Platinum-based chemotherapy remains a cornerstone in the treatment of advanced non-small cell lung cancer (NSCLC), yet its efficacy is frequently limited by drug resistance. JMJD5 (Jumonji Domain-Containing Protein 5) is a multifunctional protein implicated in tumor progression with enzymatic and non-enzymatic activities. While it has been reported to enhance the sensitivity of NSCLC cells to EGFR tyrosine kinase inhibitors (TKIs), its function in modulating response to conventional platinum chemotherapy is unknown.

A major limitation of conventional two and three-dimensional preclinical in vitro cancer models is their inability to reproduce the drug-delivery barriers. Tumor assembloids, which integrate patient-derived cancer cells with stromal, endothelial, and immune components in three-dimensional architectures, provide a manipulable framework for simulating these multicellular impediments. This review specifically examines the application of tumor assembloids to investigate drug delivery constraints, including stromal exclusion, vascular transport, immune-mediated resistance, penetration gradients, and spatially heterogeneous drug exposure. We compared three major construction strategies, including self-assembly, 3D bioprinting, and microfluidic compartmentalization, and evaluated their respective strengths for drug assessment. We also discussed assembloids' current limitations, including reproducibility, incomplete physiological dynamics, insufficient spatial analytics, and the need for standardized benchmarking. Overall, tumor assembloids represent promising mechanistic platforms for studying tumor drug delivery barriers. However, broader clinical application will necessitate rigorous validation and harmonized assay standards.

Cancer remains a leading cause of mortality, often complicated by drug resistance arising from single-target therapies. Dual inhibitors that simultaneously target multiple cancer-related defense mechanisms offer a promising strategy to overcome these limitations. Herein, we report the design, synthesis, and biological evaluation of a series of sultam-based N-acyl derivatives (8a-k and 9a-k) as potential dual inhibitors of thioredoxin reductase (TrxR1) and tumor-associated carbonic anhydrases (CA IX and XII). TrxR1 screening identified a few active compounds, with inhibitory potency strongly influenced by the type and orientation of substituents. CA inhibition assays revealed pronounced selectivity for CA IX/XII, while off-target isoforms CA I and CA II remained unaffected. These findings highlight the potential of sultam derivatives as dual-targeting anticancer agents and provide a foundation for further optimization toward selective, multi-pathway cancer therapy.

Multidrug resistance and invasive metastasis constitute pivotal clinical bottlenecks that severely compromise curative outcomes of malignant tumors. Conventional chemotherapy and immunotherapy frequently fail to achieve satisfactory efficacy due to drug resistance barriers and tumor immune escape. Herein, a hyaluronic acid‑cinnamaldehyde Schiff base micelle nanoplatform loading quaternary ammonium‑modified carbon dots (HACA@QASCDs) is rationally constructed, which achieves targeted killing of drug‑resistant tumor cells, remodeling of immunosuppressive microenvironments, and inhibition of distant metastasis via a sequential cascade of irreversible membrane perforation, mitochondria‑dependent apoptosis, and immunogenic cell death (ICD). HACA@QASCDs actively accumulate in drug‑resistant CT26 (DR‑CT26) cells through HA‑CD44 recognition and enable pH‑triggered QASCDs release in acidic tumor microenvironments. The liberated QASCDs elicit irreversible membrane perforation, leading to lactate dehydrogenase leakage, disrupted calcium homeostasis, mitochondrial depolarization, and subsequent intrinsic apoptosis. Such membrane damage simultaneously ignites ICD, and the released damage‑associated molecular patterns effectively drive dendritic cell maturation and M2‑to‑M1 macrophage polarization. In vivo evaluations in bilateral syngeneic tumor models reveal that HACA@QASCDs alone yields 54.2% primary tumor inhibition and 28.6% distant tumor inhibition. Upon combination with αPD‑L1, the distant tumor inhibition rate is markedly elevated to 68.7%. By integrating membrane perforation‑mediated direct cytotoxicity and ICD‑evoked immune activation, HACA@QASCDs offers a highly potent and clinically translatable synergistic strategy to surmount tumor multidrug resistance and block invasive metastasis.

