Symptomatic drug treatment is generally used to treat various side effects associated with paclitaxel-carboplatin (TC) or TC plus bevacizumab (TC+Bev). However, this can lead to increased adverse effects from additional drugs. Immersive virtual reality (iVR) reduces pain and anxiety.

RIOK2 is a promising therapeutic target in cancer due to its pivotal role in tumor progression. Based on our previously identified RIOK2 inhibitor CQ211, we conducted a comprehensive pharmacokinetic optimization campaign, leading to the discovery of CQ3196 as a potent and orally bioavailable RIOK2 inhibitor. CQ3196 demonstrates remarkable RIOK2 binding affinity, with a Kd value of 14 nM, and exhibits potent proliferative inhibitory activities in gastric cancer cell lines. Furthermore, CQ3196 displays favorable PK properties, it achieves an AUC(0-t) value of 3.5 × 103 μg/L·h following oral administration, ensuring sufficient drug exposure for therapeutic efficacy. Additionally, it achieves robust in vivo antitumor efficacy in an HGC-27 gastric cancer xenograft model. Oral administration of CQ3196 at 50 mg/kg resulted in a TGI value of 62.3%, highlighting its strong therapeutic potential. These compelling results underscore CQ3196 as a highly promising candidate for further development in RIOK2-targeted cancer therapy.

The cyclin-dependent kinase (CDK)/retinoblastoma protein (RB)/early region 2 binding factor (E2F) axis forms the core transcriptional machinery driving cell cycle progression. Alterations in RB1 or other pathway members occur in many cancers, resulting in heightened oncogenic E2F activity. The activity of E2F is regulated by RxL-mediated binding to the hydrophobic patch (HP) of Cyclin A; blocking this interaction results in the hyperactivation of E2F and synthetic lethality in E2F-driven tumors. While mechanistically differentiated and potentially more selective than blocking CDK activity (e.g., CDK2 or CDK4 inhibitors), the Cyclin A/E2F RxL interaction was deemed undruggable. Utilizing structure-based design, we have discovered a family of cell-permeable macrocyclic Cyclin A/B RxL inhibitors that show potent and selective activity against RB1/E2F-dysregulated cancer cell lines. Lead compound 34 demonstrated proof-of-concept efficacy via intraperiotoneal (IP) administration in mouse cell line-derived xenograft (CDX) tumor models.

Proteolysis-targeting chimeric (PROTAC) technology represents a groundbreaking approach with immense potential for treating a wide range of diseases. However, its clinical application is often limited by challenges in solubility and permeability. Herein, we have developed an innovative three-in-one nanoparticulate therapeutic agent tailored for non-small-cell lung cancer (NSCLC). This agent features a PROTAC molecule derived from ceritinib, designated as 27B, serving as a targeted degrader of anaplastic lymphoma kinase (ALK). 27B is self-assembled with vitamin A palmitate (VAP) and vitamin E poly(ethylene glycol) succinate (TPGS) to form stable nanoparticles (BVT-NPs) that exhibit a uniform spherical morphology, excellent storage stability, and robust plasma stability. With an average particle size of approximately 130 nm and a loading capacity of 27B of 20%, BVT-NPs demonstrate a pH-responsive drug release profile. In vitro studies reveal that BVT-NPs significantly inhibit the proliferation of H3122 cells more effectively than free 27B, indicating a synergistic antitumor effect. Western blot analysis further confirms the superior efficacy of BVT-NPs in downregulating ALK and P-glycoprotein and upregulating Caspase-3. BVT-NPs markedly suppress tumor growth without inducing significant tissue toxicity. This carrier-free, multifunctional nanoparticulate system integrates PROTAC-mediated protein degradation with chemotherapy, thereby improving the PROTAC absorption and generating a synergistic therapeutic effect against NSCLC.

Over 50% of newly diagnosed patients with breast cancer are aged ≥65 years. Due to age-related factors and the presence of comorbidities, these patients are particularly vulnerable to developing cardiac toxicity associated with cancer treatments, which may lead to suboptimal interventions and undertreatment, resulting in poorer health outcomes, quality of life (QoL) deterioration, and increased health care costs. Given the underrepresentation of older patients with breast cancer in clinical trials and the increasing recognition of the impact of psychosocial and behavioral factors on cardiovascular disease onset, broader and interdisciplinary studies are required to develop new and innovative best practices for this clinical population.

Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality worldwide. Despite the efficacy of oxaliplatin-based chemotherapy (CT) in CRC treatment, CT resistance remains a major obstacle to successful patient outcomes. Epithelial-mesenchymal transition (EMT), a key cellular process in cancer metastasis, plays a pivotal role in resistance to CT. The tumor microenvironment (TME), particularly cancer-associated fibroblasts (CAFs), is known to contribute to EMT and therapy resistance. Here, we employ single-cell RNA sequencing (scRNA-seq) to analyze primary CRC tumor samples from patients undergoing CT and nonchemotherapy (nCT) treatments. Our study identifies specific epithelial cell clusters resistant to oxaliplatin, elucidating the molecular pathways involved in EMT and resistance. Furthermore, we explore the role of CAF subpopulations in promoting resistance within the TME. Our findings highlight the importance of functional immune profiling and genomic analyses in identifying potential biomarkers for predicting CT responses and improving personalized treatment strategies. This work provides new insights into the molecular mechanisms of oxaliplatin resistance in CRC and supports the development of novel immune-based therapeutic approaches to enhance patient outcomes.

Liver cancer is the sixth most common cancer and the third leading cause of cancer death worldwide. The predominant type of primary liver cancer is hepatocellular carcinoma (HCC). Tumor vascular endothelial cells (VECs), a major component of cells in the microenvironment of HCC, play multifaceted roles in contributing to tumor angiogenesis, proliferation, and migration, as well as therapeutic resistance by attracting myeloid-derived suppressor cells and suppressing cytotoxic CD8 T cell differentiation and function. Recently, Wu et al reported that apatinib, an inhibitor of vascular endothelial growth factor receptor 2, can inhibit tumor VEC glycolysis by regulating phosphatidylinositol 3-kinase/protein kinase B/6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 signaling pathway to suppress HCC progression. With great interest, this editorial paper aims to review the function and key molecular signaling pathways of tumor VECs in HCC initiation and progression and summarize potential treatment options in clinical trials.

Targeted therapy combined with anti-programmed cell death 1 immunotherapy (TP) and trifluridine/tipiracil (TAS-102) combined with bevacizumab (TB) are two common therapies for patients with late-line therapy in microsatellite stable (MSS) metastatic colorectal cancer (mCRC). However, it is still unclear which therapy can bring better prognosis.

Glioblastoma (GB) is an aggressive brain tumor characterized by rapid proliferation, invasion, and resistance to therapy. The substance P (SP)/neurokinin-1 receptor (NK-1R) pathway contributes to GB progression by promoting angiogenesis, inflammation, and extracellular matrix remodeling. Aprepitant, an FDA-approved NK-1R antagonist, has shown potential as a therapeutic agent in glioma treatment.

We report the synthesis of four novel monoquaternary salts and four fused pyrrolo-phenanthridine compounds, fully characterized by NMR, FT-IR, and mass spectrometry. Guided by theoretical predictions, including molecular docking studies, we assessed their cytotoxic activity and biocompatibility. The docking results revealed notably stronger binding affinities compared to Phenstatin, a known anticancer agent, suggesting high therapeutic promise. In vitro cytotoxicity was evaluated on osteosarcoma cell lines HOS and MG-63, showing a marked cell-line-dependent response: all compounds inhibited MG-63 cell viability by approximately 50%, while their effect on HOS cells was more modest (20%-30%). No significant activity was observed against the MeWo melanoma line. Nonetheless, compounds 3a-d, 5a, and 5b demonstrated good biocompatibility at 10 and 50 µM and selective cytotoxicity toward MG-63 cells. These findings, combined with favorable docking profiles, highlight the potential of these compounds as anticancer candidates and justify further investigation.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype marked by pronounced intra-tumoral heterogeneity and frequent therapeutic resistance. In this study, we report the design, synthesis, and biological evaluation of a novel series of triazolopyrimidine-isatin hybrids against the TNBC cell lines MDA-MB-231 and MDA-MB-468. Among them, 9h emerged as the most promising candidate, exhibiting potent cytotoxic activity against TNBC cell lines. Notably, 9h demonstrated 5.7-fold greater potency than tamoxifen and slightly better efficacy than the reference drug cisplatin against MDA-MB-231 cells. Further, 9h induced a significant reduction in MDA-MB-231 cell viability through caspase-mediated apoptosis. Preliminary ADMET predictions were also carried out to assess pharmacokinetic properties.

