While Estrogen receptor alpha (ERα)+ breast cancer treatment is considered effective, resistance to endocrine therapy is common. Since ERα is still the main driver in most therapy-resistant tumors, alternative therapeutic strategies are needed to disrupt ERα transcriptional activity. In this work, we position TRIM24 as a therapeutic target in endocrine resistance, given its role as a key component of the ERα transcriptional complex. TRIM24 interacts with ERα and other well-known ERα cofactors to facilitate ERα chromatin interactions and allows for maintenance of active histone marks including H3K23ac and H3K27ac. Consequently, genetic perturbation of TRIM24 abrogates ERα-driven transcriptional programs and reduces tumor cell proliferation capacity. Using a recently developed degrader targeting TRIM24, ERα-driven transcriptional output and growth were blocked, effectively treating not only endocrine-responsive cell lines but also drug-resistant derivatives thereof as well as cell line models bearing activating ESR1 point mutations. Finally, using human tumor-derived organoid models, we could show the efficacy of TRIM24 degrader in the endocrine-responsive and -resistant setting. Overall, our study positions TRIM24 as a central component for the integrity and activity of the ERα transcriptional complex, with degradation-mediated perturbation of TRIM24 as a promising therapeutic avenue in the treatment of primary and endocrine resistance breast cancer.

Patients with ERBB2 (formerly HER2 or HER2/neu)-positive metastatic breast cancer (MBC) receiving trastuzumab deruxtecan (T-DXd), a new standard of care, may experience specific adverse events affecting their quality of life (QOL). Monitoring electronic patient-reported outcomes alongside vital signs may help improve their QOL through early detection and management of these symptoms.

Microtubule targeting agents (MTAs) constitute a vital category of tubulin-binding compounds deployed across anticancer therapies. Despite the array of MTA drugs developed by pharmaceutical entities, the quest for novel efficacious molecules continues unabated. We unveil an innovative in vitro MTA screening methodology employing nano-differential scanning fluorimetry (nanoDSF), presenting distinct advantages over known assays. This novel approach not only assesses compound-tubulin binding but also quantitatively analyzes its impact on tubulin polymerization, facilitating structure-activity relationship discovery. The proposed nanoDSF assay was rigorously validated using the Prestwick Chemical Library, which encompasses 1520 approved compounds, successfully identifying all previously known MTAs. This screening has unearthed potential antitubulin agents among drugs currently utilized for unrelated medical conditions, offering insights into their mechanisms of action in inhibiting cancer cell proliferation and/or inducing cytotoxicity. Finally, we have identified a previously unrecognized structure-activity relationship within the carbendazim and phenothiazine drug clusters, providing valuable insights for the rational optimization of compounds from these families. These discoveries open new opportunities for drug repositioning of the newly identified MTAs and significantly streamline the screening process of large chemical libraries for MTAs with novel chemical scaffolds.

Furanolides represent an emerging class of natural products known for their structural diversity and potent bioactivities, including antibiotic, cytotoxic, or algicidal effects. The systematic exploration of their biological activity profiles for the discovery of new hits for drug development thus constitutes a promising endeavor. However, their low natural abundance and the resulting difficulty in obtaining sufficient quantities have limited further in-depth investigations into their biological activity and structure-activity relationships (SARs). Building on our recent discovery of biosynthetic enzymes catalyzing furanolide core-structure assembly, we herein developed a cost-effective, one-pot enzymatic toolbox that enables the fast generation of hundreds of furanolide structural analogs. We systematically evaluated antimicrobial activities and cytotoxicity against the A549 lung cancer cell line for a representative selection of library congeners and explored their SARs. Several derivatives demonstrated significant cytotoxicity, particularly against lung cancer stem cells, offering promising insights into the development of furanolides as potential anticancer agents. Additionally, some analogs displayed promising antibacterial activity against important Gram-positive pathogens such asStaphylococcus aureus.

