Microtubule-targeting agents (MTAs) are widely used as first- and second-line chemotherapies for various cancers. However, current MTAs exhibit positive responses only in subsets of patients and are often accompanied by side effects due to their impact on normal cells. This underscores an urgent need to develop novel therapeutic strategies that enhance MTA efficacy while minimizing toxicity to normal tissues. Here, we demonstrate that inhibition of the p38 MAPK-MK2 signaling pathway sensitizes cancer cells to MTA treatment. We utilize CMPD1, a dual-target inhibitor, to concurrently suppress the p38-MK2 pathway and microtubule dynamicity. In addition to its established role as an MK2 inhibitor, we find that CMPD1 rapidly induces microtubule depolymerization, preferentially at the microtubule plus end, leading to the inhibition of tumor growth and cancer cell invasion in both in vitro and in vivo models. Notably, 10 nM CMPD1 is sufficient to induce irreversible mitotic defects in cancer cells, but not in non-transformed normal cells, highlighting its high specificity to cancer cells. We further validate that a specific p38-MK2 inhibitor significantly potentiates the efficacy of subclinical concentrations of MTA. In summary, our findings suggest that the p38-MK2 pathway presents a promising therapeutic target in combination with MTAs in cancer treatment.

Diabetic retinopathy (DR), which affects over millions of individuals globally, is the leading cause of permanent visual loss. Current therapies, including as intravitreal anti-vascular endothelial growth factor (VEGF) medications and laser photocoagulation, are limited by frequent dosing and side effects. Liposomes, with their ability to encapsulate hydrophilic and hydrophobic medications, offer tailored delivery, prolonged release, and low systemic toxicity. This study looks at advances in liposomal formulations that address DR's multifactorial etiology, including as anti-angiogenic, anti-inflammatory, and antioxidant processes. We assess new preparation methods (e.g. supercritical CO2, microfluidics) and clinical considerations, including stability and cost-effectiveness. To address the heterogeneity of DR, future endeavors will prioritize combinatorial medications and customized therapy.

The immunosuppressive roles of galectin-3 (Gal-3) in carcinogenesis make this lectin an attractive target for pharmacological inhibition in immunotherapy. Although current clinical immunotherapies appear promising in the treatment of solid tumors, their efficacy is significantly weakened by the hostile immunosuppressive tumor microenvironment (TME). Gal-3, a prominent TME modulator, efficiently subverts the elimination of cancer, either directly by inducing apoptosis of immune cells or indirectly by binding essential effector molecules, such as interferon-gamma (IFNγ).

Recently, scanning ion conductance microscopy (SICM) as a noncontact nanoprobe tool has offered great advantages for applications in revealing biophysicochemical properties of soft biological samples, specifically for living cells. These physical properties, e.g., stiffness, of the cell surface provide an efficient label-free biomarker for differing tumor from normal cells, leading to gradually increasing interest in cancer biological studies. However, expanding potential application of SICM for cancer treatment, especially targeting chemotherapy facing a challenge in drug resistance, is still rarely explored. In addition, in biology, some clues indicate that the physical factors (matrix stiffness and stress) can contribute to tumor drug resistance. Meanwhile, fundamental studies to quantify these unique physical properties of drug-resistant cancer cells correlated with leverage for targeted therapy are less known. Here, we utilized chemotherapy drugs, 5-fluorouracil (5-FU) and oxaliplatin (OXA), to establish three drug-resistant cell lines from human colorectal cancer, including DLD1, SW620, and HT29 cells. High-speed SICM measurements were performed to visualize surface characteristics of subcellular physical properties (heights, roughness, and stiffness) on the control (ctrl) sample and drug-resistant samples derived from ctrl samples. Statistical analysis of stiffness showed a reduced change from drug-resistant samples, especially those resistant to 5-FU and OXA simultaneously, in comparison to ctrl samples. This work sheds light on subcellular physical properties of drug-resistant cell lines. The SICM technique as an important strategy would provide useful assistance in biomedicine in leveraging for targeted therapy.

The emerging triple-negative breast cancer (TNBC) treatments target mitochondrial fission to combat paclitaxel (PTX) resistance. Inositol's inhibition of this process makes it a potential therapy. Multiparametric MRI provides an early and effective assessment of these innovations.

