Search Results (2,439)

Naturally inspired electrophilic scaffolds, such as chalcone, curcumin, aurone, C-5-monocarbonyl-curcumin, and bis-(arylidene)piperidone, are considered privileged structures because of their ability to interact with a variety of biological macromolecules, including receptors and enzymes. They thus serve as versatile platforms for drug discovery efforts aimed at developing structurally related analogues endowed with improved bioactivity. Five-membered nitrogen-based heterocycles, such as triazole and pyrazole, have been widely used in medicinal chemistry both as templates and spacers for the design of bioactive compounds; they indeed provide the advantage of enhancing favourable interactions with the target, while also improving solubility and bioavailability, along with reducing toxicity. This review reports the latest advances in the development of hybrids incorporating the above classes of synthons acting as potential anticancer chemotherapeutics and provides a critical summary of the design strategies that have guided the development of antitumor agents. Full article

Cancer stem cells (CSCs) represent a small but highly resilient tumor subpopulation responsible for sustained growth, metastasis, therapeutic resistance, and recurrence. Their survival is supported by aberrant activation of developmental and inflammatory pathways, including Wnt/β-catenin, Notch, Hedgehog, PI3K/Akt/mTOR, STAT3, and NF-κB, as well as epithelial–mesenchymal transition (EMT) programs and niche-driven cues. Increasing evidence shows that phytochemicals, naturally occurring bioactive compounds from medicinal plants, can disrupt these networks through multi-targeted mechanisms. This review synthesizes current findings on prominent phytochemicals such as curcumin, sulforaphane, resveratrol, EGCG, genistein, quercetin, parthenolide, berberine, and withaferin A. Collectively, these compounds suppress CSC self-renewal, reduce sphere-forming capacity, diminish ALDH⁺ and CD44⁺/CD24⁻ fractions, reverse EMT features, and interfere with key transcriptional regulators that maintain stemness. Many phytochemicals also sensitize CSCs to chemotherapeutic agents by downregulating drug-efflux transporters (e.g., ABCB1, ABCG2) and lowering survival thresholds, resulting in enhanced apoptosis and reduced tumor-initiating potential. This review further highlights the translational challenges associated with poor solubility, rapid metabolism, and limited bioavailability of free phytochemicals. Emerging nanotechnology-based delivery systems, including polymeric nanoparticles, lipid carriers, hybrid nanocapsules, and ligand-targeted formulations, show promise in improving stability, tumor accumulation, and CSC-specific targeting. These nanoformulations consistently enhance intracellular uptake and amplify anti-CSC effects in preclinical models. Overall, the consolidated evidence supports phytochemicals as potent modulators of CSC biology and underscores the need for optimized delivery strategies and evidence-based combination regimens to achieve meaningful clinical benefit. Full article

Background: The DPYD gene encodes dihydropyrimidine dehydrogenase (DPD), an enzyme essential for metabolising chemotherapeutic agents such as capecitabine, 5-fluorouracil (5-FU), and tegafur. Variants in this gene can increase the toxicity of these treatments. Methods: This study analysed data from 1478 cancer patients at Nottingham University Hospitals who received chemotherapy between December 2021 and December 2023. The study assessed the prevalence of DPYD variants across different tumour types, ethnic groups, and socioeconomic factors. Results: Overall, DPYD variants were identified in 7% of patients, with higher rates in colorectal cancer (7.9%) and among Caucasian patients (7.4%). The most frequent variant was c.1129-5923C>G (HapB3), found in 75.7% of variant-positive cases. No significant differences in DPYD testing rates were observed across socioeconomic groups or between ethnic backgrounds within our cohort. Conclusions: DPYD variants were prevalent in 7% of the cohort, and testing access was not influenced by socioeconomic status. Full article