The influence of COVID-19 vaccination on the efficacy and safety of immune checkpoint inhibitors (ICIs) in lung cancer treatment is not well understood. A cohort of 394 lung cancer patients treated with PD-1/PD-L1 inhibitors was analyzed. The incidence and types of irAEs were recorded, and the relationship between COVID-19 vaccination and progression-free survival (PFS) was assessed using univariate and multivariate analyses. Among the 394 patients, 44% (171 cases) experienced multiple irAEs, 29% (114 cases) had a single type of irAE, and 27% (108 cases) reported no adverse reactions. The most common irAEs included thyroid-related events (hypothyroidism: 18%, hyperthyroidism: 11%), skin toxicity (16%), cardiovascular toxicity (14%), skeletal muscle toxicity (8%), glycemic endocrine toxicity (7%), and pneumonia (6%). COVID-19 vaccination was associated with a decrease in the incidence of immune-related arthritis and myocarditis, while other irAEs such as pneumonia, dermatitis/rash, myositis, oculopathy, diabetes, colitis, nephritis, hypothyroidism, hyperthyroidism, hypophysitis, and transaminitis were unaffected. No significant correlation was found between COVID-19 vaccination and PFS in both univariate and multivariate analyses. COVID-19 vaccination does not increase the incidence of irAEs nor affect the PFS of lung cancer patients receiving ICIs treatment.

Cuproptosis has attracted considerable attention in cancer therapy due to its unique ability to circumvent drug resistance, while the in vivo application is hindered by systemic toxicity, rapid clearance, and limited tumor tissue penetration. Widely recognized for its noninvasive application, ultrasound has emerged as a promising method for enhancing drug tumor penetration. In this study, we developed cuproptosis-oriented Nanobots to achieve deep penetration into prostate tumors under ultrasound irradiation. Asymmetric Cu-Nanobots (∼200 nm) were prepared by ultrasound polymerization using hexachlorocyclotriphosphonitrile (HCCP), 4,4'-sulfonyldiphenol (BPS), and tannic acid (TA) as raw materials, which can efficiently load Cu2+ and trigger Cu2+ release at acidic tumor microenvironments. Under ultrasound stimulation, Cu-Nanobots showed obvious directional motion with a velocity of 19.49 μm/s continuously. In vitro cell experiments confirmed that Cu-Nanobots can significantly promote the oligomerization of dihydrolipoamide acetyltransferase (DLAT), downregulate iron-sulfur cluster proteins such as ferredoxin 1 (FDX1) and lipoic acid synthase (LIAS), and induce cuproptosis in human prostate cancer cells. In addition, Cu-Nanobots can effectively penetrate into the deep area of solid tumors in an animal model with a satisfactory tumor inhibition rate of ∼75.75% under sonication. Overall, these ultrasound-driven cuproptosis-oriented Cu-Nanobots provide optimal insights into effective tumor deep penetration and cuproptosis-based treatment.

Despite the significant antitumor potential of doxorubicin and its widespread use in the treatment of various oncological diseases, its application is associated with side effects, among which the most common are cardiotoxicity, hepatotoxicity, nephrotoxicity, neurotoxicity, and gonadotoxicity. In contemporary times, innovative strategies to overcome the toxicity of doxorubicin and improve the effectiveness of therapies are intensively researched. The aim of this review is to discuss different approaches to alleviate the common toxic effects of doxorubicin, with an emphasis on oxidative stress. In particular, the review analyzes the significance of pharmaceutical nanotechnology for reducing doxorubicin toxicity while maintaining its antitumor effect (e.g., encapsulation of doxorubicin in passively and/or actively targeted nanoparticles to tumor tissue and cells). Other strategies commented in the review are the simultaneous delivery of doxorubicin with antioxidants and the administration of its derivatives with lower toxicity.

