Despite the initial success of poly (ADP-ribose) polymerase (PARP) inhibitors, achieving durable responses and effective treatment outcomes in metastatic castration-resistant prostate cancer (mCRPC) remains challenging. Resistance to the PARP inhibitor Olaparib is primarily mediated by the induction of autophagy, which enhances the availability of free fatty acids (FFA). Cancer cells mitigate the toxic effects of excessive lipid accumulation by sequestering FFA into lipid droplets (LD) through diacylglycerol O-acyltransferase 1 (DGAT1)-mediated lipid storage. We hypothesize that inhibiting DGAT1 disrupts this protective mechanism, induces lipotoxicity, promotes oxidative stress-mediated cell death, and enhances the anti-cancer efficacy of PARP inhibitors. We evaluated the effect of combining a DGAT1 inhibitor (DGAT1i) with Olaparib in aggressive prostate cancer cell lines on lipid metabolism and oxidative stress in vitro. We assessed LD dynamics by immunofluorescence, mitochondrial integrity, FFA accumulation, and oxidative stress. Additionally, targeted protein expression analysis was conducted to examine the expression levels of proteins involved in autophagy, lipogenesis, and apoptosis. DGAT1 inhibition notably potentiated the effects of Olaparib on prostate cancer cell proliferation. Olaparib alone caused an increase in LD formation, whereas the combination treatment reduced them, suggesting a shift in lipid metabolism. Dual treatment of Olaparib and DGAT1 inhibition further promoted FFA accumulation and lipotoxicity. Additionally, the combination elevated intracellular oxidative stress and mitochondrial damage, implying that DGAT1 inhibition accelerates oxidative stress-driven cell death. Flow cytometry and apoptosis array analysis confirmed an increase in programmed cell death in the combination treatment group. Our study proposes a novel therapeutic strategy to enhance Olaparib efficacy and potentially prevent resistance by targeting autophagy-induced LD biogenesis through DGAT1 inhibition. Future studies will focus on elucidating the relationship between Olaparib-induced autophagy, lipogenesis, and DGAT1 inhibition, providing a foundation for clinical trials in patients with mCRPC.

To assess acute IOP changes after anti-VEGF injections in patients with Pseudoxanthoma elasticum (PXE) compared to other retinal diseases.

Zebrafish is a valuable model for antiangiogenic drug testing. We hypothesized that the efficacy of antiangiogenic compounds might vary in hypoxic tissue environments compared to normal tissue. To explore this, we established a chemically induced zebrafish model using DMOG, which inhibits prolyl hydroxylases, and a genetic model by knocking out vhl gene via CRISPR/Cas9 to activate hypoxia signaling. In wild-type larvae, the antiangiogenic drug sorafenib inhibited blood vessel growth. However, in the DMOG model and vhl-/- model, no inhibition occurred in sub-intestinal vessel (SIV) upon sorafenib treatment. Also, gene expression analysis showed that the DMOG induced hypoxia had 20-fold increase in phd3 expression, a marker for hypoxia signaling activation, which rose to 65-fold and 280-fold with sorafenib treatment at the concentration 0.1 μM and 0.2 μM, respectively. In the vhl-/- model phd3 expression was found to be increased to 220-fold and reaching up to 400-fold with sorafenib treatment. This increased activation of hypoxia signaling elevated the proangiogenic factors like vegfaa, vegfab and vegfd, which might have protected the SIV region from sorafenib treatment in hypoxic models. This confirms that the hypoxia zebrafish models gained resistance against chemotherapeutic drugs by increasing the cellular hypoxia levels. Thus, our zebrafish model for hypoxia provides evidence that the efficacy of chemotherapy for cancer significantly depends on hypoxic microenvironment.

