Search Results (3,724)

The increasing global burden of cancer, together with the need for more sustainable resource management, has stimulated growing interest in the valorization of agro-industrial plant residues as sources of bioactive compounds with therapeutic potential. This review highlights the potential of plant by-products—including citrus peels, olive leaves, date palm residues, and tea and coffee processing wastes—as sustainable reservoirs of polyphenols and other phytochemicals with significant anticancer activity. Key compounds such as hesperidin and naringenin from citrus peels, oleuropein and hydroxytyrosol from olive leaves, quercetin and syringic acid from date palm residues, and chlorogenic acid and epigallocatechin gallate from tea and coffee by-products have demonstrated promising antitumor effects in both in vitro and in vivo studies. These molecules exert their activity through multiple mechanisms, including the inhibition of cancer cell proliferation, induction of apoptosis, regulation of the cell cycle, and modulation of major oncogenic signaling pathways such as PI3K/AKT, MAPK, NF-κB, and EGFR. For instance, hydroxytyrosol induces apoptosis and cell cycle arrest while inhibiting the PI3K/AKT and MAPK pathways. Quercetin limits metastasis and glycolysis and suppresses VEGF, PKM2, and AKT signaling. Ferulic acid suppresses tumor growth by inhibiting the PI3K/AKT and JAK2/STAT6 pathways, thereby promoting apoptosis (in vitro and in vivo). In addition to their pharmacological potential, the recovery of these compounds from plant waste supports circular economy strategies by reducing environmental impact and promoting the development of value-added products. Future research should focus on optimizing extraction methods, improving bioavailability and stability, and validating safety and efficacy through well-designed preclinical and clinical studies. Full article

Background: Cancer is a leading cause of mortality worldwide. Discovery of small molecules as anticancer agents is an active area of research, as these molecules possess the remarkable ability to interact with specific targets within cancer cells. Objectives: In vitro anticancer activity of six hit derivatives from a series of 2-phenyl-substituted 4-amino–6, 7-dihydro-5H-cyclopenta[d]pyrimidines was tested against human cancer cell lines, viz., A549 (human lung cancer) and A431 (human skin cancer). Methods: Cytotoxicity was evaluated for six hits by the standard MTT assay. Further, their effect on clonogenic potential and cell cycle was tested using colony forming assay and flow cytometric analysis, respectively. Apoptosis-inducing potential was confirmed using Caspase-3/7 Glo assay and detection of cleaved caspase-3 by immunofluorescence. The effect on cell migration was tested using a wound healing assay. Target analysis, Molecular docking and ADMET simulations were performed to identify molecular targets, interactions and assess pharmacokinetic profiles. Results: Specific derivatives showed good to moderate cytotoxicity against A549 and A431 (with average IC50 in the range of ~30 µM), and these hits led to apoptosis and G1 arrest in these cell lines, respectively. Furthermore, identified hits inhibited cell migration in A549 cells. Computational consensus target analysis identified EGFR and CDK2 as high-confidence targets. Docking studies indicated favorable interactions and stability, whereas the ADMET analysis confirmed the drug-likeness and optimal pharmacokinetic and safety profiles of the small molecules. Conclusions: Our current study demonstrates the anticancer potential of novel pyrimidine derivatives. We envisage the use of these small molecules as promising anticancer agents, particularly in skin and non-small cell lung cancer. Full article

