A new series of aliphatic-substituted benzimidazole derivatives was synthesized and structurally characterized to evaluate their potential anticancer activity. Among the synthesized compounds, compound 4 exhibited the most potent cytotoxic effects against MCF-7 and MDA-MB-231 breast cancer cell lines, with IC₅₀ values comparable to those of cisplatin, while displaying lower toxicity toward normal breast epithelial cells (MCF-10A). Flow cytometric analysis revealed that treatment with compound 4 resulted in significant accumulation of cells in the S phase, indicating inhibition of DNA synthesis and replication. Furthermore, Annexin V/PI double-staining analysis demonstrated a marked increase in both early and late apoptotic cell populations, confirming the activation of apoptotic pathways. Molecular docking studies supported these experimental findings by revealing strong interactions of compound 4 with key regulatory proteins involved in apoptosis and cell cycle progression, including Bcl-2, Bcl-xL, CDK2, and Cyclin E. The compound exhibited the highest binding affinity toward CDK2 (-164.055 kcal/mol), forming hydrogen bonds with critical residues (LEU134, ASP145, GLN131, and LYS33) within the ATP-binding pocket, suggesting potential inhibition of kinase activity. Interactions with Bcl-2 and Bcl-xL occurred within the BH3-binding grooves, which may impair their anti-apoptotic functions and promote mitochondrial-mediated apoptosis. Collectively, the in vitro and in silico results indicate that this newly synthesized benzimidazole derivative exerts its anticancer effects through a dual mechanism involving cell cycle arrest and apoptosis induction. The selective cytotoxicity and multitarget interaction profile of compound 4 highlight its potential as a promising lead compound for the development of novel therapeutic agents against breast cancer.

Multi-target enzyme inhibition represents a promising strategy to overcome resistance and improve therapeutic outcomes in cancer therapy. In this study, a new series of 1,3,4-oxadiazole derivatives was synthesized and evaluated for cytotoxic and multi-target anticancer activities. Several compounds demonstrated potent antiproliferative effects against HepG2, MCF-7, and HCT-116 cancer cell lines with reduced toxicity toward WI-38 normal fibroblasts. Among them, compounds 1, 9, 12, and 13 emerged as the most promising candidates, showing strong cytotoxicity and favorable selectivity profiles. Enzyme inhibition assays confirmed their ability to target key oncogenic enzymes, including wild-type and mutant (T790M) EGFR, telomerase, and thymidylate synthase. Mechanistic studies revealed that compound 12 induced G1 phase cell cycle arrest and promoted apoptosis in HepG2 cells with minimal necrosis. Molecular docking, molecular dynamics simulations, and MM-GBSA analyses supported stable binding of the active compounds within the catalytic sites of the investigated enzymes. Overall, these findings identify compounds 1, 9, 12, and 13 as promising multi-target anticancer leads warranting further optimization and development.

The current thiazole Schiff base ligand was obtained upon reacting 2-amino-5-methylthiazole with 2,4-dihydroxybenzaldehyde (H2L). The transition metal chelates then were presented by reacting the ligand with Mn(II), Cu(II), and Zr(IV) salts in 1:1 molar ratio forming chelates, 1, 2 and 3, respectively. The reaction of the ligand with Cd(CH₃COO)₂ afforded Cd(II) complex, 4, in the molar ratio 2L:1 M. The type of contact that occurs between metal ions and the thiazole ligand was investigated by the assistance of magnetic susceptibility, FTIR, mass, UV-Visible and 1H NMR spectral and micro-elemental analyses. The resulting data demonstrated that the ligand-metal interaction happened via the phenolic O-atom ortho-position and the imine group N- atom which is dehydrogenated to form the metal complexes. Solvent molecules attached to the metal ions in complexes, whether present or absent were suggested using TGA in addition to thermodynamic activation parameters for the thermal decomposition steps were computed by the Eyring equation. Magnetic moment and UV-Visible measurements indicated formation of square planar Cu(II) chelate and octahedral Zr(IV) chelate, while the Mn(II) and Cd(II) ions formed tetrahedral metal chelates. XRD and TEM used to reveal structural microcrystalline data of both the organic compound (H2L) and inspected complexes. The patterns of X-ray diffraction introduced the crystalline nature of each of the free ligand, complexes 1, 3 and 4, whereas complex 3 was relatively amorphous without an even dispersion of the solid constituents throughout the precipitation procedure. The study rigorously analyzed molecular structures using Density Functional Theory (DFT) calculations, revealing significant variations in ligand bond lengths and angles upon complexation, and demonstrating the electron-donating and accepting properties of HOMO and LUMO orbitals. Biological activity for the prepared compounds was accomplished. They exhibited high activity, especially after chelation. The Antimicrobial activity afforded very auspicious data upon comparison with the applied reference antibiotic. The greatest anti-cancer activity has been achieved by Cu(II)-complex 2 which showed IC50 value = 16.89 µg/ml against MCF-7 cell lines which is greater than the IC50 value of scaled drug applied (IC50 of 5-flurouracil = 28.0 µg/ml). Promising bioactive compounds' binding affinities with HepG-2 and MCF-7 DNA helices were estimated to apply molecular docking.