This study aimed to assess the efficacy and safety of transarterial chemoembolization (TACE) in combination with apatinib (TACE-apatinib) for patients with unresectable hepatocellular carcinoma (HCC).

Tumor-associated macrophages (TAMs) are known to be involved in the manifestation of aggressive and therapy-resistant phenotypes in solid tumors. Nevertheless, the effects of dynamic intervention by TAMs on the DNA damage response of cancer cells are largely unexplored. Herein, we report that TAMs modulate the DNA damage repair pathways of ovarian cancer cells in response to platinum-(Pt) based therapeutic regimen. We demonstrate that coculture of TAMs with cancer cells directly upregulate Pol η, along with RAD18 and REV1 of the Translesion DNA synthesis (TLS) pathway, while concurrently downregulating components of the high-fidelity nucleotide excision repair (NER) mechanism. Consequently, we observed a better survival probability, DNA repair capacity, and enrichment of stemness properties in ovarian cancer cells. DNA bulky adducts produced by cisplatin are resolved through differential activation NER and TLS pathways. However, we elucidated that TAMs provide favorable conditions for activating the error-prone TLS pathway for lesion bypass over damage resolution. Furthermore, cellular crosstalk in cocultured cancer cells stimulates the nuclear translocation and expression of RelA, which recruits Pol η by acting as a potent transcription factor. In fact, with pristimerin-mediated disruption of p65 (RelA) translocation, the cancer cells become more prone to DNA damage-induced cell death and compromised regenerative potential. In both in vitro cell cultures and in vivo mouse xenograft models, cocultured macrophages exhibited predominantly M2-like phenotype with prevalence in the invasive zone of xenograft tumor margins. Taken together, our investigation revealed multifaceted crosstalk-mediated regulation of DNA damage repair between TAMs and ovarian cancer cells.

HER2-positive metastatic breast cancer (MBC) represents a challenging subtype of breast cancer, characterized by aggressive disease and poor clinical outcomes. Trastuzumab emtansine (TDM1), an antibody-drug conjugate combining trastuzumab and emtansine, has demonstrated efficacy in clinical trials as a second-line treatment for patients progressing after prior therapies. This study aims to provide real-world evidence on the efficacy and safety of TDM1 in HER2-positive MBC patients. A retrospective analysis was conducted on 70 HER2-positive MBC patients treated with TDM1 at our centre between January 2020 and December 2022. Clinical characteristics, progression-free survival (PFS), overall survival (OS), response rates, and toxicity were evaluated using hospital records. PFS and OS were calculated using Kaplan-Meier methods, and survival curves were compared with log-rank tests. The median age of patients was 47 years, with a majority presenting with advanced disease and prior treatment lines. The median PFS was 6.1 months (95% CI, 4.5-7.6), and the median OS was 14.4 months (95% CI, 10.2-18.0). The objective response rate was 75.7%, with 12.8% achieving a complete response and 62.8% a partial response. PFS was significantly longer in hormone receptor-positive patients compared to hormone receptor-negative patients (8.1 vs. 4.1 months, p = 0.035). Toxicity was manageable, with grade 3-4 adverse events including elevated transaminases (8.5%), thrombocytopenia (5.7%), and anemia (4.2%). The efficacy of TDM1 in this real-world cohort aligns with clinical trial data, though PFS and OS were somewhat lower compared to trials, likely due to the inclusion of patients with more extensive disease and prior treatments. Notably, TDM1 demonstrated activity against CNS metastases and a manageable safety profile, with higher incidence of hepatic and hematologic toxicities. Our study supports the use of TDM1 as a viable option for treating HER2-positive MBC in routine clinical practice, confirming its effectiveness and safety profile observed in clinical trials.