Marine natural products have attracted considerable attention owing to their diverse biological activities and unique structural features. Among them, the dragmacidin alkaloids represent a structurally intriguing family of marine-derived natural products. These alkaloids exhibit a wide range of biological activities, including anticancer and antimicrobial activities, which have stimulated significant interest from both the chemical and biological communities. Structurally, they are characterized by highly functionalized bisindole frameworks in which two indole units are connected via a piperazine, pyrazine, or pyrazinone ring, and can be classified into three categories based on the nature of the linking unit: (i) dragmacidin and dragmacidins A, B, C, I, J, and didebromodragmacidin, featuring a piperazine linker; (ii) dragmacidins D, E, and F, containing a pyrazinone linker; and (iii) dragmacidins G and H, incorporating a pyrazine linker. These structural features pose formidable challenges for chemical synthesis, and consequently, the dragmacidin family has served as an important platform for the development of new synthetic strategies. In this chapter, we provide a comprehensive overview of the dragmacidin alkaloids, focusing on their isolation, structural features, biological activities, and synthetic studies.

Immune checkpoint inhibitors (ICIs) are associated with various pulmonary toxicities. Their impact on pre-existing asthma remains poorly characterized.

Bladder cancer remains highly prone to cisplatin resistance, which markedly limits therapeutic efficacy and contributes to poor clinical outcomes. Although dysregulation of E3 ubiquitin ligases has been implicated in tumor progression and drug resistance, the specific ligases that drive cisplatin resistance in bladder cancer and their underlying mechanisms remain incompletely defined. In this study, integrated analysis of public transcriptomic datasets identified RBCK1 as an aberrantly upregulated E3 ubiquitin ligase associated with malignant progression and cisplatin resistance in bladder cancer. Functional assays showed that RBCK1 promoted clonogenic survival and reduced cisplatin sensitivity in bladder cancer cells. Mechanistically, RBCK1 directly interacted with the helicase-like transcription factor HLTF and facilitated its ubiquitin-proteasome-dependent degradation, thereby decreasing HLTF protein stability. Loss of HLTF relieved suppression of the JAK2/STAT3 pathway and enhanced STAT3 activation. Rescue experiments further demonstrated that HLTF depletion attenuated the cisplatin-sensitizing effect induced by RBCK1 knockdown, whereas pharmacological inhibition of STAT3 with Stattic abrogated this resistance-restoring phenotype. Collectively, these findings identify an RBCK1-HLTF-JAK2/STAT3 regulatory axis that promotes cisplatin resistance in bladder cancer cells, and xenograft validation further supports the role of RBCK1 depletion in enhancing cisplatin response in vivo. Further clinical studies are warranted to determine the translational relevance of targeting this pathway in cisplatin-treated bladder cancer.

Epithelial-Mesenchymal Transition (EMT) is a critical driver of metastasis and drug resistance in breast cancer. Repurposing FDA-approved drugs offers a rapid strategy to target EMT pathways. This study evaluates Itraconazole, an antifungal agent with reported anti-cancer properties, as a potential multi-target inhibitor of the EMT signaling network. We investigated the binding mechanism and selectivity of Itraconazole against four key EMT regulators: Smoothened (SMO), TGF-βR1, EGFR, and GLI1. Our results identify SMO as the primary target, exhibiting high binding affinity and thermodynamic stability. Conversely, EGFR and GLI1 displayed significant structural instability, indicating a lack of direct inhibition. The study provides atomic-level structural evidence supporting the repurposing of Itraconazole as a selective, combinatorial therapeutic agent to target EMT-driven metastasis.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality with limited therapeutic options and poor prognosis, particularly in advanced stages. This study integrates computational and experimental approaches to evaluate metformin as a candidate for repurposing in HCC. Key oncogenic targets EGFR, MAPK3, MMP9, and PRKACA were prioritized via protein-protein interaction network analysis. Molecular docking predicted favorable metformin binding poses for EGFR (ΔG = -7.42 kcal/mol), MAPK3 (ΔG = -7.45 kcal/mol), MMP9 (ΔG = -7.84 kcal/mol), and PRKACA (ΔG = -8.33 kcal/mol). Using AmberTools/Antechamber-derived GAFF2 parameterization and AM1-BCC partial charges for ligand topology, repeated 100 ns molecular dynamics simulations showed ligand retention with target-specific receptor and pocket RMSD adaptation and stable radius-of-gyration profiles. Network toxicology predicted low hepatotoxicity risk using ProTox-II and ADMETlab 2.0 endpoints. ITC measurements produced detectable metformin-protein binding responses and apparent dissociation constants under the reverse-orientation assay conditions (20 µM protein in the cell and 200 µM metformin in the syringe). Western blot analysis showed reduced total EGFR, MAPK3, and MMP9 expression after metformin treatment, while PRKACA changed only slightly. Triplicate MTT assays showed concentration-dependent inhibition of HepG2 cell viability, with an IC50 of 16.02 µM.

