selective progesterone receptor modulators, and PR status-guided chemoprevention—holds considerable promise. This review provides a coherent framework for translating laboratory findings into clinical diagnostics and targeted interventions. 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

More than 20 years after the discovery of lunasin, a clear shift in lunasin research is observable—from an initial focus on its direct in vitro anticancer effects toward strategies aimed at improving its bioavailability and repositioning it as a potential adjunct in cancer therapy. Lunasin, a soy-derived bioactive peptide, has been extensively studied for its antineoplastic properties. However, its limited oral bioavailability restrains its efficacy in clinical trials. Therefore, recent research on lunasin points towards the possibility of using it as an adjunct in cancer treatment, rather than as a stand-alone nutraceutical in humans. In preclinical models, in vitro and in vivo, lunasin can enhance the effects of standard anticancer drugs in breast and colon cancers. Research suggests that lunasin can potentiate the effects of drugs, such as tamoxifen, aspirin, cisplatin, and oxaliplatin, by sensitizing cancer cells to apoptosis, modulating cell cycle progression, reducing metastatic potential, and attenuating drug-resistance pathways, including PI3K/Akt, FAK/MAPK1/NF-κB, and integrin-mediated signaling. In combination with those drugs, lunasin exerts significant anticancer effects at concentrations substantially lower than those proven as effective in monotherapy, suggesting a potential role in dose reduction in conventional agents and, subsequently, mitigation of their adverse effects. Although the enhanced effect of those combinations has been shown in preclinical models, there is a distinct lack of human clinical trials in this matter. Available evidence supports a promising concept of lunasin as a molecular “priming” agent that might complement cytotoxic therapies rather than replace them. This combination-oriented paradigm may represent a shift in lunasin research and offer a novel direction for the use of bioactive peptides in precision oncology; however, further studies exploring this possibility, including human clinical trials, are needed to elucidate lunasin’s role in nutraceutical-assisted cancer therapy. 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

Nutraceuticals are bioactive compounds that can contribute to maintaining general health and supporting the treatment of various conditions. Among them, flavonoids such as curcumin (C) and quercetin (Q) are of particular interest in oncology research, including melanoma, due to their anti-tumor effects. However, due to poor bioavailability, the development of efficient delivery vehicles is of utmost importance. In this context, we aimed to assess the effectiveness of a potential treatment on the progression of cutaneous melanoma by evaluating cell viability and proliferation in the presence of encapsulated C/Q in innovative microcapsules (MDDS) embedded in a collagen matrix, as well as the anti-inflammatory and antioxidant potential. We found that tumor cell viability and proliferation were significantly reduced in the presence of C/Q, with the best results being obtained for the composite with both bioactive compounds, these results were also supported by a significant increase in pro-apoptotic markers. A decrease in pro-inflammatory markers was observed, as well as a decrease in ROS secretion over time, indicating the anti-inflammatory and antioxidant potential of the materials supplemented with the tested flavonoids, these properties being important for TME modulation. Therefore, the MDDS-CQ embedded sponge could represent a potential adjuvant therapy for cutaneous melanoma in the future. 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

Colorectal cancer (CRC) is driven by oxidative stress, chronic inflammation, and disruption of cytoprotective signaling pathways. This study aimed to evaluate whether poly(lactic-co-glycolic acid) (PLGA)-based nanoparticle delivery enhances the chemoprotective efficacy of paeonol against 1,2-dimethylhydrazine (DMH)-induced colorectal carcinogenesis, with a focus on modulation of the NRF2/HO-1 pathway. Sixty male Wistar rats were randomly assigned to six groups: control, paeonol (PNL), PNL-PLGA, DMH, DMH + PNL, and DMH + PNL-PLGA. CRC was induced using DMH over 10 weeks. Serum tumor biomarkers (AFP, CEA, CA19-9, CA125, CA15-3), oxidative stress markers (ROS, MDA, antioxidant enzymes), inflammatory cytokines, DNA damage, apoptosis- and autophagy-related gene expression, and hepatic and renal function were assessed. Histopathological and ultrastructural analyses of colonic tissues were performed. DMH exposure was markedly associated with increased tumor biomarkers, oxidative stress, and inflammatory mediators, DNA damage, and impaired liver and kidney function. It was also associated with the restoration of NRF2/HO-1 signaling, improved redox balance, suppression of inflammation, reduction in DNA damage, and preservation of regulated NRF2/HO-1 signaling, antioxidant defenses, autophagy markers, and apoptotic proteins, as well as severe histological and ultrastructural alterations. Free paeonol partially attenuated these changes. In contrast, PNL-PLGA was significantly associated with restoring NRF2/HO-1 signaling, improving redox balance, suppressing inflammation, reducing DNA damage, and preserving colonic architecture and ultrastructure. These findings demonstrate that a PLGA-based nanoformulation of paeonol markedly improves its chemopreventive efficacy against DMH-induced CRC, primarily by activating NRF2/HO-1 signaling and modulating oxidative stress, inflammation, apoptosis, and autophagy, highlighting its potential as a promising nanotherapeutic strategy for colorectal cancer. 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