Cisplatin (CDDP) is a cornerstone chemotherapeutic drug, yet its efficacy is frequently compromised by renal toxicity, primarily manifesting as acute kidney injury (AKI). Magnolol (MG) is a polyphenol from Magnolia officinalis and has been widely documented for its pronounced antioxidant and anti-inflammatory properties. This study evaluated the renoprotective effects of MG in a murine model of CDDP-induced AKI. Male C57BL/6 mice received MG (20 mg/kg) via daily intraperitoneal injection for four consecutive days, starting one day before a single CDDP injection. MG significantly reduced the serum concentrations of blood urea nitrogen and creatinine. Histopathological assessment revealed attenuated tubular damage and reduced expression of tubular injury markers. MG inhibited pro-inflammatory cytokines at both systemic and renal levels, alleviated endoplasmic reticulum stress, and suppressed activation of mitogen-activated protein kinase signaling pathways. Apoptotic damage was mitigated, as shown by the fewer TUNEL-positive cells and lowered expression of pro-apoptotic markers. In parallel, ferroptotic processes were alleviated through downregulation of pro-ferroptotic proteins and preservation of key antioxidant regulators. Importantly, MG restored nuclear factor erythroid 2-related factor 2 activity and upregulated downstream antioxidant effectors. These findings highlight the multi-targeted renoprotective actions of MG and support its possible utility as a therapeutic agent to prevent CDDP-induced renal injury. Full article

The progression of neoplastic diseases is driven by a complex interplay of biological processes, including uncontrolled proliferation, enhanced invasion, metastasis, and profound metabolic reprogramming. Among the hallmarks of cancer, as revised by Hanahan and Weinberg, the reprogramming of energy metabolism has emerged as a critical feature that enables cancer cells to meet their heightened bioenergetic and biosynthetic demands. One significant aspect of this metabolic adaptation is the accumulation of lipid droplets (LDs) dynamic, cytoplasmic organelles primarily involved in lipid storage and metabolic regulation. LDs serve as reservoirs of neutral lipids and play a multifaceted role in cancer cell physiology. Their accumulation is increasingly recognized as a marker of tumor aggressiveness and poor prognosis. By storing lipids, LDs provide a readily accessible source of energy and essential building blocks for membrane synthesis, supporting rapid cell division and growth. Moreover, LDs contribute to cellular homeostasis by modulating oxidative stress, maintaining redox balance, and regulating autophagy, particularly under nutrient-deprived or hypoxic conditions commonly found in the tumor microenvironment. Importantly, LDs have been implicated in the development of resistance to cancer therapies. They protect cancer cells from the cytotoxic effects of chemotherapeutic agents by buffering endoplasmic reticulum (ER) stress, inhibiting apoptosis, and facilitating survival pathways. The presence of LDs has been shown to correlate with increased resistance to a variety of chemotherapeutic drugs, although the precise molecular mechanisms underlying this phenomenon remain incompletely understood. Emerging evidence suggests that chemotherapy itself can induce changes in LD accumulation, further complicating treatment outcomes. Given their central role in cancer metabolism and therapy resistance, LDs represent a promising target for therapeutic intervention. Strategies aimed at disrupting lipid metabolism or inhibiting LD biogenesis have shown potential in sensitizing cancer cells to chemotherapy and overcoming drug resistance. In this review, we comprehensively examine the current understanding of LD biology in cancer, highlight studies that elucidate the link between LDs and drug resistance, and discuss emerging approaches to target lipid metabolic pathways to enhance therapeutic efficacy across diverse cancer types. Full article

Mutations in TP53 inhibit p53 protective behaviors including cell cycle arrest, DNA damage repair protein recruitment, and apoptosis. The ubiquity of p53 in genome-stabilizing functions leads to an aberrant tumor microenvironment in TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Profound immunosuppression mediated by myeloid-derived suppressor cells, the upregulation of cytokines and cell-surface receptors on leukemic cells, the suppression of native immune regulator cells, and metabolic aberrations in the bone marrow are features of the TP53-mutated AML/MDS marrow microenvironment. These localized changes in the bone marrow microenvironment (BMME) explain why traditional therapies for MDS/AML, including chemotherapeutics and hypomethylating agents, are not as effective in TP53-mutated myeloid neoplasms and demonstrate the dire need for new treatments in this patient population. The unique pathophysiology of TP53-mutated disease also provides new therapeutic approaches which are being studied, including intracellular targets (MDM2, p53), cell-surface protein biologics (immune checkpoint inhibitors, BiTE therapy, and antibody–drug conjugates), cell therapies (CAR-T, NK-cell), signal transduction pathways (Hedgehog, Wnt, NF-κB, CCRL2, and HIF-1α), and co-opted biologic pathways (cholesterol synthesis and glycolysis). In this review, we will discuss the pathophysiologic anomalies of the tumor microenvironment in TP53-mutant MDS/AML, the hypothesized mechanisms of chemoresistance it imparts, and how novel therapies are leveraging diverse therapeutic targets to address this critical area of need. Full article