In this study, several etodolac-based hydrazone, thiazolidinone, and triazole derivatives that we synthesized and characterized in our earlier research were tested against the hormone-responsive breast cell line MCF-7 and the triple-negative MDA-MB-231, as well as the murine origin fibroblast cell line L-929, at varying doses for their effects on cell viability and toxicity and for their inhibitory activity on cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) formation. Cell viability and apoptosis tests were utilized to assess the anti-cancer potential of etodolac and its derivatives after the cells were exposed to varied concentrations of synthesized compounds for three different time periods. ELISA and Western blot methods were used to detect protein levels. All synthesized compounds demonstrated higher anti-cancer activity at significantly lower doses compared to etodolac (half-maximal inhibitory concentration [IC50] of 0-50 µM range in derivatives versus 0.5-1 mM range in etodolac). Except for SGK 242, which had a major toxic effect on all cells, the chemicals SGK 206 and SGK 217 had a twice-less impact on control murine L-929 fibroblasts. Similar to proliferation, low concentrations of SGK 206 and SGK 217 (25-50 µM) significantly induced apoptosis in breast cancer cells but not in normal cells. Additionally, they inhibited COX-2 protein expression at 50 µM, and SGK 206 inhibited PGE2 release more effectively than etodolac in cancer cells. The results of this study suggest that, in comparison to a healthy control group, the thiazolidinone derivative SGK 206 and the thiazolidinone derivative SGK 217 are more effective than etodolac when it comes to the breast cancer cell lines MCF-7 and MDA-MB-231. SGK 206 exhibits a low IC50 value, a distinct dose-response relationship, and strong apoptotic effects, particularly on MDA-MB-231 cells.

Immune checkpoint inhibitors (ICIs) have improved survival for non-small cell lung cancer (NSCLC) patients, but immune-related adverse events (irAEs), like immune-mediated thyroid dysfunction (IMTD), have been reported. IMTD causes irreversible thyroid damage, affecting NSCLC patients' quality of life. This study aims to explore IMTD risk factors and develop a Nomogram to predict IMTD risk at 6, 12, and 24 months.

Neuroblastoma (NB), the most prevalent extracranial solid malignancy in children, poses significant therapeutic challenges, particularly concerning high-risk subtypes characterized by an immunologically "cold" phenotype. These tumors evade immune surveillance through mechanisms such as impaired antigen presentation and immunosuppressive microenvironment formation. Despite the incorporation of immunotherapies (e.g., GD2 monoclonal antibodies) into international clinical guidelines, the 5-year survival rate of patients with NB persistently remains lower than 50%. Small-molecule targeted agents, distinguished by their low molecular weight and superior chemical stability, offer advantages over macromolecular antibody therapies by effectively penetrating cell membranes to engage intracellular targets. Epigenetic regulation, a DNA sequence-independent gene expression modulation system, plays a pivotal role in cell fate determination via dynamic DNA methylation, histone covalent modifications, chromatin spatial reorganization, and non-coding RNA-mediated pathways. Emerging evidence has highlighted a strong correlation between epigenetic dysregulation and NB progression, establishing a molecular rationale for novel therapeutic strategies. Current epigenetic research in NB primarily focuses on histone deacetylase inhibitors and DNA methyltransferase inhibitors. These drugs exhibit unique translational potential because of their accelerated development timelines and cost-effective production, significantly enhancing therapeutic accessibility. This review systematically examines the current landscape of epigenetic modulators in NB treatment and discusses their transformative potential in improving outcomes for high-risk patients with NB.