Lanreotide and Octreotide are used to treat various endocrine and neoplastic diseases. This study aims to compare the adverse event profiles of Lanreotide and Octreotide in somatostatin-responsive diseases using FAERS data. FAERS data from Q1 2004 to Q2 2024 were reviewed for AE reports related to Lanreotide and Octreotide. Reports were categorized using MedDRA system organ classes (SOCs). Disproportionality analysis was conducted using Reporting Odds Ratios (ROR), Proportional Reporting Ratios (PRR), and Information Components (IC) to identify significant AEs. The top 20 AEs for each drug were analyzed, and chi-square tests assessed differences in AE frequencies between the drugs. Detailed comparisons were made across gastrointestinal, cardiovascular, and neoplastic AEs. Lanreotide was more associated with gastrointestinal AEs, such as diarrhea (1457 reports) and cholelithiasis (198 reports), with a notable signal for cholelithiasis (ROR 12.03, 95% CI 10.46-13.85). Octreotide had higher reports of cardiovascular AEs, including systolic (1483 reports) and diastolic (541 reports) blood pressure increases. Additionally, Octreotide was linked to neoplasm progression (1735 reports) and more frequent malignant neoplasms. Injection site reactions, including pain and nodules, were more common with Lanreotide (ROR 19.09, 95% CI 17.2-21.19). Lanreotide and Octreotide exhibit distinct adverse event profiles, with gastrointestinal signals more frequently observed for Lanreotide, and cardiovascular/neoplastic signals more apparent for Octreotide. These patterns should be interpreted with caution due to limitations of the FAERS data.

Endometrial cancer (EC) is one of the most common malignancies in women. In recent years, immunotherapy has gradually become a significant treatment option. However, the mechanisms underlying immune checkpoint inhibitor (ICI)-related Adverse Events (AEs) remain poorly understood, posing significant challenges for optimizing clinical treatment strategies. This study aims to integrate the FAERS database and single-cell transcriptomic data to investigate potential mechanisms underlying PD-1 inhibitor-related AEs in EC immunotherapy, with a focus on exploring the PD-1-associated cell communication network and its potential compensatory activation pathways. Data related to AEs were extracted from the FAERS database. Disproportionality analyses, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS), were used to quantify signals of immune-related AEs (irAEs) associated with ICIs. We compared the occurrence timing and characteristics of AEs across different drugs. Subsequently, scRNA-seq was performed to analyze the tumor microenvironment of EC, focusing on PD-1-high expressing cell populations. Cell Communication was analyzed and key receptor-ligand pairs were identified. From Q1 2004 to Q3 2024, 21,838,627 drug-related reports were retrieved from FAERS, including 2,202 related to ICIs. ICI-associated irAEs involved 26 organ systems, with general disorders, gastrointestinal disorders, and injury/poisoning as the top System Organ Class (SOC). Fatigue, product use issues, and diarrhea were the most reported Preferred Terms (PTs). PD-1 inhibitors were associated with faster onset of AEs compared to PD-L1 inhibitors and Weibull modeling indicated an early failure-type AE pattern for both treatments. Single-cell analysis further demonstrated that PD-1 was highly expressed in CD8 + cytotoxic T cells and Tfh cells, which communicated with other cells within the tumor microenvironment through key receptor-ligand pairs such as CXCL12-CXCR4 and CXCL16-CXCR6. These findings suggested that PD-1 inhibitors may induce AEs through compensatory activation of the CXCR4 and CXCR6 pathways. This study suggested that PD-1 inhibitors may contribute to irAEs in EC, potentially through compensatory activation of the CXCR4 and CXCR6 pathways. By integrating FAERS and scRNA-seq data, key receptor-ligand interactions were identified, providing preliminary insights that could inform future efforts to optimize immunotherapy efficacy and mitigate AEs. However, further validation through clinical studies and mechanistic research is needed to confirm these findings.