Carrots are exceptional sources of bioactive compounds with potential health benefits. This study investigated the relationship between the biodiversity of carrot cultivars (colour and size) and their potential chemopreventive properties. Four distinct carrot cultivars (orange, white, yellow, and purple) of normal and miniature sizes were comprehensively analysed for polyphenolic composition, bio-accessibility through in vitro simulated digestion, and in vitro antiproliferative activity against the HCT-116 colon cancer cell line. Our findings revealed that vegetable size influenced phytochemical composition more than vegetable colour, with mini purple carrots exhibiting exceptionally high polyphenolic concentrations and superior antiproliferative activity compared to orange, yellow, or white varieties. Notably, the bioaccessibility of bioactive compounds remained remarkably low across all samples, suggesting that these phytochemicals reach the colon in intact form, potentially enabling direct interaction with cancer cells. Interestingly, we found no direct correlation between total phenolic content and antiproliferative activity. In vitro cell cycle analysis revealed that mini purple carrot extracts induced S-phase arrest similar to the chemotherapeutic agent 5-FU, whereas other extracts caused G0/G1-phase arrest. The specific polyphenolic composition appears to be fundamentally important for bioactivity, with chlorogenic acid and diferulic acid-derivative isomer 2 potentially acting synergistically. These findings highlight the importance of carrot biodiversity in delivering functional foods with enhanced health-promoting properties, particularly for colorectal cancer prevention. Full article

Lysosomal inhibition by different agents like chloroquine and bafilomycin A is known to sensitize some tumor cells to chemotherapeutic drugs. The mechanism and signaling pathways are still under investigation. We showed that chloroquine sensitized tumor cells (MCF7, SKBR3, HCT116) to drugs (carboplatin, cisplatin) treatment. Treatment with the combination of platinum drugs and chloroquine resulted in the increased rate of apoptosis compared with single agent treatment. Moreover, we demonstrated the inhibition of the resumption of cell proliferation after cell cycle arrest induced by drugs treatment. Cells treated with the combination of carboplatin (or cisplatin) and chloroquine demonstrated the significant increase in Chk1 protein phosphorylation (Ser345), which together with S-phase increase indicated the induction of replication stress compared to cells treated with carboplatin (or cisplatin) alone. The rescue experiment performed by supplementation the combination of carboplatin and chloroquine with deoxyribonucleotides (dNTPs) demonstrated the reverse of inhibition of cells’ re-proliferation after cell cycle arrest caused by this combination of drugs. Treatment with carboplatin and ATR inhibitor (ceralasertib) greatly increased the level of phospho-Chk1 and induced the replication stress, which is consistent with previous studies. Supplementation of the above drug combination with chloroquine further increased Chk1 phosphorylation and decreased the number of cells able to re-proliferate after the induced stress. Here, we also demonstrated that dNTPs’ supplementation reversed the effect of chloroquine. Similar results were obtained with the combination of carboplatin and Chk1 inhibitor (prexasertib). It was also demonstrated that chloroquine could potentiate the effect of single agent treatment of tumor cells with ATRi/Chk1i in MCF7 cells. Here, we proposed a novel explanation for the chloroquine ability to potentiate the effect of chemotherapy. The results clearly demonstrated that stress induced by chloroquine is due to its ability to increase the replication stress and to reduce the availability of nucleotides. Full article