Precise control of proteolysis on target cells is important for proteolysis-targeting chimeras (PROTAC) to minimize off-tissue toxicities. Small-molecule ligand-guided PROTACs, namely, small molecule-degrader conjugates (SMDCs), offer many advantages, but some flaws in the previous designs, especially linker chemistry, cause a considerable defect in pharmacokinetics, which impedes in vivo applications. Here, we investigated the relationship of linker structures with in vivo factors, including serum stability, blood retention, controlled PROTAC release, targetability, and potency. Based on the structure-activity relationship (SAR) study, the cathepsin-responsive/carbamate linker bearing a long-circulating CBB protractor was developed to conjugate the cRGD peptide and GNE-987 PROTAC. This peptide-drug conjugate showed an excellent targeting capability, long-term stability, and favorable pharmacokinetics, which enabled the selective proteolysis of targets in an antigen-dependent manner and achieved a tumor growth arrest in vivo by a dose much lower than regular SMDCs and free PROTACs. Our results demonstrated that linker-optimized SMDC degraders can be promising modalities in precision medicine.

Cardiotoxicity from chemotherapy drugs is a major adverse effect of cancer chemotherapy, which strongly compromises therapeutic outcomes. The application of cardioprotective agents is an effective strategy to mitigate cardiotoxicity in the clinic. However, the effects of chemotherapeutic drugs and their doses, as well as the efficacy of cardioprotective agents on the function of cardiomyocytes, especially at different stages of cardiotoxicity, have not been well explored, partly owing to the lack of real-time functional parameters of cardiomyocytes after drug treatment. Herein, we constructed in vitro doxorubicin (DOX)-induced cardiotoxicity (DIC) models through culturing neonatal rat primary cardiomyocytes on polyacrylamide (PA) gels with a stiffness of around 20.0 kPa, and adding DOX at different concentrations to mimic the mild, moderate, and severe stages of chemotherapeutic drug-induced cardiotoxicity. We used scanning electrochemical microscopy (SECM) to monitor the respiratory activity, contraction frequency, and membrane permeability of cardiomyocytes after DOX treatment in situ. The SECM results obtained demonstrated that 0.25-5.0 μM DOX dosages led to decreased respiratory activity and contraction frequency, accompanied by increased membrane permeability of cardiomyocytes. We also used SECM to evaluate the cardioprotective effect of bisoprolol (a clinically approved β-blocker for cardiovascular diseases) on cardiomyocytes under DOX treatment and obtained its optimal protective efficacy for 1.0 μM DOX-treated cardiomyocytes. Our work provides in situ functional information on living cardiomyocytes under chemotherapeutic drug and cardioprotective agent treatments, contributing to a better understanding of the pathological features and prevention strategies of chemotherapy-induced cardiotoxicity.

Tremella fuciformis (TF) is a valuable edible fungus rich in various nutrients, with TF polysaccharide (TFP) as its primary bioactive component. Extensive studies have demonstrated that TFP exhibits significant bioactivities, including antioxidant, antitumor, immunomodulatory, memory-enhancing, anti-inflammatory, hypoglycemic, and hypolipidemic effects, as well as skin-protective properties and gut microbiota modulation. Due to these multifunctional properties, TFP has garnered considerable attention in the food, pharmaceutical, and cosmetic industries. This review summarizes recent research on TFP, focusing on its preparation methods, structural characteristics, and diverse biological activities. Additionally, it provides a theoretical basis for the potential applications of TFP in the food, pharmaceutical, and cosmetic industries, while also discussing future research directions and development prospects.

Anti-vascular endothelial growth factor (VEGF) intravitreal injection treatment (IVT)s are gold standard for various neovascular retinal diseases, including neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME), and macular edema due to retinal vein occlusion (RVO). Same day bilateral IVTs are commonly performed off-label worldwide to reduce patient burden, despite limited safety data. This study evaluates the safety and management of bilateral same day anti-VEGF injections within a treat-and-extend regimen (TER) and proposes a clinical guideline for coordination of bilateral treatment.

