Nitrogen mustards are a family of clinically used anticancer drugs that contain a DNA-alkylating bis(2-chloroethyl)amino group. Appending the bis(2-chloroethyl)amino alkylating agent to noncovalent DNA-binding groups such as intercalators, polyamides, or polyamines has the potential to yield DNA-targeted anticancer agents with improved potency. In the work reported here, substituted quinoxaline groups were explored as minimal intercalators expected to confer noncovalent DNA-binding properties on a bis(2-chloroethyl)anilino mustard alkylating unit. A quinoxaline unit with a cationic dimethylamino-containing side chain was found to be a more potent DNA-alkylating and cross-linking agent than the clinically used mustard chlorambucil (Chb). The results of dye displacement and multiple DNA alkylation assays showed that the quinoxaline ring binds noncovalently to duplex DNA, likely via intercalation. The quinoxaline-mustard conjugate was more active than Chb against a variety of cancer cell lines. Evidence is presented, showing that both the quinoxaline-mustard and the clinically used drug Chb formed aggregates in aqueous buffer; however, the results clearly show that the propensity to form aggregates clearly does not abrogate the DNA-alkylating properties or bioactivity of these compounds.

Advanced synovial sarcomas are associated with poor outcomes and a lack of efficacious therapeutic agents. The aim of this study was to assess the efficacy and safety of a novel, low-dose, continuous schedule of regorafenib in these patients.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends screening for four common DPYD variants to prevent severe toxicity in patients with cancer treated with fluoropyrimidines. A 50% starting dose followed by toxicity-based dose titration is advised for patients heterozygous for these variants. In this study, the appropriateness of the CPIC-recommended 5-fluorouracil (5-FU) starting dose was evaluated.

Improving our understanding of the ocular pharmacokinetics and pharmacodynamics of anti-vascular endothelial growth factor (VEGF) therapies, such as ranibizumab, is essential to enhance treatment strategies for a range of retinal diseases, and will help inform the development of novel anti-VEGF drug candidates.

Selective prodrug activation at tumor sites through noninvasive external stimuli represents a promising strategy in enhancing the therapeutic index. Here, we report a p-azidobenzyloxycarbonyl (PAzBC)-based prodrug platform activated by physiotherapy-grade ultrasound (2.0 W/cm2, 1 MHz) through radical-mediated cascade elimination. Mechanistic studies reveal that ultrasound initiates single-electron-transfer (SET) and hydrogen-atom-transfer (HAT) processes, enabling efficient azide-to-amine reduction. This activation is further amplified by superoxide anion radicals generated via acoustic sensitizers, as confirmed by DFT calculations and radical trapping experiments. The PAzBC platform demonstrates broad applicability with diverse drug functionalities (amino, hydroxyl, sulfhydryl), achieving >99% azide reduction efficiency and approximately 40% active drug release under optimized sonication conditions. Cellular studies reveal a 4.1-115.5-fold reduction in prodrug toxicity and a 11.9-169.5-fold enhancement in selective activation, highlighting its potential for clinical translation. This work establishes a robust platform for spatiotemporally controlled drug delivery, advancing the field of ultrasound-mediated precision cancer therapy.

The rapid increase in the number of elderly patients with cancer necessitates treatment strategies based on the effects of aging because of drastic side effects of cytotoxic anticancer agents. Immune checkpoint inhibitors (ICIs) are relatively less toxic and can be easily administered to vulnerable and aged patients suffering from cancer. The diversity of gut microbiota and specific bacteria affects the efficacy and safety of ICIs. Therefore, this study aimed to assess the effect of aging on gut microbiota that play crucial roles in determining antitumor efficacy of drugs.