Stress granules (SGs) are dynamic, membraneless organelles that form in response to stress and play pivotal roles in translational control, RNA metabolism, and cell survival. In cancer, SGs are increasingly recognized as central mediators of therapy resistance, enabling malignant cells to evade apoptosis, reprogram metabolism, and modulate immune responses. Understanding the mechanistic and clinical insights into SG kinetics in healthy versus cancer cells holds significant potential for targeting them in precision oncology. This review integrates current knowledge on how chemotherapeutic agents, oncogenic signaling pathways, and tumor microenvironmental stressors promote SG formation, as well as evidence of altered SG kinetics across tumor types. We further highlight how the upregulation of SG components within the tumor microenvironment shapes cancer cell behavior and adaptability, and how crosstalk between SGs and other biomolecular condensates could contribute to resistance. Finally, we discuss emerging therapeutic strategies targeting SGs, including kinase inhibitors and modulators of SG dynamics, and propose that SGs represent tractable vulnerabilities in precision oncology. By bridging mechanistic insights with clinical implications, this review positions SGs as a promising frontier in overcoming cancer therapy resistance. Full article

The rising global burden of colorectal cancer (CRC) has now positioned it as the third most common cancer worldwide. Chemotherapy regimens are known to disrupt the composition of the gut microbiota and lead to long-term health consequences for cancer patients. However, the alteration of gut microbiota by specific chemotherapeutic agents has been insufficiently explored until now. The purpose of this study was to assess changes in the gut microbiota following treatment with VERU-111 as a chemotherapy agent for the treatment of CRC. We thus performed a metagenomic study using 16S rRNA gene amplicon sequencing of fecal samples from different experimental groups in the azoxymethane (AOM) and dextran sodium sulfate (DSS)-induced murine model of CRC. To predict the functional potential of microbial communities, we used the resulting 16S rRNA gene sequencing data to perform Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. We found that the administration of VERU-111 led to a restructured microbial community that was characterized by increased alpha and beta diversity. Compared to the mice treated with DSS alone, VERU-111 treatment significantly increased the relative abundance of several bacterial species, including Verrucomicrobiota species, Muribaculum intestinale, Alistipes finegoldii, Turicibacter, and the well-known gut-protective bacterial species Akkermansia muciniphila. The relative abundance of Ruminococcus, which is negatively correlated with immune checkpoint blockade therapy, was diminished following VERU-111 administration. Overall, this metagenomic study suggests that the microbial shift after administration of VERU-111 is associated with suppression of several metabolic and cancer-related pathways that might, at least in part, facilitate the suppression of CRC. These favorable shifts in gut microbiota suggest a novel therapeutic dimension of using VERU-111 to treat CRC and emphasize the need for further mechanistic exploration. Full article

Background: As a widely used chemotherapeutic agent, cisplatin frequently induces acute kidney injury (AKI), which severely compromises patient survival and limits its clinical use. While the natural flavonoid diosmetin (Dio) shows promise in mitigating cisplatin-induced nephrotoxicity, its clinical translation is challenged by poor solubility, low bioavailability, and incompletely elucidated mechanisms. This study aimed to overcome these limitations by developing a novel drug delivery system using the microalgae Dunaliella salina (D. salina, Ds) to load Dio (Ds-Dio), thereby enhancing its efficacy and exploring its therapeutic potential. Methods: We first characterized the physicochemical properties of Ds and Dio, and then Ds-Dio complex was synthesized via co-incubation. Its nephroprotective efficacy and safety were systematically evaluated in a cisplatin-induced mouse AKI model by assessing renal function (serum creatinine, blood urea nitrogen), injury biomarkers, histopathology, body weight, and organ index. The underlying mechanism was predicted by network pharmacology and subsequently validated experimentally. Results: The novel Ds-Dio delivery system has been successfully established. In the AKI model, Ds-Dio significantly improved renal function and exhibited a superior protective effect over Dio alone; this benefit is attributed to the enhanced bioavailability provided by Ds carrier. In addition, Ds-Dio also demonstrated safety performance, with no evidence of toxicity to major organs. Network pharmacology analysis predicted the involvement of PI3K/AKT pathway, which was experimentally verified. Specifically, we confirmed that Ds-Dio alleviates AKI by modulating the PI3K/AKT pathway, resulting in concurrent suppression of NF-κB-mediated inflammation and activation of NRF2-dependent antioxidant responses. Conclusions: This study successfully developed a microalgae-based drug delivery system, Ds-Dio, which significantly enhances the nephroprotective efficacy of Dio against cisplatin-induced AKI. The nephroprotective mechanism is associated with modulation of the PI3K/AKT pathway, resulting in the simultaneous attenuation of oxidative stress and inflammation. Full article