Non-Hodgkin's lymphoma (NHL) is a diverse group of lymphoproliferative malignancies that predominantly affects older adults. Chemotherapy remains the primary modality of treatment for many NHL subtypes, yet it often brings about adverse effects such as myelosuppression, anemia, and neuropathy, all of which contribute to a heightened risk of falls in older patients. Falls in this population can lead to serious complications, including fractures and intracranial injuries, thereby impacting functional status and potentially delaying oncological treatment.

Small molecule-drug conjugates (SMDCs) represent an emerging prodrug strategy for precision targeted therapy. In this study, we developed a series of cathepsin B (CTSB)-activated SMDCs targeting Aldo-keto reductase family 1 member C3 (AKR1C3). Among these conjugates, SM-27 was identified as the optimized compound, which exhibited excellent inhibitory activity against AKR1C3 with an inhibitory concentration value of 9 ± 2 nM and could efficiently release the payload gemcitabine under the mediation of CTSB. The antitumor activity of SM-27 was dually dependent on the expression of AKR1C3 and CTSB, allowing it to precisely recognize and eliminate tumor cells with low toxicity to normal cells. In vivo xenograft tumor assays with SM-27 showed significantly superior tumor inhibitory efficacy to gemcitabine with markedly lower off-target toxicity. In conclusion, this study proposes a novel design strategy for SMDCs targeting AKR1C3, which provides a highly promising research approach to address the off-target issue in chemotherapy.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that lacks the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2). There is a lack of predictive biomarkers for the response of patients with TNBC to targeted therapies.

BACKGROUND Durvalumab is a humanized monoclonal antibody and immune checkpoint inhibitor used for the treatment of advanced non-small cell lung cancer. Myocarditis, particularly in late-onset cases, is a rare but serious adverse event associated with durvalumab. This report describes a 79-year-old woman with non-small cell lung cancer who developed late‑onset myocarditis requiring differentiation from direct pericardial invasion. CASE REPORT A 79-year-old woman with stage IIIB lung squamous cell carcinoma developed myocarditis after 11 cycles of durvalumab maintenance therapy (5 months after initiation) following chemoradiation. She presented with reduced cardiac function, pericardial effusion, and elevated high-sensitivity troponin T, initially raising concern for pericardial invasion because the primary tumor was in direct contact with the myocardium. Urgent myocardial biopsy confirmed immune checkpoint inhibitor-related myocarditis, showing mononuclear lymphocyte and macrophage infiltration. Her condition improved after discontinuation of durvalumab and initiation of high-dose corticosteroids and intravenous immunoglobulin. Cardiac function recovered within 3 weeks, and biomarkers normalized. Notably, she has maintained a complete oncologic response for more than four years without further cancer treatment or recurrence of myocarditis, suggesting a durable antitumor effect despite early discontinuation of immunotherapy. CONCLUSIONS This case highlights the diagnostic challenge of distinguishing immune checkpoint inhibitor‑induced myocarditis from direct cardiac invasion in patients with lung cancer, particularly in late‑onset presentations. Early myocardial biopsy enabled prompt diagnosis and treatment, leading to a favorable long‑term outcome. Careful cardiac monitoring is essential, and immune-related adverse events should be considered even when tumor invasion is suspected.