Immune checkpoint inhibitors have become one of the pillars of cancer treatment, but may be associated with a wide range of potential adverse effects. In this review, we discuss the presentation and management of immune-related adverse events according to their severity and organ system involvement. Tables with management guidelines are included.

Rutin (RTN) is a natural flavonoid with well-documented anti-angiogenic, antioxidant, anti-inflammatory, and anti-cancer properties. However, its therapeutic potential is limited by its extremely low water solubility, which results in poor and unpredictable bioavailability. To address these limitations, we developed a new formulation that complexes RTN with a soluble polymeric β-cyclodextrin (βCPCD). βCPCD is synthesized by cross-linking polyethylene glycol (PEG) and β-cyclodextrin (βCD). The high complexing capacity of βCPCD was demonstrated by a ∼ 50-fold increase in RTN solubility and complete dissolution within 60 min. These results suggest a dual encapsulation mechanism involving (i) the inclusion of RTN within the βCD cavity and (ii) the allocation of RTN within the free volume of the three-dimensional (3D) polymeric structure. The host-guest interaction was confirmed via UV-Vis titration, NMR, µ-Raman and FTIR-ATR spectroscopy analyses. The thermal stability of the lyophilized complex was assessed by TGA, and the morphology was investigated by SEM. Preliminary docking and molecular dynamics simulations were carried out considering a local scenario consisting of a single RTN and a βCD-PEG unit. The excellent biocompatibility of βCPCD in Danio rerio zebrafish embryos (survivability > 95%) and the notable enhancement of the antiangiogenic effect of the RTN complex compared to the free drug highlight the potential of βCPCD as an effective delivery system to improve RTN performance.

Lung cancer is the most common cancer worldwide. It is often detected in the late stages of the disease and is difficult to treat. Furthermore, the cancer often develops resistance to chemotherapy drugs such as cisplatin. This study aimed to compare the sensitivity of two variants of the A549 cell line: sensitive and resistant to cisplatin, to the action of 7-ketocholesterol. A549 cells were exposed to cisplatin for several weeks to generate a cisplatin-resistant subpopulation. They were then exposed to various concentrations of 7-ketocholesterol. The effect of 7-ketocholesterol on cell viability, apoptosis, and reactive oxygen species was examined. The results for both variants of the A549 cell line subpopulations demonstrated a slightly greater sensitivity of the cisplatin-resistant subpopulation to 7-ketocholesterol. These are preliminary, pilot studies that pave the way for more advanced research on the effects of oxysterols on chemotherapy-resistant cancer cells.