The unregulated administration of currently available antimicrobial agents resulted in overspreading of resistant microbial phenotypes. In this study, Mucor racemosus was used for biosynthesis of zinc oxide nanoparticles (ZnO NPs) through fungi-based ecofriendly approach. The biosynthesized of ZnO NPs was initially considered based on analytical practices including UV-vis spectroscopy and transmission electron microscopy (TEM). Additionally, their cytotoxicity and anticancer activity were analyzed using suitable cell lines and their antioxidant effect was also assessed. Microbiologically, their inhibitory activity was comparatively evaluated against various methicillinresistant Staphylococcus aureus (MRSA) and methicillinsensitive Staphylococcus aureus (MSSA). Characterization of ZnO NPs displayed a distinct maximum absorption peak at 320 nm appeared in the UV-vis. Also, TEM revealed predominantly spherical ZnO NPs with particle size distribution ranging from 15 to 55 nm (mean size ≃ 40 nm). The normal cell line (Wi-38) illustrated the biosafety of ZnO NPs, where results showed IC50 of 197.2 µg/mL. Furthermore, ZnO NPs exhibited promising suppressive activity on Hep-G2 cancerous cell with IC50 of 51.4 µg/mL. Besides, ZnO NPs displayed antioxidant activity where IC50 was 69.2 µg/mL. As well, the minimum inhibitory concentrations of ecofriendly ZnO NPs against the tested MRSA and MSSA isolates were ranged from 32 to 512 µg/mL. Also, their minimum bactericidal concentrations against the tested MSSA was in lower range, 32-1024 µg/mL, than the recorded range, 128-1024 µg/mL, against the MSSA. Also, the crystal violet (CV) assay showed an eradication potential of the biosynthesized ZnO NPs on MRSA and MSSA biofilm in a range of 23.24-73.96% and 6.63-74.1%, respectively. In conclusion, the ecofriendly synthesized ZnO NPs with antioxidant and anticancer activities demonstrated promising inhibitory effect on planktonic growth form of MRSA and MSSA clinical isolates with capability to eradicate their preformed biofilm. To achieve their full potential, future research needs to enhance the synthesis process to make ZnO NPs more uniform and scalable, as well as investigate their action mechanisms at the molecular level.

Pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulfonamides (MM-compounds) represent a novel class of heterocyclic compounds with promising anticancer potential. In this study, we report the synthesis and biological evaluation of two enantiomeric derivatives: the R-enantiomer (MM124) and the S-enantiomer (MM125). Both compounds exhibited potent and selective cytotoxicity against a panel of cancer cell lines derived from various tissue types, with a median IC₅₀ value of 0.35 µM. Mechanistic investigations in colorectal (HT-29) and prostate (PC-3) cancer cell lines demonstrated that the compounds induce apoptosis, oxidative stress, and DNA damage. Electrochemical assays and computational studies further suggested that MM124 and MM125 interact with DNA. Additionally, in silico pharmacokinetic and toxicological profiling indicated favorable drug-like properties. These findings support the potential of MM124 and MM125 as candidates for the development of new anticancer agents, warranting further structural optimization and preclinical evaluation.

Pemetrexed, a multi-target antifolate chemotherapeutic widely used in non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM), is associated with various adverse drug events (ADEs), some of which may be underrecognized in clinical trials. This study conducted a comprehensive pharmacovigilance analysis using two major spontaneous reporting systems-FAERS (2004Q1-2024Q3) and JADER (2007Q1-2024Q3)-to evaluate pemetrexed-related ADEs. Disproportionality analysis was performed using four algorithms: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-Item Gamma Poisson Shrinker (MGPS). Time-to-onset (TTO) patterns were assessed using Weibull distribution modeling. A total of 12,026 and 4,522 pemetrexed-related ADE reports were retrieved from FAERS and JADER, respectively. The most frequently reported ADEs included hematologic toxicities (anemia, neutropenia, thrombocytopenia), gastrointestinal disorders (nausea, vomiting, diarrhea), and renal impairment. Strong safety signals were consistently identified for these events. Notably, novel ADE signals such as hepatobiliary injury, endocrine dysfunction, and thromboembolic events were observed in both databases. Subgroup analyses revealed sex- and age-specific ADE patterns, with younger patients and males showing distinct toxicity profiles. Sensitivity analysis excluding combination therapies confirmed the robustness of primary signals. TTO analysis revealed that most ADEs occurred within the first two months after pemetrexed initiation, with a median TTO of 27 days and a predominance of early failure patterns (Weibull β < 1), highlighting the importance of close monitoring during early treatment. Rare but severe ADEs, including myocarditis, sepsis, cholestasis, and pseudocellulitis, were identified, several of which are not currently listed in official drug labeling. This study provides a comprehensive safety assessment of pemetrexed, confirming known toxicities and identifying new safety signals. Continuous pharmacovigilance is essential to optimize its clinical use and improve patient safety.

