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.

The mechanistic target of rapamycin (mTOR), a serine/threonine kinase, serves as a central regulator of cellular growth, proliferation, metabolism, and survival through its two distinct multiprotein complexes, mTORC1 and mTORC2. Aberrant activation of the mTOR signaling pathway is frequently implicated in a wide range of human cancers and is closely associated with tumor progression, therapeutic resistance, and poor clinical outcomes. Accordingly, pharmacological inhibition of mTOR has emerged as a compelling strategy in the development of anticancer therapeutics. To date, several mTOR inhibitors have received regulatory approval or are currently undergoing clinical evaluation. This review provides an up-to-date development of small-molecule mTOR inhibitors from 2019 to the present. Emphasis is placed on their structural classification, mechanisms of action, and medicinal chemistry optimization strategies. We believe that this review, together with previous summaries from other research groups, will offer valuable insights to support the rational design and development of next-generation mTOR inhibitors with improved pharmacokinetic properties and enhanced target selectivity.

SWI/SNF chromatin remodelers hydrolyze ATP to modulate chromatin accessibility and are mutated in up to 20 % of human cancers. The development of ATPase inhibitors and proteolysis targeting chimeras (PROTACs) have shown that SWI/SNF complexes can be therapeutic targets against cancers that require MYC expression for their survival (e.g., leukemias, prostate cancer, uveal melanoma). In this study we show that for cancers that do not depend on MYC expression, inhibition of both SWI/SNF ATPases by BRM014 impairs homologous recombination (HR) and sensitizes U2OS osteosarcoma cells and MDA-MB-231 triple negative breast cancer cells to chemotherapeutic agents that induce DNA double strand breaks (DSBs) and importantly, to PARP inhibitors (PARPi). BRM014 impaired DSB repair and the clearance of γH2AX foci. Moreover, BRM014 stimulated the use of non-homologous end joining (NHEJ) for DSB repair. Finally, BRM014 alone or in combination with olaparib also increased the frequency of micronuclei formation and activated the cGAS/STING response mediated by the activation of NFκB. Similar results were observed by inducing the degradation of both SWI/SNF ATPases by a PROTAC (AU-15330), which impaired the repair of DSBs, sensitized cells to DNA damage and PARPi. This study shows that inhibition or degradation of both SWI/SNF ATPases enhances the effects of chemotherapy, and activates the cGAS/STING response, which is associated with better therapeutic outcomes. This study shows that SWI/SNF chromatin remodelers are an important target to enhance the effects of chemotherapy and can affect the choice of DSB repair pathway.

Macrophage-hitchhiking drug delivery across the blood-brain barrier (BBB) has garnered considerable attention for its potential in glioblastoma (GBM) treatment. However, challenges such as the complexity of in vitro synthesis and the risk of macrophage polarization toward protumor phenotypes hinder its practical application. We developed a receptor ligand-free nanoshuttle that can hitchhike on macrophages in vivo for efficient BBB penetration and targeted drug delivery while inducing macrophage polarization toward antitumor phenotypes for GBM therapy. The nanoshuttle was constructed through surface engineering of a Fe-containing metal-organic framework (MOF) to optimize its hydrophilicity and was loaded with ginsenoside Rh2 (Rh2). Upon intravenous injection, the nanoshuttles specifically adsorbed proteins from the complement system, forming a protein corona that enhanced macrophage endocytosis and facilitated the in vivo synthesis of the macrophage-hitchhiking nanoshuttles. Exploiting the chemotaxis of macrophages toward GBM tissue, the macrophage-hitchhiking nanoshuttles efficiently penetrated the BBB and target GBM tissue. The intrinsic iron species of the nanoshuttle regulated iron metabolism in the tumor microenvironment, directing macrophage polarization toward an antitumor M1 phenotype for immunotherapy. Combined with the •OH generating capacity of Fe-MOF and the tumor-killing effects of Rh2, these nanoshuttles effectively suppressed tumor growth and improved survival in a GBM mouse model.

To investigate the effect of GRIM-19 on the resistance of carcinoma cells to the chemotherapeutic agent docetaxel in the treatment of PCa.

Immune checkpoint inhibitors (ICIs) are medications used in cancer immunotherapy. However, treatment with ICIs may lead to adverse effects, particularly myocarditis and pericarditis. This practical pharmacovigilance study investigates the relationship between ICIs and myocarditis and pericarditis using the FAERS (U.S. FDA Adverse Event Reporting System) database.

Here we present a case of bevacizumab-associated glomerular microangiopathy (Bmab-GMA), a rare and distinct glomerular pathology, in a middle-aged male patient who developed progressive renal impairment following adjuvant chemotherapy with bevacizumab for surgically resected lung adenocarcinoma. The patient presented with new-onset hypertension and mild elevation in serum creatinine. Renal biopsy revealed characteristic histopathological features, including pseudothrombotic deposits of periodic acid-Schiff (PAS)-positive hyaline material within glomerular capillaries on light microscopy, and subendothelial and mesangial electron-dense deposits with segmental widening of the subendothelial space on electron microscopy. The diagnosis of Bmab-GMA was established based on these clinicopathological findings. Management with bevacizumab discontinuation and antihypertensive therapy resulted in clinical stabilization. This case highlights the diagnostic challenges and management considerations of this rare entity, while identifying elevated soluble complement membrane attack complex (C5b-9) as evidence of complement activation, a potential pathological mechanism requiring further investigation for future therapeutic development.