Programmed death-1 (PD-1) and its ligand PD-L1 inhibitors have become pivotal agents in cancer immunotherapy, demonstrating significant efficacy across multiple malignancies. However, beyond regulating T cell activation, the PD-1/PD-L1 axis also exerts complex and critical effects on bone metabolism. Notably, both clinical observations and mechanistic studies have revealed a paradox: on one hand, PD-1/PD-L1 blockade appears to confer bone-protective benefits; on the other hand, it has been associated with bone-related adverse events (AEs) in up to 69% of patients, including pathological fractures and vertebral compression fractures. This review comprehensively explores the bidirectional regulatory effects of the PD-1/PD-L1 pathway on bone metabolism and investigates the underlying mechanisms contributing to these contradictory findings. The discrepancies may be attributed to a combination of clinical variables, microenvironmental conditions, cell-specific responses, and intricate interactions among multiple signaling pathways, including the Wnt/β-Catenin pathway and the PD-L1-PKM2 axis. We further examine the pathophysiological basis of osteoporosis and fragility fractures occurring during PD-1/PD-L1 inhibitor therapy, and argue for their recognition as a subclass of immune-related adverse events (irAEs). Finally, we propose a framework for bone health surveillance and stratified prevention strategies aimed at preserving antitumor efficacy while improving skeletal health and quality of life-offering novel insights into osteoporosis prevention and management in the context of immune checkpoint inhibition.

In neuroblastoma, MCYN amplification is associated with survival rates of <50%. Overexpression of the mitotic kinases Aurora-A and Aurora-B are also associated with low survival and exacerbate the oncogenic effects of N-Myc. As N-Myc is stabilized by Aurora-A, Aurora-A targeting proteolysis targeting chimeras (PROTACs) have been developed that reduce Aurora-A and N-Myc levels. However, simultaneous degradation of N-Myc, Aurora-A, and Aurora-B has not been previously achieved. Given the contributions of both Aurora kinases to MYCN-amplified neuroblastoma, we designed PROTACs capable of degrading both Aurora-A and Aurora-B. Dual-degrading PROTACs dAurAB2 and dAurAB5 potently degraded Aurora-A (DC50 = 59 nM and 8.8 nM, respectively) and Aurora-B (DC50 = 39 nM and 6.1 nM), eliminated 89% - 97% of Aurora-A and Aurora-B, and reduced N-Myc levels by 38% and 45% in MCYN-amplified IMR32 neuroblastoma cells. Global proteomics screening revealed that while dAurAB2 demonstrated good selectivity, dAurAB5 downregulated additional targets including threonine tyrosine kinase (TTK). Interestingly, TKK is also associated with MCYN-amplified neuroblastoma, and multi-target PROTAC dAurAB5 reduced the viability of neuroblastoma IMR32 cells by 55% at 24 hours. The development of dAurAB2 and dAurAB5 generates new modalities for inhibiting the oncogenic activities of Aurora-A, Aurora-B, N-Myc, and TTK in neuroblastoma and other cancers.

The cell nucleus, as the central hub of cellular physiological activities, represents an effective target for cancer therapy. Targeting strategies aimed at the cell nucleus can enhance the delivery of more drugs into the tumor cell nucleus, thereby improving therapeutic efficacy. Such approaches can overcome the limitations of previous tissue- and cell-level treatments, such as insufficient specificity and excessive toxic side effects. Currently, researchers have integrated carbon nanoparticles (CNPs), therapeutic molecules, and nucleus-targeting components to construct various nucleus-targeted carbon nanoparticle delivery systems for tumor imaging and treatment. These systems not only increase drug concentration within the cell nucleus but also enable certain CNPs to utilize their intrinsic fluorescence for imaging monitoring. This review summarizes the latest classification progress of nucleus-targeted CNPs, their mechanisms of action in cancer-targeted diagnosis and treatment, and their applications in cancer therapy. Additionally, the article discusses the current challenges and future directions in this field, aiming to provide valuable reference information for precision cancer treatment.

Glioblastoma is the most aggressive and lethal primary brain tumor in adults, with current treatment options offering only limited improvement in patient survival. Despite the advancement of modalities such as immunotherapy, targeted therapy, gene therapy, focused ultrasound, and tumor-treating fields, therapeutic efficacy remains unsatisfactory due to challenges such as the blood-brain barrier, tumor heterogeneity, and treatment resistance. Nanotechnology has emerged as a promising platform to enhance the delivery, specificity, and combinatorial potential of these therapies. By enabling precise and multifunctional delivery of therapeutic agents, nanoscale systems hold the potential to overcome critical biological and pharmacological barriers in glioblastoma treatment. This review provides an overview of recent progress in nanomedicine-based strategies for glioblastoma, critically examines the key challenges that limit their clinical translation, and highlights innovative approaches designed to improve therapeutic outcomes. Future perspectives on how nanotechnology may reshape the landscape of brain tumor treatment are also discussed.