Therapeutic regimens for pediatric malignancies such as neuroblastoma remain complex and are often associated with severe systemic toxicity. The development of more efficacious and less toxic therapeutic strategies is imperative to enhance both overall survival and the quality of life for high-risk patients. Cancer nanomedicine has emerged as a transformative platform in oncology, enabling precision therapies and targeted delivery of chemotherapeutic agents. In this study, we designed solid lipid nanoparticles encapsulating the topoisomerase II inhibitor etoposide, aiming to reformulate this agent for oral administration in the treatment of aggressive neuroblastoma. Nanoencapsulation significantly improved the pharmacokinetic and biodistribution profiles of the drug, enhancing its bioavailability and tumor accumulation. To simulate a metronomic dosing regimen, MYCN-amplified SK-N-BE(2) tumor-bearing mice received up to ten oral administrations over a 30-day period. The nanoformulation demonstrated superior antitumor efficacy and a markedly reduced toxicity profile compared to both oral and intravenous commercial formulations. These findings support the potential of nanomedicine-based strategies as safer and more effective alternatives to conventional chemotherapy in neuroblastoma.

Cancer immunotherapy harnesses and amplifies the host's anti-tumor immune responses to eradicate malignant cells. Tumor neoantigens serve as ideal targets due to high specificity and immunogenicity. Circular RNA (circRNA), with a stable covalently closed structure, can be engineered as a novel vector for neoantigen expression. Here, we developed a circRNA-based vaccine encoding multiple melanoma neoantigens (circRNAMNA). circRNAMNA significantly suppressed tumor growth in both prophylactic and therapeutic murine models and induced robust anti-tumor immunity. Mechanistically, using single-cell RNA sequencing, we elucidated the antitumor mechanisms and alterations in the tumor and immune microenvironment following vaccination. circRNAMNA immunization nearly eliminated the Ccl6+Mel subcluster-highly active in chemokine signaling, leukocyte recruitment, and antigen presentation pathways. While residual Cdk1+Mel and Cdhr4+Mel subclusters exhibited downregulation of immune-response-related pathways. Furthermore, circRNAMNA vaccination reshaped myeloid cell composition, markedly increasing infiltration of monocytes/macrophages (Monocyte/MФ) with antitumor phenotypes, including classical inflammatory monocytes (Mono-Vcan), Macro-C1qc, and activated M1-like macrophages (Macro-Ifng). Chemokine signaling was enriched in Ccl6+Mel and Monocyte/MФ clusters. Moreover, circRNAMNA enhanced T cell-mediated antitumor responses, elevating T cell receptor (TCR) clonotype diversity and expansion of TCR clonotypes especially in CD4+ effector (CD4 Eff) and CD8+ cytotoxic (CD8 Cyto) T cells. Notably, Tigit was identified as the most highly expressed checkpoint receptor in CD8+ exhausted T cells (CD8 Tex), and combining circRNAMNA with anti-TIGIT/PD1 blockade produced synergistic antitumor effects. Collectively, this study systematically elucidates the therapeutic potential and immune mechanisms of the neoantigen circRNA vaccine in melanoma, providing a mechanistic framework for developing personalized RNA vaccines and rational combination immunotherapies.

Doxorubicin (DOX), an anthracycline chemotherapeutic agent, induces significant male reproductive toxicity, however, its molecular mechanisms remain incompletely defined. Although oxidative stress is implicated in DOX-induced testicular injury, the roles of iron dysregulation and antioxidant suppression have not been fully characterized in the testis. We investigated time-dependent effects of DOX on testicular morphology, iron homeostasis, and oxidative stress, and evaluated the potential protective effects of (4-(methylthio)phenylthio) methane bisphosphonate (MPMBP), an iron-chelating and antioxidant compound. Male ICR mice received a single intraperitoneal injection of DOX (5 mg/kg). In Experiment 1, testes were collected at 24 h, 48 h, and 1-5 weeks to assess morphological changes, germ cell counts, transcriptional alterations in apoptosis-, antioxidant-, and iron metabolism-related genes, and iron deposition using electron probe microanalysis (EPMA). In Experiment 2, MPMBP (10 mg/kg) was administered either concomitantly with DOX or starting 5 days later, and testicular endpoints were evaluated at 5 weeks. DOX induced progressive testicular atrophy and depletion of early-stage germ cells. Apoptosis-related genes exhibited biphasic upregulation, accompanied by iron accumulation and downregulation of Gpx4 and mitochondrial ferritin (Ftmt). EPMA confirmed iron deposition within seminiferous tubules and interstitial regions. MPMBP co-administration was associated with partial preservation of testicular architecture, reduced iron accumulation, and modest restoration of Gpx4 and Ftmt expression, although these effects were incomplete under the present experimental conditions. These findings associate iron dysregulation and impaired antioxidant defense with DOX-induced testicular injury and support further preclinical investigation of iron-chelating and antioxidant strategies aimed at mitigating chemotherapy-associated reproductive toxicity.