Epithelial ovarian cancer (EOC), accounting for 90-95% of all ovarian cancer (OC) cases, is the most lethal gynaecological malignancy, primarily due to late-stage diagnosis and the development of chemoresistance. While initial responses to Platinum- and Taxane-based chemotherapy are favorable, nearly 70% of patients relapse within five years. Although signaling pathways such as PI3K/AKT, MAPK, NF-κB, Notch, and Wnt/β-catenin have been individually studied in the context of chemoresistance, recent evidence highlights the importance of dynamic feedback loops and crosstalk among these networks in sustaining the resistant phenotype. Moreover, dysregulated microRNAs (miRNAs), as post-transcriptional regulators, fine-tune these pathways, creating self-sustaining circuits that promote drug efflux, inhibit apoptosis, and maintain cancer stemness. Reciprocal regulation between miRNAs and signaling components establishes robust networks that amplify chemoresistant phenotypes. The review provides a comprehensive overview of the molecular mechanisms driving chemoresistance, emphasising critical elements of signalling pathways and associated miRNAs that contribute to resistance and may function as biomarkers or therapeutic targets to mitigate chemoresistance. To improve clinical outcomes, future research should focus on identifying resistance-associated miRNA signatures and targeting nodal points within miRNA-signaling networks, thereby enabling the development of personalized therapies to overcome drug resistance in EOC.

Understanding how genes influence drug responses is critical for advancing personalized cancer treatments. However, identifying these gene-drug interactions in a physiologically relevant human system remains a challenge, as it requires a model that reflects the complexity and heterogeneity among individuals. Here we show that large-scale CRISPR-based genetic screens, including knockout, interference (CRISPRi), activation (CRISPRa), and single-cell approaches, can be applied in primary human 3D gastric organoids to systematically identify genes that affect sensitivity to cisplatin. Our screens uncover genes that modulate cisplatin response. By combining CRISPR perturbations with single-cell transcriptomics, we resolve how genetic alterations interact with cisplatin at the level of individual cells and uncover an unexpected link between fucosylation and cisplatin sensitivity. We identify TAF6L as a regulator of cell recovery from cisplatin-induced cytotoxicity. These results highlight the utility of human organoid models for dissecting gene-drug interactions and offer insights into therapeutic vulnerabilities in gastric cancer.

Multiple myeloma (MM) is a blood cancer that, unfortunately, has a high morbidity and mortality rate. The VMP regimen, which includes bortezomib (BOR), melphalan (MEL), and prednisolone (PRD), is a safe and effective salvage regimen for refractory or relapsed MM. Up to now, there is no established analytical method to determine the VMP regimen, nor has any study investigated the kinetic interactions among its components, thereby highlighting the need for further clinical investigation. In light of this, an environmentally friendly, fast, sensitive, and precise LC-MS/MS method was established to determine bortezomib, melphalan, prednisolone, and sildenafil (an internal standard) simultaneously as part of the in vivo pharmacokinetics research carried out on rats. The established LC-MS/MS method was applied using a mobile phase composed of a mixture of methanol: 0.1% aqueous solution of formic acid and a ZORBAX Eclipse Plus C18 column (4.6 mm × 150 mm, 5 μm) as a stationary phase. The cited drugs were ionized through positive ionization and detected using multi-reaction monitoring (MRM) mode with the following precursor→product transitions: m/z 367.3→226.3 for BOR, m/z 305.0→168.2 for MEL, m/z 545.0→147.5 for PRD, and m/z 475.3→283.4 for SIL. Following FDA guidelines, the developed method was validated and showed acceptable ranges. Subsequently, it was employed in an in vivo investigation using rats, where the quantitative assessment of each drug was performed following both single and combined treatment. This allowed for the investigation of potential drug-drug interactions and the calculation of all pharmacokinetic parameters to monitor the therapeutic effects of those medications. To ensure the safety and environmental friendliness of the developed method, four assessment tools were applied: the assessment of green profile (AGP), blue applicability grade index (BAGI), analytical greenness metric for sample preparation (AGREEprep), and green analytical procedure index (GAPI).