Liver cancer, particularly hepatocellular carcinoma (HCC), remains a global health challenge with limited therapeutic options for advanced stages. Transarterial chemoembolization (TACE), the first-line treatment for intermediate and advanced-stage HCC, faces limitations such as incomplete tumor embolization and systemic toxicity. This review synthesizes recent advancements in nanotechnology to address these challenges, focusing on nanoparticles (NPs) as embolic agents, drug carriers, and imaging contrast agents. Nanoparticle-based drug delivery systems (eg, gold NPs, liposomes) enable localized drug release in tumors, enhancing chemotherapy efficacy while minimizing systemic side effects. Multimodal imaging NPs (eg, superparamagnetic iron oxide NPs, gadolinium-based NPs) enhance real-time visualization of tumor vasculature during TACE, facilitating precise embolization and treatment monitoring. Additionally, combining NPs with photothermal therapy or anti-angiogenic agents (eg, sorafenib) demonstrates synergistic effects in inhibiting tumor recurrence and metastasis. In conclusion, nanotechnology significantly enhances TACE's precision and efficacy through targeted delivery and multimodal imaging, though challenges in biocompatibility, safety, stability, and large-scale production require urgent attention. Future studies should focus on developing multifunctional nanocarriers and personalized nanomedicine strategies to optimize clinical outcomes for HCC patients.

Proton pump inhibitors (PPIs), including esomeprazole, impact the acidic tumor microenvironment, potentially influencing cancer cell behavior. By examining the combined effects of esomeprazole and cisplatin on SNU-1 gastric carcinoma cells, this study sought to elucidate the mechanisms through which esomeprazole enhances cisplatin's cytotoxicity, potentially allowing for effective treatment with reduced cisplatin dosages. SNU-1 cells were treated with varying doses of esomeprazole and cisplatin, alone and in combination. Cell viability was assessed using the XTT assay. Oxidative stress (TAS/TOS), apoptosis (Annexin V, cleaved PARP), mitochondrial membrane potential, and DNA damage (8-oxo-dG, γH2AX, ATM) were evaluated using flow cytometry and ELISA. Statistical significance was determined by ANOVA. Esomeprazole alone showed no significant effect on SNU-1 cell viability, oxidative stress (TAS/TOS), apoptosis, mitochondrial membrane potential, or DNA damage. Cisplatin, however, significantly reduced cell viability (IC50 = 3.024 µg/mL), increased oxidative stress (decreased TAS, increased TOS), diminished apoptosis (increased Annexin V binding and cleaved PARP levels), disrupted mitochondrial membrane potential, and caused significant DNA damage (increased H2AX and ATM phosphorylation, and elevated 8-oxo-dG) (p < 0.001). Notably, the combination of esomeprazole and cisplatin synergistically enhanced cisplatin's effects. The combination resulted in a significantly greater reduction in cell viability (CI < 1), a further increase in oxidative stress, a higher level of apoptosis, amplified mitochondrial depolarization, and potentiated DNA damage compared to cisplatin alone (p < 0.001). Esomeprazole potentiates cisplatin-induced cytotoxicity in SNU-1 gastric cancer cells by enhancing oxidative stress, apoptosis, mitochondrial dysfunction, and DNA damage. This suggests a potential therapeutic strategy to improve cisplatin efficacy and overcome resistance in gastric cancer.