Hedysarum polybotrys Hand.-Mazz. (Hongqi, HQ) is a prized Qi-tonifying herb in Traditional Chinese Medicine (TCM), historically employed to enhance the body's resistance and modulate immune function. While its anti-tumor properties are recognized, the specific immunomodulatory mechanisms by which HQ empowers Natural Killer (NK) cells to combat prostate cancer (PCa) remain under-explored.

Immune checkpoint inhibitors (ICIs) show increasing promise for cancer therapy. However, patients can experience adverse events, particularly those with pre-existing autoimmune disease. We determined that the microbiome can drive ICI-induced systemic toxicity in a mouse model of autoimmune susceptibility. Specifically, ICI treatment of specific pathogen-free (SPF) Act1-/- mice, which develop spontaneous autoimmunity due to a deficiency in an immune adaptor, resulted in systemic adverse events that were ameliorated by topical antibiotics. Moreover, germ-free (GF) Act1-/- mice failed to develop ICI toxicity. Transfer of gut or skin microbiota from SPF Act1-/- mice to GF Act1-/- mice showed that only the skin microbiota rendered exGF mice sensitive to ICI toxicity. Notably, therapeutic application of topical antibiotics decoupled ICI-induced toxicity from anti-tumor efficacy in SPF Act1-/- mice. This model provides a paradigm for future translational studies in cancer patients to mitigate adverse effects of ICIs and maximize their efficacy by targeting skin microbes.

Cancer remains a formidable disease with significantly high mortality rates worldwide. Herein, we attempted to design and evaluate a new class of VEGFR-2 and HDAC dual acting anticancer agents. The rationale was based on the defined pharmacophores of VEGFR-2 inhibitors and HDAC inhibitors, as we synthesized new quinazolinone based-benzamides that bring together both features. The new candidates showed considerable in vitro activity against MDA-MB-231 and HCT-116 cancer cell lines, in particular 4-hydroxyphenylbenzamide derivative of 3-ethylquinazolinone 7d, which revealed IC50 of 5.39 ± 0.08 μM and 4.11 ± 0.13 μM, in comparison with IC50 of 29.13 ± 2.28 μM and 33.50 ± 2.43 μM, obtained for the reference drug, sorafenib, respectively. So, 7d was approximately 5.4-fold and 8.2-fold more potent than sorafenib against the aforementioned cell lines, respectively. Additionally, 7d had far better selectivity to cancer cells, showing selectivity indices of 5.11 and 6.68, compared to 1.73 and 1.51 recorded for sorafenib against the two cancer cell lines, respectively. Furthermore, it also showed a significant dual inhibition of VEGFR-2 and HDAC-2. It showed IC50 of 0.407 ± 0.015 μM against VEGFR-2, revealing approximately half the potency of sorafenib. Whereas, It was approximately 1.26 times more potent than vorinostat against HDAC-2, demonstrating an IC50 of 0.363 ± 0.013 μM. Furthermore, 7a was proven to be an apoptotic inducer to HCT-116 cells, increasing the apoptosis rate by 10-folds and causing cell cycle arrest at the G1 phase. Meanwhile, the expression level of caspase-3 and the BAX/BCL-2 ratio were markedly elevated in HCT-116 cells treated with 7d. Finally, the presented data are reliable for developing dual VEGFR-2 and HDAC inhibitors as anticancer drugs and reveal lead molecules for such purpose.