BH3 mimetic drugs that inhibit BCL-2, BCL-XL, or MCL-1 have limited activity in solid tumors. Through assessment of xenograft-derived 3D prostate cancer models and cell lines we find that tumors with RB1 loss are sensitive to BCL-XL inhibition. In parallel, drug screening demonstrates that disruption of nucleotide pools by agents including thymidylate synthase inhibitors sensitizes to BCL-XL inhibition, together indicating that replication stress increases dependence on BCL-XL. Mechanistically we establish that replication stress sensitizes to BCL-XL inhibition through TP53/CDKN1A-dependent suppression of BIRC5 expression. Therapy with a BCL-2/BCL-XL inhibitor (navitoclax) in combination with thymidylate synthase inhibitors (raltitrexed or capecitabine) causes marked and prolonged tumor regression in prostate and breast cancer xenograft models. These findings indicate that BCL-XL inhibitors may be effective as single agents in a subset of solid tumors with RB1 loss, and that pharmacological induction of replication stress may be a broadly applicable approach for sensitizing to BCL-XL inhibitors.

Heparanase (HPSE) is the sole mammalian endoglycosidase that degrades heparan sulfate (HS) proteoglycans, disrupting the extracellular matrix (ECM) and promoting cancer invasion and metastasis. Although HPSE overexpression is linked to tumor progression, no clinically approved HPSE inhibitors exist. We developed aminoglycoside-based HS mimetics with defined sulfation and hydrophobic modifications to target HPSE's lipophilic pockets, a novel approach distinct from traditional HS glycans. Computational modeling showed that these mimetics engage HPSE through hydrophobic and π-π stacking interactions, enhancing affinity. The most potent compounds inhibited HPSE-driven ECM degradation, tumor cell proliferation, and invasion. In vivo, the lead candidate significantly reduced metastatic burden in B16 melanoma and MPC-11 myeloma models, showing tumor growth inhibition (TGI = 83.1%) versus SST0001 (TGI = 58.6%) and matching bortezomib. Importantly, the compound was well-tolerated with no notable toxicity. These results support HPSE as a cancer target and highlight aminoglycoside-based HS mimetics as promising therapeutics for metastatic cancer.

Aprepitant, a neurokinin-1 receptor (NK1R) antagonist, has the potential as a novel anticancer agent. This study explored the impact of chronotherapy on the antitumor effect of aprepitant in a mouse model of colorectal carcinoma. Aprepitant inhibited the proliferation of Colon-26 cells in vitro in a concentration-dependent manner and reduced the expression of cell cycle-related genes. Diurnal variations in NK1R mRNA and protein levels were observed in Colon-26 tumors, peaking at zeitgeber time (ZT) 2 and ZT 10, respectively. Administration of aprepitant at ZT 6, achieving peak plasma concentration at ZT 10, significantly reduced the tumor volume compared with administration at ZT 18. Despite the lower plasma concentrations and AUC0-12 h in the ZT 6 group, superior antitumor effect suggests a dosing time-dependent efficacy due to variations in NK1R expression rather than its pharmacokinetics. These findings indicate that the antitumor activity of aprepitant against colorectal cancer can be enhanced by aligning its administration with NK1R expression rhythms, warranting further exploration of aprepitant chronotherapy in cancer chemotherapy.

This post hoc study aimed to evaluate the cost-effectiveness of hepatic artery infusion chemotherapy (HAIC) with fluorouracil, leucovorin and oxaliplatin (HAIC-FO) compared with sorafenib in patients with advanced hepatocellular carcinoma (HCC). The analysis was conducted from the perspective of Chinese payers.