The development of acquired drug resistance in breast cancer (BC) significantly compromises treatment efficacy and patient survival, yet the underlying molecular mechanisms remain completely understood. In this study, we investigated the role of the Hippo signaling pathway and its regulatory factor, LIM Domain Only 4 (LMO4), in the acquired Adriamycin (ADR)-resistant MCF-7 (AdrR) cells. Using a combination of bioinformatics and experimental approaches, we demonstrated that AdrR cells exhibit defective apoptosis upon ADR treatment, characterized by abnormal expression of apoptotic proteins such as BAX and BCL2. RNA sequencing (RNA-seq) and ATAC sequencing (ATAC-seq) revealed significant dysregulation of the Hippo pathway in AdrR cells compared to parental MCF-7 cells, suggesting its involvement in mediating drug resistance. Further experiments showed that small interfering RNA (siRNA)-mediated knockdown of LMO4 (siLMO4) altered the expression of apoptotic proteins and partially restored ADR sensitivity in AdrR cells. Mechanistically, LMO4 was found to modulate the Hippo pathway, as evidenced by changes in the nuclear translocation of YAP and the phosphorylation levels of key Hippo pathway components (MST1/2 and YAP). Inhibition of the Hippo pathway using a Lats kinase inhibitor further confirmed its role in regulating drug resistance. Our findings highlight the critical involvement of the LMO4-Hippo signaling axis in ADR resistance and propose LMO4 as a potential therapeutic target for reversing chemoresistance in BC. This study provides novel insights into the molecular mechanisms of drug resistance and offers a foundation for future research aimed at improving treatment strategies for ADR-resistant breast cancer.

Rational design of chiral metallodrugs with precise stereochemical control and enhanced photodynamic performance is pivotal for advancing precision oncology. Herein, we report the stepwise assembly of homochiral dinuclear Ir(III) triple-stranded metallohelices (ΔΔ-/ΛΛ-Ha) via dynamic imine ligation followed by reductive stabilization, yielding configurationally stable amine-bridged helical architectures with locked chirality. While both enantiomers exhibit comparable dark toxicities, the ΔΔ-enantiomer demonstrates enhanced photodynamic activity against multiple cancer cell lines under white light irradiation. Mechanistic studies─including intracellular reactive oxygen species production, scavenger experiments, mitochondrial damage, apoptosis assays, ethidium bromide displacement, and DNA docking─link this enantioselectivity to chirality-dependent DNA recognition. The stronger DNA-binding affinity of the ΔΔ-enantiomer facilitates a more efficient spatial utilization of the generated singlet oxygen. This work provides a robust synthetic route to homochiral metallohelices and elucidates the critical role of molecular chirality in optimizing photodynamic therapeutics.

Pancreatic cancer organoids (PCOs) have gained extensive attention as promising in vitro models that can advance our understanding of translational cancer biology and biomedical research. To date, PCOs are mostly cultured in animal-derived matrices, which are limited by their low similarity with native tumors due to batch-to-batch variations, stringent operating conditions, and uncontrollable physicochemical properties. Here, we developed a more controllable hydrogel matrix comprising sodium alginate (NaA) and hyaluronic acid (HA) that can mimic the mechanical properties of native tumor tissue, such as extracellular matrix (ECM) components and stiffness. The PCOs cultured in the hydrogel matrix exhibited similar viability and growth rate with that in commercial Matrigel. Furthermore, we observed improvements of PCOs in 1% NaA-HA hydrogel matrices over tumor-specific features observed previously in animal-derived matrices. Transcriptional analysis revealed the activation of signaling pathways associated with ECM organization in the PCOs generated in hydrogel. Moreover, we noted that the biomimetic stiffness of hydrogel enhanced the drug resistance of PCOs of conventional chemotherapy agents but improved the sensitivity to targeted antitumor drugs (Erlotinib) of the PCOs with EGFR mutation. This work represents foundation for the customizing hydrogel stiffness that can be utilized to mimic the native tumor tissue, as well as a new platform for performing pancreatic cancer research and antitumor drug screening in the future.