Melia azedarach L. is a plant known for its traditional medicinal uses. Limonoids (triterpenes), which have a wide range of pharmacological effects, are the most critical active ingredients; however, their potential effects on liver cancer remain to be further explored. In this study, seven limonoids were isolated from the bark of Melia azedarach, including two new compounds, 11α-hydroxy-12-Oxo-Meliarachin I (1) and 29-Oxo-12-dehydroneoazedarachin D (3), along with five known compounds (2, 4–7), to evaluate their effect on liver cancer in vitro. The results showed that compounds 1–7 exhibited varying degrees of inhibitory effects on Hep3B cells. Among these, compound 6, Isotoosendanin (ITSN), displayed the most potent activity, with an IC₅₀ value of 15.06 μg/mL. Mechanism studies have shown that ITSN inhibits cell proliferation and promotes apoptosis in Hep3B cells. It induces reactive oxygen species (ROS) accumulation to trigger oxidative stress injury, suppresses the activation of the MAPK and PI3K/AKT signaling pathways, further activates the p53 pathway to induce cell cycle arrest, and ultimately initiates the apoptotic cascade. ITSN can also inhibit tumor growth in immunodeficient mice receiving allogeneic transplantation. In summary, we systematically studied the limonoids in the bark of Melia azedarach and elucidated the anti-hepatocarcinoma activity of ITSN in vitro and in vivo, providing promising evidence for its potential use as a natural active ingredient in the prevention and treatment of cancer. Full article

Triploid turbot (Scophthalmus maximus) exhibit superior growth and survival, yet the molecular basis of their sterility—a key trait for aquaculture—remains largely unexplored. This study investigated ovarian development and transcriptomic profiles in diploid and triploid S. maximus at three key stages (6, 10, and 20 months post-hatch, mph) to elucidate the stage-specific molecular mechanisms underlying triploid sterility. Histological analysis revealed that diploid ovaries progressed through normal oogenesis to the early vitellogenic stage by 20 mph, whereas triploid ovaries were arrested at the oogonial stage, with only occasional primary oocytes and extensive connective tissue infiltration. Comparative transcriptomic analysis identified 13,305, 14,599, and 13,331 differentially expressed genes (DEGs) between triploid and diploid ovaries at 6, 10, and 20 mph, respectively. Functional enrichment analysis showed that DEGs were significantly associated with meiotic processes, cell cycle regulation, energy metabolism, and apoptosis. Key meiotic genes (spo11, dmc1, sycp3) were consistently upregulated in triploids across all stages, while the DNA repair gene rad51 was paradoxically downregulated, indicating attempted but aberrant meiotic initiation. Oogenesis regulators (gdf9, bmp15, pou5f3) and energy metabolism genes (ndufa11, sdha, cox5a) were significantly downregulated, whereas apoptosis-related genes (eif2ak3, apaf1) were upregulated. Notably, KEGG pathway analysis revealed stage-specific shifts from stress-induced apoptosis and p53 signaling at early stages to proteasome activation at later stages, suggesting a transition from active germ cell elimination to maintenance of cellular homeostasis in developmentally arrested ovaries. Collectively, these findings demonstrate that triploid sterility is associated with coordinated dysregulation of meiotic progression, metabolic, and apoptotic pathways, providing a high-resolution molecular framework for understanding reproductive failure in triploid fish and informing strategies for optimizing triploid production in aquaculture. Full article

Plant-derived peptides have become one of the most promising classes of compounds in cancer research due to their specificity, safety, and different therapeutic actions. Generally, plant peptides have a size of 2 to 100 amino acids, and they can be extracted from different parts of the plant including leaves, seeds, stems, and roots. The present review brings together more than 300 prominent plant peptides, their sources, structural classes, extraction methods, anticancer effects, and mechanisms of action. We show the cytotoxicity of plant peptides against a wide range of human cancer cell lines (such as MCF-7, A549, HL-60, and HCT-116), as well as their effectiveness in preclinical animal models of cancer, where they resulted in lesser tumor growth and metastasis. Moreover, we go into the anticancer activity of plant peptides and reveal the interconnectedness of apoptosis, cell cycle arrest, angiogenesis inhibition, metastasis suppression, and the modulation of signaling pathways as some of the mechanisms through which plant peptides perform. In addition to their therapeutic potential, many of these peptides are derived from edible plant sources and can be delivered through functional foods or dietary supplements, offering a promising avenue for cancer prevention and adjunctive nutritional support. The review also touches upon the major hurdles in peptide drug development at present, such as stability, oral bioavailability, and large-scale production, while at the same time giving future perspectives that include bioengineering, nanotechnology-based delivery systems, and combination therapies for translating these natural products into clinical oncotherapeutics and health-promoting foods Full article