Marijuana use is associated with HPV-positive head and neck squamous cell carcinoma (HNSCC). However, cannabinoid use continues to increase in the US general population for recreational purposes as well as in cancer patients for palliative care. In this study, we explored the role of cannabidiol (CBD) in promoting anti-tumor activity by modulating immune response in HPV-positive HNSCC by using pre-clinical models.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death globally, characterized by high heterogeneity and drug resistance, which significantly impacts clinical outcomes. The tumor microenvironment (TME) plays a critical role in HCC initiation and progression, with immune cell infiltration and immune checkpoint expression closely linked to tumor prognosis. N-glycosylation of proteins modulates immune responses within the TME. ALG3, a key N-glycosylation enzyme, is involved in protein glycosylation. Although ALG3 expression has been studied in various tumors, its role in regulating the immune microenvironment and its prognostic significance in HCC remain unclear.

Thymidine phosphorylase (TP) is a key enzyme involved in angiogenesis, tumour growth and closely linked to cancer progression and metastasis. This study represents the first comprehensive 3D-QSAR pharmacophore-based approach to identifying potential 1,3,4-oxadiazole derivatives as targeted TPIs for anticancer therapy. A dataset of 76 analogues with an experimental IC50 values was used to develop pharmacophore models. The BEST conformation method identified an optimal model (Hypo 2), featuring HBA, HBD and RA as key activity determinants with strong statistical validation (r2 = 0.69, ΔCost = 77.41, Q2 = 0.68 and MAE = 0.23). A virtual screening of 12,353 drug-like 1,3,4-oxadiazole compounds from PubChem and ChEMBL yielded 329 potential TPIs (IC50 < 10 μM). MD Docking using CDOCKER (PDB ID: 1UOU) identified the top hits interacting with critical TP residues (Thr151, Gly152, Lys221, Ser217, Thr118). ADMET analysis confirmed their drug-likeness with no significant toxicity. ChEMBL2058305 exhibited the highest binding stability (-85.508 kcal/mol), the lowest HOMO-LUMO gap (0.066 ha), and superior TP affinity, highlighting its potential as a promising TP inhibitor for anticancer therapy. This first report with integration of pharmacophore modelling, virtual screening, MD Docking, ADMET, MMGBSA and DFT will be beneficial for the discovery of novel TPIs.

Pancreatic cancer is a highly malignant tumor with a poor prognosis, making it a leading cause of cancer-related deaths. While immune checkpoint inhibitors (ICIs) have shown efficacy in treating various solid tumors, their effectiveness in pancreatic cancer is limited due to its unique tumor immune microenvironment (TIME). Thus, developing novel combination therapies is critical. Ginsenoside compound K (CK), a natural product with antitumor and immunomodulatory properties, holds the potential for combination therapy with ICIs. This study investigates the therapeutic effects of CK combined with Anti-PD1 inhibitors in a Panc02 tumor model. The combination therapy significantly improved survival, enhanced T-cell infiltration and activation, remodeled the tumor stroma by reducing collagen I and α-SMA, and improved vasculature formation. RNA sequencing revealed changes in genes associated with T-cell activation, chemokines, and angiogenesis. These findings suggest that CK combined with Anti-PD1 therapy offers a promising strategy for pancreatic cancer treatment by modulating TIME and enhancing antitumor activity.