This study explores platinum(II) phototherapy using cycloplatinated compounds with bidentate 2-(4-substituted) benzoxazole ligands, [Pt(L)(R)(X)] (C1-C5). The compounds were synthesized and fully characterized, and their photophysical, cytotoxic, and phototoxic properties were analyzed. Time-dependent Density Functional Theory (TD-DFT) calculations supported the analysis of the complexes absorption and photoluminescence, with high-energy absorption showing 1L'LCT/1MLCT [π(Cl, Me) → π*(C^N)] contributions. Among the complexes, C4 (L = C^N, R = κ1-N-C^N, X = Cl) exhibited the highest quantum yield (ΦF = 48%) and showed strong antiproliferative activity in breast carcinoma (MCF-7) and gastric adenocarcinoma (AGS) cell lines. C1-C5 (C1, L = N^N, R = Cl, X = Cl, C2, L = N^N, R = Me, X = Me; C3, L = C^N, R = DMSO, X = Cl; C4, L = C^N, R = C^N, X = Cl, and C5, L = C^N, X = Me, R = DMSO) also demonstrated potential as photoactivatable agents. Mechanistic studies indicated that the complexes triggered ROS generation, mitochondrial dysfunction, and lysosomal damage, with C4 showing promise for photochemotherapeutic treatment of gastric and breast cancer due to its selectivity and effectiveness in targeting mitochondria and lysosomes.

Pyrazole derivatives have emerged as versatile scaffolds in the development of receptor tyrosine kinase inhibitors, offering promising avenues for targeted cancer therapy. Their therapeutic potential in cancer therapy is notable in many FDA-approved anticancer drugs. This review provides a comprehensive overview of the latest research from 2021 regarding novel pyrazole, pyrazoline, and fused pyrazole derivatives targeting receptor tyrosine kinases, namely: AXL, DDR, EGFR, FGFR, MET, CSF1R, RET, and VEGFR-2. This study focuses on the most active and promising candidates within each series of compounds. Key aspects covered include their cytotoxicity and enzyme inhibition results, with comparisons to reference drugs. The review also covers the molecular docking studies, highlighting critical binding interactions between the compounds and the protein kinase residues, and unveiling their molecular mechanisms of action. Structure-activity relationship analyses are also discussed, revealing the influence of structural modifications on biological activities. Furthermore, synthetic pathways for each series or key compounds are presented, offering a practical guide for researchers in the field. By integrating these elements, this review provides a solid foundation and rationale for the design, synthesis, and optimization of new pyrazole-based anticancer agents targeting receptor tyrosine kinases.

Lung cancer is one of the most common and deadly cancers across the world nowadays, and the morbidity and mortality of lung cancer will continue to increase for a long period. Chemotherapy, which can kill cancer cells, shrink tumors, and improve patient survival and quality of life, plays a crucial role in lung cancer therapy. However, chemotherapy has several disadvantages, mainly manifested in severe side effects, limited efficacy, and the tendency to develop drug resistance. Histone deacetylase (HDAC) inhibitors, which work by inhibiting the activity of HDACs, can help to re-express tumor-suppressor genes that have been silenced due to epigenetic changes, thus inhibiting the growth and proliferation of lung cancer cells. Hydroxamic acid hybrids as potent HDAC inhibitors exhibited robust in vitro and in vivo efficacy against drug-sensitive and drug-resistant lung cancers, representing crucial templates in creating innovative anti-lung cancer agents. This article will introduce the latest research progress on hydroxamic acid hybrids with anti-lung cancer activity developed since 2020. The structure-activity relationships will be summarized, and the mechanisms of action will be discussed to provide references for future research.

Gastrointestinal (GI) infections, which often result in or stem from intestinal dysbiosis, can affect the efficacy of immune checkpoint inhibitors (ICIs) and increase the risk of adverse effects, such as colitis. In this study, we explored the impact of GI infections before initiation of ICI therapy on the incidence and severity of immune-mediated colitis (IMC) and survival.

Cisplatin and its derivatives remain a cornerstone in the treatment of solid malignancies. Resistance is a major factor limiting their clinical utility.