Hepatocellular carcinoma (HCC) frequently develops resistance to lenvatinib, a multikinase inhibitor, necessitating the development of novel therapeutic strategies. Here, we identify bikinin as a potent eIF5A2 inhibitor through structure-based virtual screening (> 100,000 compounds) and demonstrate its synergistic effect with lenvatinib in HCC cells. Mechanistically, bikinin suppresses deoxyhypusine synthase (DHS)-mediated hypusination of eIF5A2, thereby downregulating the expression of transcription factor EB (TFEB). Furthermore, while DHS knockdown enhanced the sensitivity of HCC cells to lenvatinib, the addition of bikinin treatment provided no further significant sensitization. We also observed that the combination of bikinin and lenvatinib significantly promoted apoptosis and suppressed proliferation in HCC cells. Although TFEB overexpression conferred resistance to lenvatinib and activated autophagy, these effects were reversed by co-treatment with bikinin, which restored lenvatinib sensitivity and inhibited autophagic flux. Bikinin disrupts TFEB-driven autophagy, as evidenced by reduced LC3-II conversion, p62 accumulation, and decreased autophagosome formation. In in vivo experiments, the combination therapy with lenvatinib and bikinin achieved marked tumor regression, accompanied by suppressed Ki-67 expression and elevated TUNEL positivity. Finally, RNA-seq data identified TFEB downregulation as a critical mediator of this therapeutic sensitization. Our work unveils a novel therapeutic axis wherein targeting eIF5A2 hypusination disrupts TFEB-dependent autophagy to overcome lenvatinib resistance in HCC cells.

We report a case of occult small-cell lung cancer with durable disease control during durvalumab therapy for 51 months. The patient developed immune checkpoint inhibitor-related inflammatory arthritis with polymyalgia rheumatica-like features, highlighting diagnostic challenges and the importance of functional independence in older adults.

Pachymic acid (PA) is a natural active component of Poria cocos(Schw.)Wol. Although PA exhibits antitumor activity in multiple cancers, its effects and mechanisms against glioma remain elusive. This study aimed to investigate the anti-glioma effects of PA and identify its potential candidate core targets and pathways. Functional experiments demonstrated that PA significantly inhibited the proliferation, migration, and invasion of glioma cells and induced apoptosis in a dose-dependent manner. Using network pharmacology, machine learning, and bioinformatics analysis, we screened six candidate targets: PDE4D, CAPN2, MAPK9, EPHB6, CCKBR, and FAAH. TCGA analysis confirmed that CAPN2 and PDE4D were upregulated in glioma, while the others were downregulated. Molecular docking, an in silico predictive approach, suggested that PA may potentially form favorable binding conformations with these core targets based on calculated binding energies. Further verification revealed that PA treatment was associated with reduced AKT and mTOR phosphorylation, suggesting that the PI3K-AKT-mTOR pathway may be involved in mediating its anti-glioma activity. In conclusion, PA exerts dose-dependent anti-glioma cellular effects through multi-gene regulation, and the suppressed activation of the PI3K-AKT pathway may correlate with its anti-tumor function. These results provide a theoretical basis for developing PA as a potential therapeutic agent for glioma.

Tigliane and daphnane diterpenoids are structurally and biologically diverse natural products mainly found in the Thymelaeaceae and Euphorbiaceae plant families, characterized by polyoxygenated functionalities in the polycyclic skeleton. In this study, ten undescribed polyoxygenated diterpenoids, including seven daphne yuanhuarines A-G (1-7) and three tigliane yuanhuasines L-N (8-10), along with twelve analogues (11-22), were identified from the flower buds of Daphne genkwa. The structures of them were elucidated by the methods of extensive spectroscopy and computational chemistry. 12-O-neodecanoyl-7-oxo 5-ene-phorbol-13-acetate (12) showed significant cytotoxicity against HCT-116 cells with an IC50 of 8.40 μM. Further investigation showed that 12 was able to markedly inhibit cell migration and colony formation of HCT-116 cells. HCT-116 cells, treated with 12, displayed the characteristic pyroptotic morphology of cell swelling and membrane ballooning in transmission electron microscopic assay. The mechanism investigation suggested that 12 induced the pyroptosis via caspase-3/GSDME activation by inhibiting STAT3 phosphorylation. Overall, this study showed that compound 12 was a natural pyroptosis inducer, which may facilitate the development of pyroptosis-induced anti-tumor drugs.