Bidens pilosa L., a traditional Chinese medicinal herb, has been used in clinical practice for the treatment of inflammatory diseases and cancer. BPA, an extract derived from the whole herb of B. pilosa L., has been shown to possess potent immunomodulatory properties by regulating tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) within the tumor microenvironment (TME) in a mouse syngeneic colorectal cancer (CRC) model. RT-PCR and flow cytometry analyses showed that BPA, together with its flavonoid and polyacetylene constituents, effectively suppressed the differentiation of M2-TAMs and Tregs by downregulating Arg-1 and CD25 expression. They had minimal effects on the expression of markers associated with M1-TAMs and promoted the proliferation of CD4⁺ T cells that were inhibited by M2-TAMs and Tregs. In mice, BPA markedly inhibited the growth of syngeneic CRC tumors, accompanied by decreased serum levels of the immunosuppressive cytokine IL-10 and reduced expression of the proliferative marker Ki67 in tumor tissues. Moreover, BPA downregulated the mRNA expression of markers associated with M2-TAMs and Tregs, while increasing markers associated with M1-TAMs. Western blot analyses of tumor tissues revealed that BPA reduced the expression of marker proteins associated with M2-TAMs and Tregs, while increasing the expression of the immune-stimulatory markers CD80, GITR and CD4. In addition, combined treatment with BPA and 5-fluorouracil (5-FU), a commonly used chemotherapeutic agent for CRC, notably enhanced the anti-tumor effect in mice. These findings indicate that BPA, an active extract of B. pilosa L., showed antitumor activity in mice by suppressing the differentiation of pro-tumorigenic TAMs and Tregs within the TME. Full article

Quercetin (Q), a bioactive flavonoid, exerts potent antioxidant and redox-modulating effects by activating the nuclear factor erythroid 2-related factor 2/antioxidant response Element (Nrf2/ARE) pathway and upregulating endogenous antioxidant defenses, including enzymatic antioxidants such as superoxide dismutase (SOD) and catalase (CAT), as well as non-enzymatic glutathione (GSH) and lipid peroxidation (MDA). Gemcitabine (Gem), a widely used antimetabolite chemotherapeutic, often shows limited efficacy under hypoxic and oxidative stress conditions driven by hypoxia-inducible factor 1-alpha (HIF-1α) and vascular endothelial growth factor (VEGF)-mediated angiogenesis. This study investigated the redox-mediated synergistic effects of Q and Gem in MDA-MB-231 human breast cancer cells. Combination treatment significantly reduced cell viability beyond the expected Bliss value, indicating a synergistic interaction and enhanced apoptosis compared with single-agent treatments. Increased reactive oxygen species (ROS) production was accompanied by depletion of GSH and accumulation of MDA, establishing a pro-apoptotic oxidative stress environment. Q alone enhanced SOD and CAT activities, whereas the combination induced exhaustion of antioxidant defenses under oxidative load, reflecting a redox-adaptive response. Molecular analyses revealed downregulation of HIF-1α and VEGF, alongside upregulation of Bax and Caspase-3, confirming suppression of hypoxia-driven survival and activation of the intrinsic apoptotic pathway. Transcriptomic and enrichment analyses further identified modulation of oxidative stress- and apoptosis-related pathways, including phosphoinositide-3-kinase–protein kinase B/Akt (PI3K/Akt), HIF-1 and VEGF signaling. Collectively, these results indicate that Q potentiates Gem cytotoxicity via redox modulation, promoting controlled ROS elevation and apoptosis while suppressing hypoxia-induced survival mechanisms, highlighting the therapeutic potential of redox-based combination strategies against chemoresistant breast cancer. Full article