An efficient, diastereoselective synthesis of spiropyrrolidines by the three component reaction between isatin, 1,2,3,4-tetrahydro-β-carboline and 5-arylidene thiazolidine-2,4-dione by green protocol is reported here. The reaction resulted in a single regioisomer in excellent yields which was isolated by simple filtration. DFT calculations using B3LYP/6-31G(d,p) level of theory confirmed the diastereoselectivity of the reaction. Among all the products synthesized, the bromo-substituted compound displayed appreciable anticancer activity on MCF-7 breast cancer cells which was further studied by employing a range of in vitro assays. The MTT assay, used to assess cytotoxicity, indicated a concentration-dependent reduction in cell viability (IC50, 5.23 ± 0.014 μg/mL). AO/EtBr and Hoechst staining, used to analyse the apoptotic morphology, revealed apoptotic characteristics such as chromatin condensation, nuclear fragmentation, and loss of membrane integrity. Measurement of intracellular oxidative production, using DCFDA labelling, indicated a significant and dose-dependent increase in ROS levels. Migration analysis revealed a delayed wound closure in treated cells. Gene expression analysis of key apoptotic regulators demonstrated increased expression of pro-apoptotic genes and suppression of anti-apoptotic markers, examined by quantitative real-time PCR. All these results, demonstrate the excellent anticancer efficacy of the bromo-substituted compound and position it as a potent molecule for further investigations.

Cyclin-dependent kinase 1 (CDK1) is a key regulator of cell cycle progression and a potential therapeutic target for invasive malignancies. However, developing selective CDK1 inhibitors with manageable toxicity remains a significant challenge. In this study, a novel series of 1,2,4-triazolobenzene sulfonamide derivatives were designed and synthesized based on the structure of JNJ7706621 and its derivative 3n, and subjected to comprehensive bioactivity evaluation and structure-activity relationship discussion. Among them, 11l emerged as a highly promising lead compound, exhibiting nanomolar inhibitory activity against CDK1 (IC50 = 5.5 nM) with high selectivity over CDK2, Aurora A, and CDK4, showing selectivity indices of 4.7-, 14.1-, and 73.2-fold, respectively. In vitro, 11l exhibited broad antiproliferative activity, particularly against HCT116 colon cancer cells. Unlike conventional kinase inhibitors that solely suppress catalytic activity, 11l induced G2/M phase arrest and downregulated CDK1, cyclin B1, and the replication initiation factor CDC45. Further investigation revealed that 11l induces severe DNA replication stress, subsequently activating the p53 signaling pathway to trigger apoptosis. This mechanism was recapitulated in CDC45 knockdown models. In vivo efficacy evaluation demonstrated that 30 mg/kg 11l achieved a tumor growth inhibition (TGI) rate of 56.4%, without inducing significant body weight loss or observable organ toxicity. Collectively, these findings identify 11l as a safe CDK1 inhibitor with a distinct mechanism of action, supporting its potential as a promising therapeutic strategy for cancer treatment.

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking defined molecular targets and characterized by high rates of recurrence and metastasis. Aberrant activation of the epidermal growth factor receptor (EGFR) contributes to tumor progression and immune evasion in TNBC. Although EGFR inhibitors can temporarily suppress tumor growth, compensatory signaling and therapeutic resistance limit their effectiveness. Therapeutic strategies that modulate multiple pathways while enhancing antitumor immunity are needed, and selective nanoparticle-based delivery offers a means to improve potency while reducing nonspecific toxicity. We developed ND-dsRNA-VHH, a biocompatible carbon-based nanomaterial platform that codelivers EGFR-specific nanobodies (VHHs) and immunostimulatory double-stranded RNA, polyinosinic-polycytidylic acid (poly(I:C)). Optimized ND surface chemistry supported efficient dsRNA payload and stable VHH conjugation, yielding nanoparticles with EGFR-binding specificity and serum stability. Subsequent studies demonstrated that ND-dsRNA-VHH induced apoptosis, oxidative stress, and immunogenic cell death, leading to dendritic cell activation. Additional assessments indicated that treatment with ND-dsRNA-VHH reduced tumor growth, extended survival, increased T-cell infiltration, and shifted the tumor microenvironment toward a more proinflammatory, immunologically active state. The modular nature of this platform supports ligand exchange for broader applicability across EGFR-driven malignancies such as glioblastoma, underscoring its potential to enhance immunotherapy through combined ICD induction and immune priming.