The advent of research using drug-delivery vehicles with nanoparticles (NPs) in treating and diagnosing lung cancer has created a potential development in cancer therapeutics. Using certain NP-based compositions, specifically hybrid NPs, the cancer cells could be detected with enhanced fluorescence ability and treated using targeted drug release while minimizing adverse effects. A modified microwave-based synthesis approach was used in this study to synthesize spherical core-shell hybrid cobalt oxide carbon nanodot (Co3O4@CND) NPs of a smaller size of around 20 nm. Four different targeting ligands─folic acid, heparin, PEGylated silica (SiO2), and transferrin─and the anticancer drug doxorubicin (DOX) were conjugated to the hybrid NPs, and their physicochemical characterizations were evaluated for their applications. The bioimaging, antioxidant, biocompatibility, cancer-targeting ability, and anticancerous specificity effect of the hybrid NPs were examined using A549 (lung cancer) cells and compared with CNDs, Co3O4 NPs, and the ligand-conjugated NPs. The Co3O4@CND NPs demonstrated high fluorescence from their synergistic properties, leading to a better bioimaging ability in human cells. The Co3O4@CND hybrid NP-transferrin-DOX composite targeted 50% of A549 cells with a much less adverse effect on EAhy926 (endothelial) cells at the same concentrations. Increased anticancer activity of the Co3O4@CNDs and improved biocompatibility were achieved via a receptor-mediated active targeting approach using specific ligands, proving the potential multifunctional applications such as bioimaging, antioxidant, and anticancer activity. After transferrin conjugation, the NP composite is more anticancerous to A549 and shows decreased toxicity to EAhy926 cells. The outcomes, while in the early stage, suggest that the Co3O4@CND hybrid NPs with ligand conjugation are a potential approach to the development of a multifunctional theranostic agent.

Recurrence and metastasis remain significant challenges in the clinical treatment of hepatocellular carcinoma (HCC). The integration of photodynamic therapy and immunotherapy has emerged as a promising strategy for treating cancer in terms of safety and efficacy. However, conventional photodynamic therapy and anti-tumor immunotherapy face several limitations, including inadequate light source penetration, poor targeting precision, low response rates, and immune-related adverse effects. To address these issues, we developed a tumor microenvironment responsive polymer nano-immunomodulator for precise photodynamic immunotherapy of HCC. The nano-immunomodulator is self-assembled from glutathione responsive amphiphilic polymers (TPS) and pH-activatable photosensitizers (LET-Br), and is further loaded with the anticancer drug docetaxel. Additionally, it is conjugated with small-molecule agonists of Toll-like receptor 7/8 (TLR 7/8) and cyclic RGD (cRGD) targeting peptides. Upon reaching the tumor site, the PNI undergoes hydrolysis, enabling the efficient release of anticancer drugs in response to the tumor microenvironment. Furthermore, under near-infrared (NIR) photoirradiation, the PNI exerts potent photodynamic effects to directly eliminate tumors. Remarkably, the PNI also functions as an in situ light-activated cancer vaccine, capable of inducing systemic antitumor immune responses and remodeling the immunosuppressive tumor microenvironment to establish long-lasting immune memory. This synergistic combination of photodynamic therapy and targeted antitumor immune responses effectively inhibits tumor growth. Thus, this study not only presents a novel strategy for designing vaccine-like prodrugs to precisely modulate cancer immunotherapy, but also opens new avenues for the development of advanced therapies for HCC.

Dose-expansion cohort (DEC) has been increasingly used as the pivotal trial to demonstrate preliminary efficacy and safety of target anticancer drugs. We aimed to investigate the reporting quality in the published articles of DECs.

To investigate the prophylactic effect of compression therapy against chemotherapy-induced peripheral neuropathy (CIPN) through meta-analytic evaluation.

The persistence of drug resistance and relapses post-remission in B-chronic lymphocytic leukemia (B-CLL) underscores the exploration of novel therapeutic interventions. Given the pivotal role of autophagy in cancer cell resistance to apoptosis, this study aims to investigate the therapeutic potential of Berberine in modulating autophagy function associated with drug resistance in B-CLL. Peripheral blood mononuclear cells (PBMCs) from 10 CLL patients and 5 healthy individuals were treated with Berberine and Idelalisib (as a control). Flow cytometry analysis was employed to assess the protein expression levels of Beclin1, indicative of autophagy function, and high mobility group protein 1 (HMGB1), serving as an internal control for drug resistance. Furthermore, qRT-PCR was utilized to measure the expression levels of drug resistance markers including Beclin1, HMGB1, heat shock factor binding protein 1 (HSBP1), and receptor for advanced glycation end products (RAGE). Our findings revealed that Berberine exhibited a dual suppressive effect on Beclin1 and HMGB1 levels compared to the control drug. Moreover, Berberine downregulated the expression of the primary HMGB1 receptor, RAGE, in PBMCs from CLL patients. Notably, no significant alteration was observed in HSBP1 expression, a mediator of autophagy induction, upon Berberine treatment. These findings suggest that Berberine may target specific mechanisms associated with autophagy-mediated drug resistance, underscoring its therapeutic potential in B-CLL. Further clinical trials are warranted to validate the therapeutic efficacy of Berberine in B-CLL.

