Search Results (4,665)

Background/Objectives: The lack of canonical biomarkers and strategies to target radioresistance contribute to poor patient outcomes in triple-negative breast cancer (TNBC). Identifying and targeting novel radioresistance genes will benefit in enhancing radiotherapy response and treatment outcomes in TNBC patients. Methods: A genome-wide CRISPR screen was performed to identify radioresistance genes in the TNBC cell line. An in vitro clonogenic assay was used to assess the antiproliferative effects of Artemis knockout or pharmacologic inhibition of Artemis, either alone or in combination with RT. Tumor doubling time and animal survival were assessed using an in vivo xenograft model. RNA-seq analysis was performed to identify genes and pathways deregulated under Artemis knockout conditions, both alone and in combination with RT. Cellular senescence was evaluated using a β-galactosidase assay. Results: Our CRISPR screen identified Artemis as a top hit in RT-treated TNBC cells, whose depletion led to radiosensitization in TNBC. Artemis knockout significantly reduced cell proliferation and enhanced the antiproliferative effects of RT in vitro. Compared to mice-bearing control MDA-MB-231 xenografts, Artemis knockout exhibited prolonged survival that was further enhanced with RT. Bulk RNA-sequencing indicated that the antiproliferative and radiosensitization effects of Artemis depletion were mediated by the activation of cellular senescence which was confirmed with a β-galactosidase assay. Conclusions: Taken together, our results highlight the critical role of Artemis in TNBC cell proliferation and response to radiation. Our findings identify Artemis as a potential biomarker indicative of sensitivity to radiation and a putative target that could be inhibited to enhance the efficacy of RT in TNBC. Full article

Melanoma is an aggressive malignancy with poor prognosis in advanced stages, and current therapeutic options provide only limited benefits, highlighting the need for novel treatments. Chetomin, a fungal metabolite isolated from Chaetomium cochliodes, has been reported to exhibit diverse biological activities, yet its effects on melanoma cells remain poorly understood. In this study, we evaluated the antitumor potential of chetomin using the human A375 melanoma cell line. Cell viability was assessed with MTT and CellTiter-Glo^® assays, which revealed a significant dose- and time-dependent reduction in proliferation following chetomin exposure. Apoptotic effects were confirmed through Annexin V staining, and immunocytochemical analysis demonstrated a concentration-dependent increase in cleaved PARP1, indicating activation of programmed cell death pathways. Collectively, these findings demonstrate that chetomin effectively inhibits melanoma cell growth and promotes apoptosis. The results suggest that chetomin represents a promising lead compound for melanoma therapy, warranting further investigation into its precise molecular mechanisms. Full article

Background: Prostate cancer (PC) progression is strongly driven by dysregulated signaling pathways, with NF-κB playing a central role. Sesquiterpene lactones have been reported to modulate this pathway. This study evaluated and compared the cytotoxic effects of two structurally distinct sesquiterpene lactones: Tatridin A, a germacranolide, and desacetyl-β-cyclopyrethrosin, a eudesmanolide derivative. Their mechanisms of action were also examined, focusing on oxidative stress induction and NF-κB modulation. Methods: Chemical structures were confirmed by NMR and X-ray crystallography. Cytotoxicity was assessed in DU-145 and 22Rv1 PC cells using real-time cell analysis. Reactive oxygen species (ROS) and mitochondrial membrane potential (ΔΨm) were measured with fluorometric assays. NF-κB activity was determined in THP-1 reporter cells and by Western blot of IκBα phosphorylation. Results: Tatridin A markedly reduced viability, showing lower IC₅₀ values (81.4 ± 2.7 µM in DU-145 and 50.7 ± 1.9 µM in 22Rv1 cells) than desacetyl-β-cyclopyrethrosin (166.9 ± 3.2 µM and 290.3 ± 8.3 µM, respectively). It also inhibited proliferation at markedly lower concentrations, with clonogenic IC₅₀ values of 7.7 µM in DU-145 and 5.24 µM in 22Rv1cells. Both compounds increased ROS, but tatridin A induced earlier and stronger responses and ΔΨm loss. Furthermore, tatridin A more effectively inhibited NF-κB signaling than classical inhibitors. Conclusions: Tatridin A exerts cytotoxic effects through oxidative stress, mitochondrial impairment, and NF-κB inhibition, supporting the therapeutic potential of germacranolides for the treatment of advanced PC. Full article