Oral adjuvant hormone therapy for early breast cancer, despite its proven importance in terms of survival and prevention of recurrence, does not fall within the scope of clinical pharmacy programs set up for oral anticancer drugs, even though issues of therapeutic adherence have been clearly identified. The aim of our study was to explore the perception of healthcare professionals regarding the prescription and dispensing of this hormone therapy, in order to identify the risks for these patients and determine the clinical pharmacy actions that could address these risks.

Doxorubicin is a commonly used antitumor drug for the treatment of various cancers. However, its clinical application is greatly restricted by its severe cardiotoxicity. At present, doxorubicin-induced cardiotoxicity is categorized into acute and chronic forms, depending on the dosage and duration of exposure, which may eventually lead to the occurrence of heart failure. The pathogenesis of doxorubicin cardiotoxicity is associated with oxidative stress, mitochondrial damage, calcium overload, dysregulation of autophagy, and apoptosis. In forensic medical practice, cases of poisoning or even cardiac death caused by doxorubicin showed no obvious changes in cardiac morphology through routine forensic pathological examinations. The paper aims to summarize the research on the mechanisms of action of doxorubicin-induced cardiotoxicity in recent years, analyze and discuss the possible pathways of cardiomyocyte injury caused by doxorubicin, and provide references for research on the mechanisms of doxorubicin-induced cardiotoxicity and forensic application.

Denosumab, an anti-bone resorptive agent composed of the anti-receptor activator of nuclear factor-κB ligand (RANKL) monoclonal antibody, and nivolumab, an immune checkpoint inhibitor composed of the anti-programmed death-1 (PD-1) antibody, are administered to suppress cancer growth. The present study examined the effects of the administration of anti-RANKL antibody alone and in combination with anti-PD-1 antibody on cancer-induced osteolysis in mice.

FDA approval of selective CDK4/6 inhibitors (CDK4/6i) marked a groundbreaking development in cancer treatment. Decades of pre-clinical studies elucidated the route that certain cancer cells take to gain the cancer hallmark of uncontrolled proliferation, uncovering CDK4/6 as key players. Further investigation into the molecular underpinnings of this process revealed interconnected signaling between the CDK4/6 and estrogen receptor (ER) signaling axes, providing evidence that CDK4/6i would be particularly relevant in estrogen-driven cancers. Three FDA-approved CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, were independently developed and all exhibited efficacy against in vivo models of ER+ breast cancer. Clinical trials then confirmed the safety and efficacy of these drugs in patients. Ongoing clinical trials are now testing CDK4/6i in several other cancer models, including other hormone-driven cancers. Further mechanistic insights should reveal predictive biomarkers of response, and potential combination therapies to overcome resistance. This chapter provides an overview of the development of these drugs, their current utility, and their potential use in the treatment of multiple malignancies.

Steroid Hormone Receptors (SHRs) when bound to its ligand can act as transcription factors, which are responsible for transcription of important genes via hormone responsive element in our genome. Many studies have revealed the molecular mechanisms involved with SHRs. Cancer specific aberrant expression pattern of SHR and variation in their mechanism created an opportunity to specifically target SHRs for developing highly effective anti-cancer therapeutics. Further, these receptors can be targeted using different nanodelivery systems thus proving to be a potent target. The anticancer nanodelivery system can selectively target cancer cells due to the newly discovered aberrant nature of SHRs in cancer making it unique from other membrane bound receptors that are relatively more easily accessible as these are mostly overexpressed on the surface of the cells. One such interesting receptor which is present in the cytoplasm of the cells and ubiquitously expressed in both cancer and non-cancer cells is glucocorticoid receptor (GR). GR as studied earlier behaves in a unique way in cancer cells which facilitates the nanodelivery system including small molecules to selectively target cytoplasmic GR and hence makes the anticancer therapeutics more precise in its own way. Here, we will summarize the knowledge of SHR providing information about its role in its molecular mechanisms in cells and mostly to dig into its anticancer therapeutic roles in cancer cells. Most importantly how the lipid nanoformulation can modulate the SHRs ligand binding domain in cancer therapeutics is also discussed. This also deals with all the SHRs including estrogen, progesterone, mineralocorticoid receptors and androgen receptors.