Adipogenesis is a critical factor in causing obesity, which is a global health problem associated with metabolic disorders, such as insulin resistance and cardiovascular diseases. Natural compounds with anti-adipogenic activity may represent potential approaches for modulating adipocyte function. However, despite increasing interest in natural products, the anti-adipogenic potential of acridone alkaloids, particularly prenylated derivatives, remains largely unexplored. This study examined the effects of N-methylatalaphylline (NMA), a prenylated acridone alkaloid, on adipocyte differentiation, lipid accumulation, and glucose uptake. NMA exhibited anti-adipogenesis, particularly toward preadipocytes, and significantly reduced lipid accumulation in murine 3T3-L1 and human PCS-210-010 adipocytes at nontoxic doses (1.5–6 µM). At 3–6 µM, NMA downregulated adipogenic regulators, including PPARγ, C/EBPα, and SREBP1, along with adipogenic effectors, such as FABP4, adiponectin, LPL, PLIN1, and FAS. Mechanistic studies indicated that NMA treatment was associated with reduced phosphorylation of AKT, ERK, and p38, accompanied by cell-cycle arrest and inhibition of mitotic clonal expansion. Meanwhile, activation of AMPK-ACC signaling, which may contribute to suppression of adipogenesis and reduced glucose uptake, was observed in differentiated 3T3-L1 cells after treatment with 6 µM NMA for 48 h. Additionally, molecular docking and molecular dynamics simulations suggested potential interaction between NMA and ERK1, supported by hydrogen bonding and hydrophobic contacts. Overall, these findings suggest that NMA exerts anti-adipogenic effects in vitro by modulating adipocyte proliferation, differentiation, and lipid metabolism. These findings highlight NMA as a promising acridone alkaloid scaffold for anti-adiposity applications, warranting further in vivo validation. Full article

Background/Objectives: Propolis is well recognized for its antioxidant, anti-inflammatory, and wound-healing properties, supporting its cutaneous application in phytopharmaceuticals for the management of ultraviolet B (UVB)-induced skin damage. However, the application of propolis is limited by its intense coloration, stickiness, and poor user convenience. In situ film-forming systems (FFS) represent a novel dosage form designed to overcome these challenges, although efficacy data for using FFS remains limited. Consequently, this study aimed to develop a propolis-based FFS and evaluate its efficacy in mitigating UVB-irradiated HaCaT keratinocytes. Methods: Apis mellifera propolis was macerated and analyzed for total phenolic content (TPC) and total flavonoid content (TFC), radical scavenging activity (DPPH assay), and nitric oxide scavenging capability. Bioactive compounds were identified using high-performance liquid chromatography analysis (HPLC). The propolis extract was formulated into FFS and investigated on UVB-damaged HaCaT keratinocytes. An MTT viability assay, propidium iodide flow cytometry for cell cycle analysis, and a scratch wound healing assay were used to evaluate the therapeutic effects of the FFS. Results: The 72 h macerated propolis extract contained high levels of TPC, TFC, and targeted phytochemicals. The propolis extract exhibited free radical scavenging and nitric oxide inhibitory activities. Seven formulations exhibited suitable performance, with formulation F7 (FFS-F7) demonstrating superior drying time and dose-dependent free radical scavenging. Notably, FFS-F7 (≥12.5 µg/mL) significantly enhanced HaCaT proliferation, mitigated UVB-induced cell cycle arrest, reduced cellular damage, and accelerated wound closure. Conclusions: This study successfully developed an FFS that not only overcomes these physical drawbacks but also preserves the biological activity of the extract. The significant protective and restorative effects against UVB-induced HaCaT damage demonstrate the therapeutic potential of Thai Apis mellifera propolis and establish the FFS as a versatile base with the potential for delivering other bioactive compounds. Full article