Auranofin, an FDA-approved antirheumatic gold drug, has gained ongoing interest in clinical studies for treating advanced or recurrent tumors. However, gold ion's dynamic thiol exchange nature strongly attenuates its bioactivity due to the fast formation of covalent albumin-gold adducts. Here we report that newly-added thiols can modulate the dynamic albumin-gold binding and recover the therapeutic efficacy. Initially, we find that auranofin supplemented with its own thiol ligand, TGTA (1-thio-β-D-glucose tetraacetate), significantly restores the anticancer activities in cells and patient-derived xenograft models. Then, screening a collection of ligand fragments followed by machine learning evaluation unveils diverse synergizing thiols, including pantethine, that effectuate auranofin at a low dosage for rheumatoid arthritis. Interestingly, the thiol exchange inside cells accounts for a cuproptosis-like phenotype that auranofin induces. Together, we believe the ligand-enabled dynamic modulation strategy is of value to researchers and clinicians contemplating metallodrugs and ligand-like molecules in cancer therapy.

The first-line treatment for extensive-stage small cell lung cancer (ES-SCLC) has evolved from chemotherapy alone to chemoimmunotherapy. However, the improvements in overall survival (OS) and progression-free survival (PFS) have been modest. Therefore, this study employs a comprehensive multidimensional evaluation framework to identify optimized therapeutic combinations with enhanced efficacy and improved safety profiles in the immunotherapy era.

Sericin is a globular protein known to have antioxidant potential due to presence of amino, carboxyl and hydroxyl groups in its structure. This study was designed to investigate the antiproliferative and apoptotic potential of sericin and sericin chitosan conjugated silver nanoparticles against colorectal cancer cells. To investigate the antiproliferative and apoptotic activity of sericin and sericin chitosan conjugated silver nanoparticles (SChiAgNPs), three human colorectal cancer cell lines (SW480, SW620, HCT116) were used. Sericin was isolated by the degumming process followed by the characterization by using FTIR, UV, XRD, and SEM techniques to confirm the isolation process and successful synthesis of SChiAgNPs. MTT assay was carried out to analyze the antiproliferative activities, while expression profiling of the genes i.e., GADD45A, BCL2, and TNF was assessed by qRT-PCR analysis. Sericin (S-Ext) and SChiAgNPs showed significant antiproliferative activities in SW480, SW620 and HCT 116 cells. Overall, there was 29-34 inhibition of viability for sericin S-Ext and 35-43 for SChiAgNPs in the three cell lines in comparison to untreated control. Expression profiling indicated the significant stimulation of GADD45A, BCL-2 and TNF genes expression in SW480, SW620 and HCT 116 cells. The GADD 45 A showed induction by 1.43-1.71-fold in SW480, 1.09-1.56-fold in SW620 and 1.25-4.55-fold in HCT 116 cells in response to treatment groups. The BCL2 showed the induction by 1.35-2.53, 1.38-3.1, and 2.32-3.76-fold in SW480, SW620, and HCT116 cells, respectively. TNF was induced by a factor of 3.9-6.43, 2.53-5.41, and 2.7-5.31-fold in in SW480, SW620, and HCT116 cells, respectively, after the exposure with compounds. Sericin and S-ChiAgNPs, showed significant growth inhibition and gene expression profiling modifications in the colorectal cancer cells. The findings provide evidence about sericin and its nanoparticle conjugates as potential anticancer medicine for colorectal cancer.

The development of de novo resistance is a major disadvantage in molecularly targeted therapies. While much focus is on cell-intrinsic mechanisms, the microenvironment is also known to play a crucial role. This study examines interactions between cancer cells and cancer associated fibroblasts (CAFs) to understand the local crosstalk facilitating residual disease. Using a hybrid-discrete-continuum model, we explore how treatment-induced stress responses can elicit CAF activation and how breaks in treatment allow microenvironment normalisation. We investigate how fluctuating environmental conditions shape the local crosstalk and ultimately drive residual disease. Our experimentally calibrated model identifies environmental and treatment conditions that allow tumour eradication and those that enable survival. We find two distinct mechanisms that underpin residual disease: vasculature-limited drug delivery and CAF-mediated rescue. This work provides a better understanding of the mechanisms that drive the creation of localised residual disease, crucial to informing the development of more effective treatment protocols.

Toward developing anticancer agents, heterocycle-based carboxymethyl cellulose conjugates have been synthesized. 2-Cyano-N'-(aryl/heteroarylethylidene)acetohydrazides and ethyl 2-cyano-3-(heteryl)acrylates were utilized as precursors for the synthesis of pyridine-based compounds. The chemical structures of the synthesized derivatives were characterized using various spectroscopic techniques, including 1H-, 13C-NMR, Fourier transform infrared spectroscopy (FTIR), as well as scanning electron microscopy (SEM).The anticancer effects of compounds on HCT-116, MCF-7, PC3 and A549 cancer cell lines were investigated and their cytotoxicity against RPE-1 normal cells was estimated to determine their safety. Compounds 4b and 7c exhibit high selectivity toward cancer cells while maintaining a strong safety margin for normal cells. The results demonstrated that the novel heterocycle-based carboxymethyl cellulose conjugates are promising and can be further evaluated as a potential therapeutic agent.