Ferroptosis is pivotal in colon cancer progression and immunity. While the natural flavonoid luteolin has anticancer properties, its ferroptosis targets and immunomodulatory effects in colon cancer are unclear.

Colon and breast cancer are among the leading causes of mortality worldwide. The limited efficacy of current treatments highlighted an urgent need for improved therapeutic options. Bergenia ligulata, known for its anticancer properties in Indian traditional and folk medicine, has shown promise. However, the molecular basis of its effects, particularly its anti-metastatic properties, remains poorly understood. Anti-prostate cancer activity of a polyphenol-rich fraction from Bergenia ligulata (PFBL) rhizome extract, defined by LC-MS, has already demonstrated promising results in preclinical models.

Photodynamic therapy (PDT) is a promising strategy for cancer treatment, yet the reliance on rare, expensive, and potentially toxic heavy metals limits the practical application of many current photosensitizers. In this study, we synthesized and evaluated a series of iron(III)-N-heterocyclic carbene (Fe(III)-NHC) complexes (1-7) bearing diverse substituents to explore their potential as cost-effective alternatives for cancer therapy. While none of the complexes exhibited significant singlet oxygen generation under light excitation, several (particularly complexes 1, 2, 3, and 7) showed strong cytotoxicity toward cancer cells even in the absence of photodynamic activation. Structure-activity analysis revealed that hydrophobic or moderately electron-donating groups enhanced cellular uptake and bioactivity, while polar or bulky substituents reduced efficacy of cellular uptake, as confirmed by ICP-MS and confocal fluorescence microscopy. Further biological studies suggested that the cytotoxic effects of these compounds may stem from mitochondrial damage, potentially caused by disruption of mitochondrial membrane potential through iron-mediated redox processes. These findings highlight the promise of Fe(III)-NHC complexes as potential chemotherapeutic agents and underscore the importance of rational ligand design in modulating their biological activity.

Synthetic polymers with protein-like functions have the potential to revolutionize the way of modulating physiological processes. Pyroptosis, a form of gasdermin-driven programmed necrosis, is widely viewed as a promising strategy to ignite antitumor immunity. Yet, the intrinsic silence or absence of gasdermins (GSDMs) in tumor cells and the complex intracellular activation process limit its wider applications. Inspired by the pore-forming mechanism of activated N-terminal gasdermins (N-GSDMs), we here develop a synthetic zinc coordination polymer, DPDPA-Zn, that functions similarly to N-GSDMs. DPDPA-Zn can selectively adhere to anionic phospholipid-containing liposomes and form oligomeric structures on their surfaces. This oligomerization incites membrane curvature and effectively perforates the acidic phospholipid-containing liposomes. Once internalized by mammalian cells, DPDPA-Zn functions like N-GSDMs by acting as an executor of pyroptosis, effectively inducing cell death through an N-GSDM-independent pyroptosis. Local treatment with DPDPA-Zn significantly reduces tumor burden in mice challenged with breast, colorectal, and melanoma cancers. Moreover, DPDPA-Zn-induced pyroptosis leads to the release of cytosolic inflammatory cytokines and tumor antigens, effectively activating robust systemic antitumor immunity and protecting mice against subsequent tumor rechallenges. Collectively. This N-GSDM-mimicking polymer possesses enormous potential for addressing the lack of GSDMs in cancer cells and activating a robust in situ vaccine effect.