Many metastatic clear cell renal cell carcinomas (ccRCC) are resistant to immune checkpoint inhibitor therapies, however the mechanisms underlying sensitivity or resistance remain incompletely characterised. We demonstrate that ccRCCs in the Vhl/Trp53/Rb1 mutant mouse model are resistant to combined anti-PD-1/anti-CTLA-4 therapy alone and in combination with additional therapeutic agents that reflect current ccRCC clinical trials. However, in some animals in vivo checkpoint therapy allowed isolated splenic T cells to recognise cultured ccRCC cells from the same animal, implicating the tumour microenvironment in suppression of T cell activation. We identified putative immunosuppressive myeloid cell populations with features similar to myeloid cells in the microenvironment of human ccRCC. The expression patterns of immune checkpoint ligands in both the mouse model and in human ccRCC suggests that several checkpoint systems other than PD-1 and CTLA-4 are likely to represent the dominant T cell suppressive forces in ccRCC. Our findings characterise an autochthonous mouse ccRCC model of immune checkpoint inhibitor therapy resistance and pave the way for a systematic functional dissection of the identified potential molecular barriers to effective immune therapy of ccRCC.

Bladder cancer is the most common malignant tumor of the urinary tract. In this study, 90 lupane triterpene derivatives, previously synthesized in the laboratory, were systematically evaluated for their potential effects against bladder cancer by cytotoxicity screening against five urinary tumor cell lines. Bioinformatics and molecular dynamics methods were used to investigate the mechanism of action of compound 27 in depth. Most of the derivatives effectively inhibited tumor cell growth, and structure-activity relationship analysis revealed that introducing an indole moiety significantly enhanced the biological activity. The peak activity was reached when the dibromoalkyl chain length was C = 5 (IC50 = 1.121 μM). By integrating transcriptomic data and TCGA findings, we identified 11 key targets, among which DUSP5 and SCG2 showed significant differential expression. Further analysis revealed meaningful insights into the clinical association, 10-year survival prognosis, and immune infiltration. The present study further clarified the effects of compound 27 on the expression of DUSP5 and SCG2 in tumor cells after treatment by a combination of RNA-seq and RT-qPCR. Molecular docking confirmed the stable binding of compound 27 to DUSP5, which was confirmed by molecular dynamics simulations. Compound 27 inhibited bladder cancer progression by upregulating DUSP5 expression and negatively regulating the p38 MAPK pathway, modulating the immune response and promoting apoptosis.

Oxaliplatin, a key chemotherapeutic agent, often induces resistance in colorectal cancer (CRC) treatment, highlighting the urgent need for reliable biomarkers to predict treatment efficacy. In this study, we aimed to identify key genes associated with oxaliplatin resistance in CRC and to evaluate their potential as prognostic biomarkers. Using CRC patient data from the TCGA dataset, we categorized patients into oxaliplatin-resistant and -sensitive groups and conducted differential expression analysis. Key feature genes were identified through univariate Cox analysis, LASSO regression, and stepwise multivariate Cox regression. The predictive value of the identified markers was validated using logistic regression, weighted gene co-expression network analysis (WGCNA), and external validation in GEO cohorts. The tumor microenvironment (TME) was assessed using the MCP-counter algorithm, and CRC cell experiments were performed to evaluate changes in drug sensitivity following oxaliplatin exposure. Based on TCGA CRC data, we constructed a prognostic index derived from a three-gene signature associated with oxaliplatin resistance. This index was significantly correlated with progression-free survival (PFS) in oxaliplatin-resistant CRC patients and showed robust prognostic performance, with AUCs of 0.848 and 0.861 in gastric cancer and pancreatic adenocarcinoma cohorts, respectively. Notably, TNFAIP2 knockout significantly reduced clonogenic ability in CRC cells following oxaliplatin treatment. Our results identify TLE4, TNFAIP2, and ARGLU1 as key contributors to oxaliplatin resistance in CRC. The oxaliplatin resistance-related gene signature (ORGSig) serves as a promising tool for predicting treatment response and prognosis in CRC patients receiving oxaliplatin-based chemotherapy. This signature also offers potential for guiding personalized therapy and overcoming drug resistance in clinical practice.