Prevalent cancers primarily include breast, lung and bronchus, prostate, and colorectal cancers. In contrast, cancer of the epididymis is very rare, and we propose that this tissue could carry inherent anticancer components, in particular, small extracellular vesicles (EVs) with antineoplastic properties. All cell types release extracellular vesicles (EVs) into their intercellular space, which act in the crosstalk required to achieve homeostasis. Among these, small EVs, which are membrane-bound vesicles with an average diameter of 30–200 nm, can transfer cell-specific cargo, such as lipids, proteins, DNA and RNA, which can be selectively received by neighboring or distant cells, and trigger specific cell processes, such as growth, division, or apoptosis. Here, we isolated small EVs from epididymis tissue, and examined their effect on morphology, viability, apoptosis, cell cycle phases, and certain gene and protein expression levels, particularly of the pro-apoptotic p53 protein, in HCC38 and MCF-7 breast cancer cell lines, as well as in a normal fibroblast cell line. The various analyses demonstrated effects on breast cancer cells but not on normal cells. Specifically, epididymis-derived EVs (Ep-EVs) selectively induced apoptosis and cell cycle arrest in cancer cells, while normal cells were unaffected. Moreover, the relative uptake of Ep-EVs in HCC38 and MCF-7 breast cancer cells was significant, indicating a direct association between vesicle internalization and the biological response. Taken together, these findings demonstrate a solid experimental foundation supporting the therapeutic potential of Ep-EVs in breast cancer, with promising implications for their development as a broader anticancer platform. Full article

Acute myeloid leukemia (AML) is a complex blood cancer that primarily affects relapsing or refractory patients receiving conventional chemotherapy. Nonsteroidal anti-inflammatory drugs (NSAIDs) have anticancer properties with restricted clinical efficacy attributable to cyclooxygenase (COX)-induced toxicities. To address this issue, a group of benzylamide analogs of the classical NSAIDs (NSI-1–NSI-9) were developed and synthesized to mask the carboxylic acid moiety and minimize COX-induced adverse effects while maintaining anticancer activity. The cytotoxic effect of such substances has been demonstrated in some leukemia cell lines (HL-60, MV4-11, KG1a, and K562). NSI-5 exerted the highest anti-leukemic activity among these sulindac analogs, as determined at a sub-micromolar level in all cell lines studied, by IC50. This mechanistic data also demonstrated that NSI-5 induced apoptosis that was dose-dependent, especially in HL-60 cell lines, and increased the sub-G1 cell fraction. This apoptotic process was also accompanied by a significant decrease in mitochondrial membrane potential, which is characteristic of the induction of the intrinsic apoptotic process. Interestingly, NSI-5 decreased the intracellular reactive oxygen species (ROS) and the expression of most antioxidants (catalase and glutathione synthetase), as well as the redox balance. Gene characterization in vitro also suggested activation of apoptotic pathways, where expression of Bax, Bak1, and Caspase-3 increased, suggesting a potential p53-independent apoptotic pathway, in contrast to control for Bcl-2 expression. Collectively, these findings indicate that NSI-5 is a promising in vitro anti-leukemic lead compound, with activity associated with mitochondrial dysfunction and altered redox regulation. The observed effects are consistent with previously reported COX-independent activity of structurally related NSAID derivatives, and support further investigation of NSI-5 in preclinical models. Full article