The gut microbiome possesses a diverse range of biological properties that play a role in maintaining host health and preventing disease. Gut microbial metabolites, including short-chain fatty acids, natural purine nucleosides, ellagic acid derivatives, and tryptophan metabolites, have been observed to have complex and multifaceted roles in the gut and in wider body systems in the management of disease, including cancer. Triple-negative breast cancer is the most aggressive subtype of breast cancer, with restricted treatment options and poor prognoses. Recently, preclinical research has investigated the antiproliferative potential of gut microbial metabolites against this type of breast cancer with promising results. However, little is understood about the mechanisms of action and molecular pathways driving this antiproliferative potential. Understanding the complex mechanisms of action of gut microbial metabolites on triple-negative breast cancer will be instrumental in the investigation of the combined administration with standard chemotherapeutic drugs. To date, there is a paucity of research studies investigating the potential synergistic interactions between gut microbial metabolites and standard chemotherapeutic drugs. The identification of synergistic potential between these compounds may provide alternate and more effective therapeutic options in the treatment and management of triple-negative breast cancer. Further investigation into the mechanistic action of gut microbial metabolites against this breast cancer subtype may support the administration of more cost-effective treatment options for breast cancer, with an aim to reduce side effects associated with standard treatments. Additionally, future research will aim to identify more potent metabolite–drug combinations in the mitigation of triple-negative breast cancer progression and metastasis. Full article

Background: Tyrosinase is a copper-dependent oxyreductase capable of catalyzing the oxidation of mono- and diphenols. Its activity is crucial in the biosynthetic pathway of melanin, the pigment responsible for the pigmentation of mammalian skin and fur, and protecting their skin from harmful UV radiation. Overproduction of this pigment leads to numerous pathological conditions, including the most severe form of skin cancer—malignant melanoma. Furthermore, tyrosinase produced in plant tissues leads to the browning of damaged vegetables and fruits. Therefore, the search for compounds that effectively and efficiently control tyrosinase activity is desirable for both pharmaceutical and food applications. Methods: A group of six boronate derivatives of thiosemicarbazones was synthesized, and their inhibitory properties against tyrosinase were determined. Furthermore, their ability to inhibit melanogenesis and proliferation in SK-MEL-3 and Hs294T cells was investigated. Docking simulations were performed to determine the nature of the inhibitor–protein interactions. Results: The tested inhibitors exhibited half-maximal inhibitory concentrations (IC₅₀) in the micromolar range. The best inhibitor, compound 6, had an IC₅₀ of 1.4 µM. The tested compounds exhibited poor selectivity for cell lines capable of high and low tyrosinase overexpression, with inhibitor 4 proving to be the most selective compound among those tested. Molecular modeling results indicate that the compounds with the highest activity against tyrosinase interact with the active cavity and the copper ions present within it via a boron moiety substituted on the aromatic ring of the thiosemicarbazones. Cell-based experiments indicated limited antiproliferative effects up to 100 µM across the tested lines. The compounds demonstrated weak antiproliferative effects in SK-MEL-3 and Hs-294T up to 100 µM. Conclusions: Our results show that the introduction of a boronic acid moiety is an alternative to carboxylic acid derivatives, improving the inhibitory activity of boron analogs (by fourfold) against fungal tyrosinase. Full article

Indole carboxylic acids are endogenous tryptophan metabolites that have demonstrated a variety of bioactivities, including anticancer effects. Specifically, indole acetic acid (IAA) elicits anticancer activity when combined with ultraviolet B or reactive oxygen species (ROS) generators. Primaquine (PQ) is an approved drug which elicits antimalarial activity through ROS generation. We investigated the effects of ICA, IAA, PQ, their combination and PQ–indole carboxamide conjugates on the viability of selected cancer cell lines. We identified PQ–indole carboxamide 2 which elicited more potent antiproliferative effects than PQ and ICA/PQ combination. Our data revealed that compound 2 derived a significant part of its antiproliferative effect from ROS generation. Full article