Liquids irradiated with nonequilibrium atmospheric pressure plasma exert antitumor effects. Here, we produced plasma-activated acetated Ringer (PAA) and plasma-activated sodium acetate (PASA) solutions, each at 1%, 3%, and 5% mass concentrations. We evaluated the antitumor effects of PAA and PASA on gastric cancer (GC). Two GC cell lines (MKN1-Luc and MKN45-Luc) as well as normal human peritoneal mesothelial cells were subjected to cell viability assays using PAA, 1% PASA, 3% PASA, and 5% PASA. To elucidate the functional mechanisms, we examined morphological changes induced by 3% PASA following 10 min of irradiation. To further elucidate the underlying biological processes, we compared the expression of apoptosis-related proteins following the administration of 3% sodium acetate solution without plasma exposure and 3% PASA irradiated for 10 min. Additionally, MKN45-Luc cells were intraperitoneally injected into mice, followed by intraperitoneal administration of acetated Ringer's solution without plasma exposure (control-1 group), 3% sodium acetate solution without plasma exposure (control-2 group), and 3% PASA irradiated for 10 min (treatment group). Peritoneal dissemination was observed using in vivo bioluminescent imaging and laparotomy. PAA and PASA achieved an antitumor effect in a sodium acetate concentration-dependent manner. PAA and 3% PASA caused significantly less damage to normal peritoneal mesothelial cells compared to GC cells at 5 and 10 min of plasma exposure (p < 0.001). Blebs, indicative of apoptosis, were observed at 1.5 h after 3% PASA treatment in GC cells. 3% PASA treatment increased the expression of phosphorylated MKK3/MKK6 and phosphorylated p38 MAPK, suggesting that apoptosis may be mediated through the p38 MAPK pathway. The intraperitoneal administration of 3% PASA significantly reduced the number of peritoneal nodules, and no adverse events were detected. Here we show that PASA exerted an antitumor effect on GC, indicating that the intraperitoneal administration of 3% PASA may serve as a novel treatment for the peritoneal dissemination of GC.

Uterine serous carcinoma (USC) accounts for 40% of endometrial cancer-related deaths. The standard of care for stages III and IV USC yields a 20%-30% survival at 2 years and a 10%-20% survival at 3-5 years. Recent advances in the second-line treatment of advanced or recurrent USC are rapidly evolving. Targeted therapeutic approaches with the use of lenvatinib plus pembrolizumab, as well as the use of trastuzumab deruxtecan, offer new hope for successful second-line therapies for patients. However, further investigation into novel targeted therapeutic approaches is warranted, given the high burden of disease associated with this aggressive histological subtype. USC shares clinical and genomic similarities with epithelial ovarian cancer, suggesting a correlation with 'BRCAness'. Niraparib, a potent PARP1 and PARP2 inhibitor, was shown to have a positive impact on platinum-sensitive recurrent ovarian cancer, regardless of the presence or absence of BRCA status. Our hypothesis is that patients with stage III, stage IV and platinum-sensitive recurrent USC receiving niraparib maintenance in addition to standard therapy for USC may have an improved progression-free survival.