Previous in vitro studies have shown the therapeutic potential of bee venom (BV) against different types of glioblastoma cells. Our aim was to evaluate the cytotoxic effect of BV on glioma in the zebrafish model. First, safe concentrations of BV and melittin were determined by determining the LD50 for each substance. Two human glioma cell lines, 8MGBA and LN-229, were used in this study. After staining the tested cells for visualization under UV light, they were then implanted into 2-day-old zebrafish embryos. Zebrafish were incubated for 3 days with crude BV and melittin at concentrations of 1.5 and 2.5 µg/mL vs. control group. Tumor growth was assessed with a stereo microscope. We found differential proliferative responses of two human glioma lines in a zebrafish model. The 8MGBA cell line, but not LN-229, showed proliferative potential when implanted into 2-day-old zebrafish embryos. This study showed a dose-dependent cytotoxic effect only for BV against 8MGBA cells. The observed cytotoxic effect is not dependent on the presence of the peptide melittin-the main BV component with the greatest cytotoxic potential. Simultaneously, a slight increase in LN-229 cell proliferation was observed after 3 days of incubation with melittin at a concentration of 2.5 µg/mL. This indicates that any consideration of bee venom as a therapeutic substance must take into account the type of glioblastoma.

Gelatin methacrylate (GelMA) microgels serve as promising bioscaffolds for tissue engineering and drug screening. However, conventional solid GelMA microgels often exhibit limited mass transfer efficiency and provide insufficient protection for embedded cells. In this study, we developed a droplet-based microfluidic platform to fabricate core-shell structured GelMA microgels. This system enabled precise control over microgel size and core-to-shell ratio by modulating flow rates. Encapsulation of A549 cells within these core-shell microgels preserved cellular viability and facilitated the formation of three-dimensional tumor spheroids. These outcomes confirmed both the protective function of the core-shell architecture during encapsulation and the overall biocompatibility of the microgels. The developed GelMA core-shell microgel system presents considerable applicability in research domains such as organoid modeling and high-throughput pharmacological screening.

In this study, a series of novel β-phenylalanine derivatives were synthesised and evaluated for their anticancer activity. The 3-(4-methylbenzene-1-sulfonamido)-3-phenylpropanoic acid (2) was prepared using β-phenylalanine as a core scaffold. The β-amino acid derivative 2 was converted to the corresponding hydrazide 4, which enabled the development of structurally diverse heterocyclic derivatives including pyrrole 5, pyrazole 6, thiadiazole 8, oxadiazole 11, triazoles 9 and 12 with Schiff base analogues 13 and series1,2,4-triazolo [3,4-b][1,3,4]thiadiazines 14. These modifications were designed to enhance chemical stability, solubility, and biological activity. All compounds were initially screened for cytotoxicity against the A549 human lung adenocarcinoma cell line, identifying N-[3-(3,5-dimethyl-1H-pyrazol-1-yl)-3-oxo-1-phenylpropyl]-4-methylbenzenesulfonamide (5) and (E)-N-{2-[4-[(4-chlorobenzylidene)amino]-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]-1-phenylethyl}-4-methylbenzenesulfonamide (13b) as the most active. The two lead candidates were further evaluated in H69 and H69AR small cell lung cancer lines to assess activity in drug-sensitive and multidrug-resistant models. Schiff base 13b containing a 4-chlorophenyl moiety, retained potent antiproliferative activity in both H69 and H69AR cells, comparable to cisplatin, while compound 5 lost efficacy in the resistant phenotype. These findings suggest Schiff base derivative 13b may overcome drug resistance mechanisms, a limitation commonly encountered with standard chemotherapeutics such as doxorubicin. These results demonstrate the potential role of β-phenylalanine derivatives, azole-containing sulphonamides, as promising scaffolds for the development of novel anticancer agents, particularly in the context of lung cancer and drug-resistant tumours.