Erica spiculifolia Salisb. (Balkan heath) is an evergreen shrub growing in the mountain shrublands of Eastern Europe. E. spiculifolia was used as a diuretic, anti-inflammatory, and antioxidant herbal remedy. The present study aims to conduct an evaluation of the phytochemical composition and antitumor activity of the methanol–aqueous extract from E. spiculifolia aerial parts to explore its potential in cancer treatment. Overall, a total of 54 secondary metabolites, including 28 hydroxybenzoic, hydroxycinnamic acids, and phenolic glycosides, and 10 triterpene acids, together with 17 flavonoids, were identified or annotated in the assayed E. spiculifolia extract using liquid chromatography-high-resolution mass spectrometry. The cytotoxic activity of the extract, alongside gallic, protocatechuic, and oleanolic acids as its constituents, was screened against a panel of malignant human cell lines of different origin (LAMA-84, HL-60, MDA-MB-231, MCF-7, and CASKI). The most prominent antiproliferative effect of the studied extract (with IC₅₀ 16.6 μg/mL), matched with the highest tumor selectivity (SI > 120), was observed in the LAMA-84 myeloid cells. These findings were further supported by gallic and oleanolic acid (IC₅₀ 6.2 and 1.7 μg/mL, respectively), accounting for a more distinct cytotoxicity. The strongest selective antineoplastic activity was achieved towards the triple-negative breast carcinoma cell line MDA-MB-231, with an IC₅₀ of 32.5 μg/mL. This study provided compelling evidence for a wide spectrum of E. spiculifolia antitumor activity, indicating its potential as a natural alternative for future therapeutic applications. Full article

Pulmonary arterial hypertension (PAH) is a rare condition characterized by high pulmonary artery pressure leading to right ventricular dysfunction and potential life-threatening consequences. It primarily affects the pre-capillary pulmonary vascular system. The exact pathophysiological mechanisms underlying PAH are not entirely known. Environmental factors; genetic predisposition; mitochondrial and microRNA dysfunction; and inflammatory, metabolic, and hormonal mechanisms may be involved. A central role is played by the dysfunction of the pulmonary vascular endothelium. This alteration is characterized by a reduction in vasodilatory and antiproliferative factors such as prostacyclin and nitric oxide and an increase in vasoconstrictive and mitogenic substances such as endothelin and thromboxane A2. Such imbalance leads to a progressive increase in pulmonary vascular resistance. The aim of the present review is to focus on the vascular endothelium and its role as a potential therapeutic target in PAH. Full article

The hybrid Sechium edule H387 07, commonly known as chayote, has shown potential as an antiproliferative, cytotoxic, and pro-apoptotic agent in the murine leukemia cell lines P388 (macrophagic) and J774 (monocytic) and in the myelomonocytic leukemia cell line WEHI-3. However, despite these reported bioactivities, its pharmacokinetic profile remains largely unexplored. Understanding the absorption, distribution, and elimination of this hybrid is critical for addressing unmet therapeutic needs and for advancing the development of natural product-based therapies. These effects are attributed to the presence of phenols, flavonoids, and cucurbitacins in its organic extracts. In this study, the pharmacokinetic parameters of secondary metabolites from methanolic extracts of Sechium H387 07 were evaluated after oral administration in mice, while its segregant H387 M16 was subjected to complementary phytochemical characterization. Methanolic extracts of Sechium edule H387 07 were orally administered to mice at doses of 8, 125, and 250 mg/kg, and plasma, liver, and urine samples were collected at 1, 6, 24, and 48 h post-treatment. High-performance liquid chromatography (HPLC) identified polyphenols and cucurbitacins, notably cucurbitacin B (CuB) and cucurbitacin IIA (CuIIA), in the biological samples, and pharmacokinetic variables such as the maximum plasma concentration (C_max), time to reach maximum concentration (T_max), half-life (T_1/2), and volume of distribution (V_d) were determined. For instance, CuB exhibited a C_max of 37.56 µg/mL at 1 h post-dose after oral administration of 125 mg/kg, confirming its rapid absorption and systemic distribution. Notably, the presence of CuIIA in plasma was documented for the first time, along with the pharmacokinetic profiles of apigenin, phloretin, CuB, CuE, and CuI. In parallel, the segregant H387 M16 was characterized via colorimetric assays, thin-layer chromatography (TLC), HPLC, and antioxidant activity tests, which revealed high levels of flavonoids, phenols, and cucurbitacins, with an antioxidant activity of approximately 75% at the highest tested dose (1 mg/mL), supporting its suitability for future bioassays. Overall, these findings not only provide novel pharmacokinetic data for key metabolites of the H387 07 hybrid but also establish the phytochemical and antioxidant profile of its segregant H387 M16. This dual characterization strengthens the evidence of the therapeutic potential of Sechium genotypes and provides a valuable foundation for future studies aiming to develop standardized protocols and explore translational applications in drug development and natural product-based therapies. Full article