Immunotherapy has become a promising treatment for gastric cancer. However, its effectiveness varies significantly across subtypes because of heterogeneous immune microenvironments and genomic alterations. Here, we established Immune&Driver molecular subtypes CS1 and CS2 by systematically integrating multi-omics data for immune-related and driver genes. CS1 was linked to a better prognosis, while CS2 represented a poorer prognostic phenotype. CS1 displayed enhanced genomic instability, marked by higher mutation frequency and chromosomal alterations. In contrast, CS2 exhibited higher immune activity, with a higher density of immune cell infiltration and increased expression of chemokines and immune checkpoint genes. Among FDA-approved anti-cancer agents included in a pan-cancer drug sensitivity prediction framework, CS1 was predicted to be more sensitive to conventional chemotherapeutic agents, whereas CS2 was predicted to be more responsive to immune-related agents. In melanoma datasets, a CS2-like transcriptomic pattern was associated with improved response to anti-PD-1 therapy, with the combination of anti-PD-1 and anti-CTLA-4 showing more favorable response patterns compared to anti-PD-1 monotherapy. Additionally, we developed an immunotherapy response prediction model using PCA-based logistic regression according to the transcriptional expression of CS biomarkers. The model was trained in melanoma immunotherapy cohorts and validated across independent melanoma datasets, and it further achieved a higher AUC in an external gastric cancer cohort treated with anti-PD-1 therapy. Collectively, this study highlights immune and genomic heterogeneity in gastric cancer and provides a hypothesis-generating framework for exploring immunotherapy response. Full article

Background/Objectives: Docetaxel is a widely used chemotherapeutic agent for several malignancies and is an established treatment for castration-resistant prostate cancer. However, its poor aqueous solubility, systemic toxicity, and the emergence of drug resistance limit its clinical benefit. Zein, a prolamin, forms micelles that enhance the solubility and delivery of hydrophobic drugs. As PEG length and ligand presentation govern micelle behavior, we investigated transferrin-functionalized PEGylated zein micelles as docetaxel nanocarriers and examined how PEG chain length (5 K vs. 10 K) and transferrin-mediated targeting affect delivery to prostate cancer cells. Methods: Docetaxel-loaded zein micelles bearing 5 K or 10 K PEG chains were prepared and conjugated to transferrin. Formulations were characterized for size, charge, morphology, critical micelle concentration, colloidal stability, drug loading and transferrin density. Cellular uptake and mechanisms were assessed in PC-3-Luc, DU145 and LNCaP cells by confocal microscopy, flow cytometry and pharmacological inhibition. Anti-proliferative activity was determined by MTT assays. Results: Both PEG5K and PEG10K micelles formed micellar dispersions with low polydispersity and high encapsulation efficiency. PEG5K micelles achieved higher transferrin conjugation and drug loading. Transferrin-functionalized PEG5K micelles showed enhanced uptake in DU145 and LNCaP cells but lower internalization in PC-3-Luc cells. Inhibitor studies indicated receptor-dependent uptake via clathrin- and caveolae-mediated endocytosis. Free docetaxel remained the most potent. However, among nanocarriers, transferrin-targeted PEG5K micelles showed the greatest anti-proliferative efficacy relative to their non-targeted counterparts, whereas transferrin-targeted PEG10K micelles were less potent than the non-targeted PEG10K micelles across all three cell lines. Conclusions: PEG chain length and ligand presentation are key determinants of uptake and cytotoxicity of docetaxel-loaded zein micelles. Shorter PEG chains favor effective transferrin display and receptor engagement, whereas longer PEG likely induces steric hindrance and reduces targeting, supporting transferrin-conjugated PEG5K zein micelles (the lead formulation in this study) as a targeted delivery platform that improves performance relative to matched non-targeted micelles in vitro, while free docetaxel remains more potent in 2D monolayer assays. Full article