Phthalocyanines (Pcs) are well-established photosensitizers in photodynamic therapy, valued for their strong light absorption, high singlet oxygen generation, and photostability. Recent advances have focused on covalently conjugating Pcs, particularly zinc phthalocyanines (ZnPcs), with a wide range of small bioactive molecules to improve selectivity, efficacy, and multifunctionality. These conjugates combine light-activated reactive oxygen species (ROS) production with targeted delivery and controlled release, offering enhanced treatment precision and reduced off-target toxicity. Chemotherapeutic agent conjugates, including those with erlotinib, doxorubicin, tamoxifen, and camptothecin, demonstrate receptor-mediated uptake, pH-responsive release, and synergistic anticancer effects, even overcoming multidrug resistance. Beyond oncology, ZnPc conjugates with antibiotics, anti-inflammatory drugs, antiparasitics, and antidepressants extend photodynamic therapy's scope to antimicrobial and site-specific therapies. Targeting moieties such as folic acid, biotin, arginylglycylaspartic acid (RGD) and epidermal growth factor (EGF) peptides, carbohydrates, and amino acids have been employed to exploit overexpressed receptors in tumors, enhancing cellular uptake and tumor accumulation. Fluorescent dye and porphyrinoid conjugates further enrich these systems by enabling imaging-guided therapy, efficient energy transfer, and dual-mode activation through pH or enzyme-sensitive linkers. Despite these promising strategies, key challenges remain, including aggregation-induced quenching, poor aqueous solubility, synthetic complexity, and interference with ROS generation. In this review, the examples of Pc-based conjugates were described with particular interest on the synthetic procedures and optical properties of targeted compounds.

The artichoke (Cynara cardunculus L. subsp. scolymus) is an endemic perennial plant of the Mediterranean area commonly consumed as food. It is known since ancient times for its beneficial properties for human health, among which its antioxidant activity due to polyphenolics stands out. In the frame of our ongoing studies aiming to highlight the biodiversity and the chemodiversity of natural resources, we investigated the phenolic and saponin content of the cultivar "Carciofo di Procida" collected at Procida, an island of the Gulf of Naples (Italy). Along with the edible part of the immature flower, we included in our analyses the stem and the external bracts, generally discarded for food consuming or industrial preparations. The LCMS quali-quantitative profiling of polyphenols (including anthocyanins) and cynarasaponins of this cultivar is reported for the first time. In addition to antioxidant properties, we observed a significant cytotoxic activity due to extracts from external bracts against human neuroblastoma SH-SY5Y cell lines with 43% of cell viability, after 24 h from the treatment (50 μg/mL), and less potent but appreciable effects also against human colorectal adenocarcinoma CaCo-2 cells. This suggests that the different metabolite composition may be responsible for the bioactivity of extracts obtained from specific parts of artichoke and foresees a possible exploitation of the discarded material as a source of beneficial compounds.

Macrophage-mediated inflammation is known to be involved in the epithelial-mesenchymal transition (EMT) of various types of cancer. This makes macrophage-derived inflammatory factors prime targets for the development of new treatments. This study uncovers the therapeutic potential and action mechanism of DAB-2-28, a small-molecule derived from para-aminobenzoic acid, in the treatment of breast cancer. The luminal MCF-7 and the triple-negative MDA-MB-231 cancer cell lines used in this study represent, respectively, breast cancers in which the differentiation states are related to the epithelial phenotype of the mammary gland and breast cancers expressing a highly aggressive mesenchymal phenotype. In MCF-7 cells, soluble factors from macrophage-conditioned media (CM-MØ) induce a characteristic morphology of mesenchymal cells with an upregulated expression of Snail1, a mesenchymal marker, as opposed to a decrease in the expression of E-cadherin, an epithelial marker. DAB-2-28 does not affect the differential expression of Snail1 and E-cadherin in response to CM-MØ, but negatively impacts other hallmarks of EMT by decreasing invasion and migration capacities, in addition to MMP9 expression and gelatinase activity, in both MCF-7 and MDA-MB-231 cells. Moreover, DAB-2-28 inhibits the phosphorylation of key pro-EMT transcriptional factors, such as NFκB, STAT3, SMAD2, CREB, and/or AKT proteins, in breast cancer cells exposed to different EMT inducers. Overall, our study provides evidence suggesting that inhibition of EMT initiation or maintenance is a key mechanism by which DAB-2-28 can exert anti-tumoral effects in breast cancer cells.