Breast cancer remains a leading cause of morbidity and mortality among women globally, with increasing incidence projected in the coming years. Despite advances in standard oncologic therapies, there is a growing interest in supportive interventions that enhance treatment efficacy and reduce adverse effects. This review critically evaluates preclinical and clinical data on the medicinal mushroom Coriolus versicolor and its bioactive compounds—primarily polysaccharide-K, polysaccharopeptide, and laccase—as potential adjuvants in breast cancer therapy. A systematic PubMed search identified 11 original studies from 2010 to 2025 examining the impact of C. versicolor on breast cancer cell lines, animal models, and human subjects. Findings consistently demonstrate antiproliferative, pro-apoptotic, necroptotic, anti-invasive, and immunomodulatory effects across various breast cancer subtypes, including triple-negative breast cancer. One phase I clinical trial also reported good tolerability and immunological benefits in patients post-chemotherapy. The review highlights molecular mechanisms involving apoptosis, necroptosis, and modulation of the tumor microenvironment. While promising, these results underscore the need for standardized preparations, pharmacokinetic data, and larger placebo-controlled trials. Overall, C. versicolor shows potential as a safe, natural adjunct to conventional therapy, offering prospects for integrative strategies in breast cancer management. Full article

The rising incidence of cancer and the limitations of current therapeutic strategies underscore the urgent need to identify novel bioactive compounds for antitumor drug development. Cyanobacteria are widespread Gram-negative, photoautotrophic prokaryotes that have been recognized as an important source of biologically active secondary metabolites with vast potential for application in the fields of pharmaceutics. The aim of the present study was to analyze the phytochemical composition, antioxidant, and antitumor activities of low-temperature (LT) and high-temperature (HT) aqueous extracts of the cyanobacterium Chroococcus sp. R-10. Extracts were prepared and analyzed for phytochemical composition using UPLC-DAD, and antioxidant activity was tested via multiple assays. Antiproliferative effects were evaluated on human tumor cell lines, and the effects on cell cycle progression studied using flow cytometry. Fluorescence microscopy was employed to examine extract-induced cytomorphological changes in the treated cancer cells. UPLC-DAD analyses showed very similar chromatographic profiles of the extracts and identified glycogen as their main constituent. Both extracts displayed concentration-dependent antioxidant activity, with notable radical scavenging and ferric-reducing capacity. LT extract demonstrated higher phenolic content and antioxidant capacity. Both extracts reduced cell viability, particularly in MCF-7 and MDA-MB-231 breast carcinoma cell lines. Flow cytometry and fluorescent microscopy analyses revealed that the suppressed proliferative activity of the cancer cells was associated with a retardation of cell cycle progression and apoptosis induction. This study identifies Chroococcus sp. R-10 as a promising source of phytochemical compounds with pharmaceutical relevance and provides a rationale for further investigations to identify the primary bioactive constituents and elucidate their mechanisms of anticancer action. Full article

Robinetin, a naturally occurring polyhydroxylated flavonol, has gained attention due to its broad spectrum of biological activities and potential therapeutic applications. This review presents a comprehensive summary of the current knowledge concerning the natural occurrence, extraction, spectroscopic characterization, and pharmacological properties of robinetin. Ethnobotanical evidence highlights its presence in various medicinal plants, particularly within the Fabaceae family, where it contributes to traditional treatments of infections, inflammation, and metabolic disorders. Robinetin exhibits diverse bioactivities, including antiviral, antibacterial, antiparasitic, antioxidant, anti-mutagenic, and enzyme-inhibitory effects. Notably, it inhibits HIV-1 integrase and acetylcholinesterase and demonstrates moderate antiproliferative activity in cancer cell lines. Despite limited water solubility, its redox behavior and metal-chelating capabilities support its antioxidant potential. Recent in vivo studies indicate its hepatoprotective and metabolic regulatory effects. Additionally, computational models reveal promising interactions with molecular targets such as CDK1. Collectively, these findings underscore the multifaceted therapeutic potential of robinetin and advocate for further pharmacokinetic and clinical investigations to validate its efficacy as a lead compound for the development of phytochemically derived pharmaceuticals. Full article