Quercetin, a plant-derived dietary flavonoid, has multifunctional biological activities, including anticancer action; however, its applications may be restricted due to limited bioavailability. Thus, novel synthetic quercetin derivatives (QDs) with improved properties and/or drug combinations should be designed and tested. In the present study, anticancer activity of fourteen newly synthesized QDs was investigated using four cellular models of melanoma, namely A375, MM370, G-361, and SH-4 cells. Thioquercetins (thioQ, thioQ(OAc)4, and thioQ(OAc)5), when used at low micromolar range, induced apoptotic cell death in melanoma cells compared to normal cells. Thioquercetins also reduced the population of spheroid-forming cells and suppressed the growth of A375 cells in 3D spheroid models. Thioquercetin-mediated antimelanoma action was potentiated upon heat shock protein 90 (HSP90) inhibition. Co-treatment with the HSP90 inhibitor 17-DMAG and thioquercetins augmented oxidative stress (increased superoxide production, decreased levels of antioxidant proteins SOD1, and PRDX1-2), and impaired the aryl hydrocarbon receptor (AhR)/cytochrome P450 1A1 (CYP1A1) signaling pathway-based detoxification of thioquercetins by the inhibition of AhR translocation to the nucleus and AhR-mediated stimulation of CYP1A1 expression leading to enhanced cytotoxic effects against melanoma cells. The senolytic activity of thioQ(OAc)4 with four acetylated hydroxy groups against cisplatin-induced senescent melanoma cells was also revealed in selected experimental settings. We suggest that the use of novel thioquercetin-based derivatives along with HSP90 inhibitors should be further validated in vivo and considered for the design of more effective antimelanoma strategies in the future.

Immune-mediated diarrhea and colitis (IMDC) is a high-risk toxicity frequently experienced by patients treated with immune checkpoint inhibitors (ICIs) and requiring rapid supportive care interventions. Delays in IMDC reporting and inconsistent guideline adherence increase symptom burden and emergency department (ED) utilization. Although current practice guidelines provide IMDC management recommendations, adherence in routine oncology care remains uncertain. This study evaluated management and guideline concordance for clinically significant IMDC at a single National Cancer Institute-designated comprehensive cancer center to identify workflow opportunities to improve supportive management.

Patients with a DPYD genetic deficiency who receive capecitabine are at increased risk of severe, potentially fatal toxicities due to impaired drug metabolism. Genetic testing for this deficiency allows for proactive dose adjustments to mitigate these risks. We evaluated the cost-effectiveness of DPYD genotyping prior to capecitabine administration, followed by dose modification for patients with metastatic breast cancer.

AKT is a critical mediator of the phosphoinositide 3-kinase (PI3K) signalling cascade, playing a key role in regulating essential cellular processes. The identification of AKT as one of the most dysregulated pathways in cancer led to the development of multiple classes of inhibitors. Despite numerous inhibitors entering clinical investigation and leading to the FDA approval of Capivasertib, an ATP-competitive AKT inhibitor, in November 2023, AKT modulation through inhibition was characterised by toxicity and poor clinical efficacy. Targeted Protein Degradation (TPD) spearheaded by PROTACs boasted a paradigmatic shift in drug discovery and was demonstrated to be a valid therapeutic alternative to modulate AKT. To date, numerous AKT-targeting PROTACs have been disclosed. The majority of them outperformed the inhibitors in suppressing AKT activity, nurturing higher potency and improved selectivity. Notably, enhanced antiproliferative effects, sustained by more robust and prolonged inactivation of the AKT downstream signalling was observed. This review highlights AKT as a central therapeutic target in oncology and focuses on AKT modulation through a targeted protein degradation approach mainly using PROTACs. The review aims at illustrating all the AKT-targeting PROTACs disclosed in literature to date, a powerful new pharmacological tool that might remarkably expand the scope of AKT-targeted therapies and further elucidate the role of AKT in both normal and cancer-related phenotypes.

Atezolizumab plus bevacizumab (Atezo/Bev) is the standard first-line therapy for unresectable hepatocellular carcinoma (uHCC). In the IMbrave150 trial, bevacizumab-related adverse events (AEs) frequently required dose interruption or discontinuation, raising concerns regarding optimal dosing. The effect of initiating therapy with low-dose bevacizumab remains uncertain.