Clear cell renal cell carcinoma (ccRCC) is strongly aetiologically associated with von Hippel‒Lindau (VHL) tumour suppressor gene mutations, which result in constitutive activation of hypoxia-inducible factors and pathological angiogenesis. Although accumulating evidence indicates that antiangiogenic therapies targeting VEGF signalling can prolong the survival of ccRCC patients, the frequent development of therapeutic resistance to tyrosine kinase inhibitors such as sunitinib remains a critical clinical limitation. Through integrated multiomics analyses of sunitinib-resistant cell models, patient-derived xenografts, and clinical specimens, we systematically identified CYP1B1 as a central mediator of treatment resistance. Transcriptomic and genomic profiling revealed that CYP1B1 overexpression in resistant tumours functionally contributes to enhanced angiogenic potential and maintenance of the resistant phenotype. Mechanistic investigations demonstrated that CYP1B1 stabilizes hypoxia-inducible factor 2α (HIF2α) by facilitating USP5-mediated deubiquitination, thereby preventing proteasomal degradation. Notably, we identified VHL as a novel E3 ubiquitin ligase that regulates CYP1B1 turnover; notably, VHL deficiency in ccRCC promotes CYP1B1 protein accumulation by suppressing ubiquitination. These findings establish a feed-forward regulatory axis in which VHL loss-induced CYP1B1 stabilization promotes HIF2α signalling persistence, ultimately driving sunitinib resistance. Our study delineated the CYP1B1-USP5-HIF2α signalling cascade as a critical resistance mechanism and thus reveals a targetable vulnerability in treatment-refractory ccRCC.

Acute myeloid leukemia (AML) is a type of hematological malignancy with a poor prognosis caused by diverse genetic mutations. One effective treatment approach is to induce the differentiation of AML cells, which may help curb their unrestrained proliferation. In search of novel differentiation-inducing drug candidates, a phenotypic screen of a chemical library was performed, and Azvudine, a new anti-HIV agent approved by the China FDA in 2021, was identified as the most effective agent. Azvudine efficiently drove differentiation in multiple human AML cell lines, which was strongly associated with G2/M cell cycle arrest and apoptosis in vitro. In vivo analyses using murine xenograft models showed that this drug efficiently stimulated the differentiation of AML cells, diminished the tumor burden and metastasis, and prolonged the survival of mice. Importantly, the anti-leukemic effects of Azvudine were recapitulated in AML patient samples with various mutations, including TP53, a genetic lesion associated with adverse risk. Mechanistic studies showed that the inhibitory activity of Azvudine was directed mainly against telomerase reverse transcriptase (TERT), causing telomerase dysfunction and telomere shortening. This was accompanied by a DNA damage response, culminating in p21 upregulation and subsequent cellular differentiation in AML. In addition, increased ROS levels in the mitochondria by Azvudine modulated the Bcl-2 family proteins and promoted apoptosis, acting as a further anti-AML mechanism. Considering that telomerase-targeted therapies are currently under active clinical investigation, these compelling preclinical data justify the repositioning of Azvudine as an AML differentiation-inducing therapy.

The mitochondria-mediated apoptotic pathway is an important anti-tumor strategy. Based on the cell membrane and mitochondria, dual targeting system was explored to enhance the antitumor efficacy. In this study, celastrol (CEL) showing anti-tumor effect through mitochondria-mediated apoptotic pathways, triphenylphosphine (TPP) presenting mitochondria targeting ability, hyaluronic acid (HA) exhibiting cell membrane targeting ability, and immune adjuvants resiquimod (R848) were prepared to form co-delivery system with dual targeting function, which could achieve chemo-immunotherapy for breast cancer. CEL, R848, and TPP were self-assembled into inner core (TCR) via Van der Waals force and electrostatic interactions. After decorating hyaluronic acid (HA) via electrostatic interactions, the codelivery system (H/TCR NPs) was obtained successfully. H/TCR NPs showed uniform core-shell structure with the average particle size of approximately 164 nm. H/TCR NPs presented the good storage stability and media stability. Due to the active targeting property of TPP, H/TCR NPs presented the high accumulative rate in mitochondria, resulting in promoted antitumor efficacy of CEL through mitochondria-mediated apoptotic pathways. At the low frequency of administration in 4T1 tumor-bearing mouse model, the tumor inhibition rate of H/TCR NPs was 66.5 %, 3-fold higher than paclitaxel injection that was first-line treatment drug of breast cancer in clinic. In summary, this study revealed that co-delivery nanoparticles with dual targeting ability existed combining antitumor effects and presented the potential application in clinic, such as addressing unmet needs in breast cancer treatment or overcoming drug resistance.