Background/Objectives: Omentin, also known as intelectin-1, is a secreted adipokine with anti-inflammatory, insulin-sensitizing, and immune-modulatory functions, primarily expressed in visceral adipose tissue. While omentin has been associated with favorable metabolic outcomes, its role in cancer pathogenesis appears context-dependent and remains poorly understood. This review investigates the biological functions, expression patterns, and clinical relevance of omentin across gastrointestinal malignancies. Methods: A comprehensive review of the literature was conducted using PubMed, Scopus, and Web of Science up to August 2025 to evaluate the role of omentin in gastrointestinal cancers. Both preclinical and clinical studies evaluating omentin, its analogues and omentin-enhancing agents in gastric, colorectal, hepatic, pancreatic, and esophageal cancers were included. Results: Omentin exhibits anti-proliferative, anti-inflammatory, and anti-angiogenic effects within the tumor microenvironment in several GI malignancies. However, evidence also indicates a dual role. High intratumoral omentin expression correlates with improved prognosis in colorectal, gastric, and hepatic cancers; in contrast, elevated circulating levels–particularly in colorectal and pancreatic cancers–have been paradoxically associated with increased cancer risk and poor outcomes. Mechanistically, omentin modulates PI3K/Akt, NF-κB, AMPK, and oxidative stress pathways, and interacts with TMEM207. However, most available studies are small-scale and heterogeneous, with methodological inconsistencies and limited multi-omics integration, leaving major knowledge gaps. Conclusions: This review highlights omentin’s distinct systemic and local roles across GI cancers, underscoring its translational implications. Omentin emerges as a promising but context-dependent biomarker and therapeutic target, with future research needed to address heterogeneity, standardize assays, and validate its clinical utility in large-scale prospective studies. Full article

Background/Objectives: Colorectal carcinoma (CRC) is among the most commonly diagnosed cancers in both men and women. Although CRC mortality is generally decreasing, new therapeutic options are needed for unresponsive subgroups of CRC patients. Methods: A series of known and new tyrphostin derivatives was tested for their efficacy against three CRC cell lines with varying KRAS, p53, and/or BRAF statuses. Growth inhibition, apoptosis induction, and inhibition of EGFR and VEGFR-2 were investigated. Results: Tyrphostin A9, the known RG13022-related tyrphostin 1a and its dichlorido(p-cymene)ruthenium(II) complex 1b, and the new SF₅-substituted compounds 2a and 2b showed selective antiproliferative activity against KRAS-mutant HCT-116 CRC cells expressing wildtype p53, while p53-knockout HCT-116 and KRAS-wildtype BRAF/p53-mutant HT-29 CRC cells were distinctly less sensitive. In HCT-116 cells, only tyrphostin A9 increased mRNA expression of caspases 3 and 8, as well as the kinases MEK1 and MEK2, whereas 2a reduced caspase 8 mRNA levels. Tyrphostin A9 increased caspase 3 activity and induced apoptosis in HCT-116 p53-wildtype cells while simultaneously inhibiting the receptor tyrosine kinases EGFR and VEGFR-2 at low nanomolar concentrations. Conclusions: Tyrphostin A9 could be a promising therapeutic option for the treatment of KRAS-mutant CRC that expresses wildtype p53. Full article

Background/Objectives: The search for natural alternatives in breast cancer (BC) management has spurred interest in plant-derived extracts, particularly oregano variants and their bioactive compound carvacrol (Cv). However, Mexican oregano (Lippia graveolens) infusion (MoI) remains unexplored. This study aimed to chemically characterize MoI and compare its anticancer effects with Cv across BC cell lines, including aggressive triple-negative (TN) subtypes. Methods: MoI was analyzed for composition, antioxidant capacity (ABTS, DPPH, FRAP, total phenols/flavonoids), and phytochemical profile (FTIR, HPLC). Anticancer activity was assessed via MTT and LDH assays. Results: MoI exhibits strong antioxidant capacity and concentration-dependent antiproliferative effects, with IC50 values ranging from 0.08 to 0.18 mg/mL across BC lines, significantly higher (i.e., less cytotoxic) than Cv IC50 of 121–211 µM. Importantly, MoI displayed markedly lower cytotoxicity toward non-cancerous cells (IC50 0.18 mg/mL) compared to Cv (IC50 110 µM). Conclusions: While both agents reduced metabolic activity, Cv induced a more acute suppression. These findings position MoI as a promising, selective candidate for BC therapy, particularly for poor-prognosis subtypes like TN BC, warranting further mechanistic investigation. Full article