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with a poor prognosis. While sorafenib serves as the first-line therapy for advanced HCC, its efficacy is frequently hampered by side effects and the development of drug resistance, necessitating the development of novel agents to enhance HCC sensitivity to sorafenib. In this study, we demonstrate that the antihistamine astemizole significantly enhanced the antitumor efficacy of sorafenib in HCC cell lines. This combination treatment cooperatively inhibited HCC cells’ proliferation and induced cell cycle arrest at the G1 phase, as evidenced by decreased cyclin D1 and p-Rb levels and increased p27 expression. Furthermore, the combination of astemizole and sorafenib synergistically inhibited HCC cells’ migration, invasion, and adhesion. It also reduced F-actin polymerization and the expression of metastasis-regulating proteins, including p-Integrinβ1, FAK, and MMP1. Additionally, the combination treatment suppressed tube formation in HUVECs, accompanied by downregulation of HIF-1α and reduced VEGF secretion. Co-inhibition of Eag1 and the ERK/MAPK signaling pathway may underlie the enhanced anti-HCC effects of sorafenib by astemizole. Collectively, these findings indicate that astemizole significantly enhanced the antitumor activity of sorafenib by inhibiting proliferation, metastasis, and angiogenesis in HCC cells, suggesting its potential as a promising adjuvant to improve sorafenib-based therapy in HCC. Full article

Iodoacetic acid (IAA), a highly cytotoxic disinfection byproduct commonly detected in drinking water, poses a potential risk to female reproductive health. The direct molecular mechanisms underlying its effects on the reproductive system epithelium remain unclear. This study demonstrates that IAA induces glycational stress in primary porcine uterine (UECs) and oviduct epithelial cells (OECs), representing an early event contributing to extensive cellular toxicity. IAA exposure inhibited Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) enzymatic activity and promoted the accumulation of advanced glycation end products (AGEs) Nε-(carboxymethyl)lysine (CML), triggering mitochondrial dysfunction, redox imbalance, calcium dyshomeostasis, and endoplasmic reticulum stress. These disturbances activated a dysregulated signaling network involving the p38 MAPK, AKT, and NF-κB pathways, ultimately causing G1/S cell cycle arrest and apoptosis. Notably, pretreatment with the AGE inhibitor pyridoxamine reduced CML accumulation, restored mitochondrial function, and alleviated apoptotic cell death. These findings identify glycational stress as a key initiating mechanism for IAA-induced reproductive epithelial toxicity, providing mechanistic insight into the potential health risks of environmental disinfection byproducts. Full article

Chondrosarcoma (CHS), the second most common primary malignant cartilage tumor, is largely resistant to conventional therapies, making surgical resection the standard treatment. Proton therapy offers a physical advantage through the Bragg peak, enabling targeted irradiation while sparing surrounding tissues. However, differential biological responses between malignant and normal cartilage cells remain poorly understood. In this study, CHS SW1353 cells and normal chondrocytes (MC615) were exposed to proton irradiation. Biological responses were assessed via clonogenic survival, cell viability, apoptosis (caspase 3/7), micronucleus formation, cell cycle profiling, and oxidative stress markers. Proteomic changes were analyzed using mass spectrometry and bioinformatics. CHS cells exhibited higher radioresistance (D₁₀ = 6.45 Gy) than normal chondrocytes (D₁₀ = 5.08 Gy), oxidative stress adaptation, G1 arrest and proteomic plasticity, whereas normal chondrocytes displayed increased oxidative stress, extracellular matrix fragility and impaired integrin signaling. Notably, the tumor-specific increased levels of Tyrosine-protein kinase Fyn and Yes1-associated transcriptional regulator (YAP1) signaling suggest molecular drivers of radioresistance. Overall, proton irradiation elicits distinct biological and proteomic responses in malignant versus normal cartilage cells. These findings highlight potential radiosensitization targets, including Fyn/Src and YAP1/Hippo pathways, while underscoring the need to optimize proton therapy to enhance tumor control while minimizing damage to healthy cartilage. Full article