Photodynamic therapy (PDT) has demonstrated efficacy in cancer treatment, with recent advancements concentrating on photosensitizers that generate high levels of reactive oxygen species (ROS) upon light irradiation while exhibiting minimal dark toxicity. In this study, we explored the photophysical properties of ommatins, specifically xanthommatin (Xa), decarboxylated xanthommatin (Dc-Xa), and protected uncyclized xanthommatin (Uc-Xa), and assessed their potential applications in anticancer PDT. Uc-Xa exhibited light-dependent activity against HepG2 cells, with an EC50 of 266 nM under blue light, while remaining inactive in the dark. High-content imaging of HepG2 cells treated with Uc-Xa and blue light showed ROS levels 2.2 times higher than in cells treated in the dark. Transcriptomic analysis of Uc-Xa-treated HepG2 cells under blue light revealed activation of genes associated with stress-responsive pathways, including the integrated stress response, p53 signaling, and p38 MAPK, which may contribute to oxidative stress-associated cellular injury and cell death.

Phosphatidylinositol 3-kinase alpha (PI3Kα) and cyclin-dependent kinase 7 (CDK7) play key roles in the growth of multiple cancers. PI3Kα indirectly activates and enhances CDK7 expression. Our preliminary findings from screening recombinant PI3Kα on the Kinome Array showed that it may directly activate CDK7 and presents promising targets for the development of novel drugs with dual inhibition. In this work, we designed and synthesized two hybrids, HY3 and HY5, employing the strategy of combining the cores of Alpelisib and SY-5609, known selective inhibitors of PI3Kα and CDK7, respectively. HY3 showed 98% inhibition against CDK7 and 10% against PI3Kα. 10-point titration of HY3 was determined against CDK7 with an IC50 = 10.8 nM. We then developed a potent hybrid inhibitor (HY5) employing X-ray structure-based drug design. HY5 showed dual inhibition, 87% inhibition with IC50 of 87.9 nM against PI3Kα and 89% inhibition with IC50 of 638 nM against CDK7. We also screened HY5 for cytotoxicity against HCT116, SKOV3 and MCF7 cells exhibiting IC50s of 360 nM, 490 nM, and 820 nM, respectively. To compare selective killing of cancer cells, we tested HY5 against several normal cell lines: human fibroblast (WI-38), retinal pigmented epithelial cells (RPE), mouse embryonic cell line (10 T1/2), and canine kidney (MDCK). HY5 was significantly less toxic against WI-38 and showed similar toxicity against 10 T1/2, RPE and MDCK cells at 5, 10 and 20 μM which is comparable to the Alpelisib + SY-5609 combination. HY5 showed high selectivity for MCF7 cells where 80% were killed at 1 μM compared to only 10-50% of normal cells at 20 μM.

Doxorubicin (DOX), an extensively used anthracycline anticancer drug, can lead to toxicity in various body organs, especially the heart, which limits its clinical use. We aimed to investigate the protective effects of Artemisia dracunculus L. extract (ADE) against DOX-induced cardiotoxicity. This investigation was conducted on 48 male Wistar rats divided into six groups: Sham, Vehicle (DOX intraperitoneally 2 mg/kg every 48 h for 12 days), ADE groups (DOX + ADE orally 50, 100 and 200 mg/kg/day), positive control (DOX + Vitamin E orally 100 mg/kg/day) for 20 days and starting from four days before DOX. Transthoracic echocardiography, heart damage biomarkers, histological evaluations, oxidative stress, inflammatory, anti-inflammatory, and fibrotic markers were assessed. Our results revealed that DOX remarkably decreased body weight, heart tissue weight, glutathione (GSH), and interleukin (IL)-10 levels while increasing lactate dehydrogenase (LDH), troponin, creatine kinase (CK-MB), malondialdehyde (MDA), IL-6, TNF-α, TGF-β, and histopathological damage in heart tissue (q < 0.001 for all). Additionally, DOX significantly increased left ventricular (LV) end-systolic diameter (LVESd) and LV end-diastolic diameter (LVEDD) while decreasing LV fractional shortening (LVFS) and LV ejection fraction (LVEF) rather than the sham group (q < 0.001 for all). Nonetheless, treatment consisting of all three doses of ADE and vitamin E meaningfully ameliorated all these changes following the DOX-induced cardiotoxicity (q < 0.05 to q < 0.001). ADE effectively ameliorated DOX-induced cardiotoxicity through anti-oxidative, anti-inflammatory, and anti-fibrotic properties. Therefore, ADE may be considered a suitable candidate for treating many heart diseases. Howbeit, more clinical investigations are needed to verify its effectiveness.