Colorectal cancer (CRC) remains a major cause of cancer-related mortality worldwide, and effective therapeutic options for advanced disease are still limited. Oridonin (ORI), a naturally derived diterpenoid compound, has shown anti-tumor activity in several malignancies, but its molecular mechanisms in CRC remain incompletely understood. In this study, the anti-cancer effects of ORI were evaluated in HT-29 and HCT116 colorectal cancer cells using in vitro assays, integrated transcriptomic and proteomic analyses, Western blotting, and an HT-29 xenograft model. ORI reduced cell viability in a time- and concentration-dependent manner, induced G1-phase cell cycle arrest, increased cell death, and reduced wound closure under the tested in vitro conditions. Integrated omics analyses in HT-29 cells identified extensive alterations in gene and protein expression, with significant enrichment of pathways related to cell cycle regulation and apoptosis. Western blotting further showed that ORI increased the expression of BAX, BID, CYCS, and CASP3 while decreasing BCL2 expression. In vivo, ORI significantly inhibited tumor growth in nude mice bearing HT-29 xenografts. These findings indicate that ORI suppresses CRC growth through coordinated regulation of cell cycle progression and apoptosis and suggest that ORI may serve as a potential therapeutic candidate for colorectal cancer. Full article

Background: Skin carcinoma is among the most common cancers globally, necessitating the urgent development of innovative chemotherapeutic drugs that exhibit great selectivity and diminished toxicity towards normal cells. This study assessed a series of recently synthesized compounds (4–15) for screening their anticancer efficacy against A 431 human skin carcinoma cells to find effective and selective treatment candidates. Methods: Compounds were synthesized via a one-pot, three-component reaction. Cytotoxicity was evaluated using the MTT assay, with 5-fluorouracil (5-FU) as the reference standard, which exhibited potent activity against A 431 skin cancer cells. The activity of these drugs against normal BJ cells was evaluated, with mechanistic investigations encompassing topoisomerase I/II enzyme inhibition, cell-cycle analysis, and Annexin V–FITC/PI apoptosis assays. Results: Most compounds exhibited dose-dependent cytotoxicity, with compound 14 demonstrating the highest potency (IC₅₀ = 76.7 µg/mL), exceeding that of 5-FU (IC₅₀ = 83.7 µg/mL) while preserving selectivity for BJ cells. Compound 14 exhibited moderate inhibition of topoisomerases I and II (IC₅₀ values of 17.5 and 17.3 µM), as confirmed by docking studies. Flow cytometry indicated G0/G1 phase arrest (64.09% vs. 58.18% in control), while apoptosis assays confirmed induction of both early and late apoptosis, accompanied by significant necrosis. Conclusions: Compound 14 is the most efficacious and selective drug in this series, functioning through topoisomerase inhibition, G0/G1 cell cycle arrest, and apoptosis, thereby representing a strong candidate for subsequent preclinical research. Full article

This study aims to investigate the potential anticancer effects of erucin, an isothiocyanate derived from Eruca sativa, in triple-negative breast cancer (TNBC) by predicting molecular targets and evaluating its in vitro effects on TNBC cell proliferation, apoptosis and cell cycle distribution. Potential protein targets of erucin were identified using SwissTargetPrediction, resulting in 117 targets, of which 84 overlapped with TNBC-related genes sourced from GeneCards, DisGeNET, and OMIM. Protein–protein interaction analysis was performed to identify key hub genes. In vitro experiments were conducted using MDA-MB-231 TNBC cells to assess dose-dependent effects on cell viability. Flow cytometry was employed to evaluate apoptotic cell populations and cell cycle distribution. Protein–protein interaction analysis identified ten hub genes, including AKT1, STAT3, EGFR, and MMP9, representing highly connected nodes within the predicted interaction network. In vitro studies showed dose-dependent reduction in MDA-MB-231 cell viability following erucin treatment, with an IC₅₀ of approximately 48.87 µg/mL. Flow cytometry revealed increased apoptotic cell population and G1 phase accumulation. These findings suggest that erucin is associated with cytotoxic and antiproliferative effects in TNBC cells and may interact with multiple cancer-related targets. However, the identified molecular targets and pathways are based on computational predictions and require further experimental validation. Overall, this study provides a preliminary integrated framework linking computational predictions with experimental observations, which may support future mechanistic and preclinical investigations of erucin in TNBC. Full article