Search Results (416)

Mitomycin C (MMC) is a widely employed chemotherapeutic agent, particularly in non-muscle invasive bladder cancer (NMIBC), where it functions by inducing DNA cross-linking and promoting tumor cell apoptosis. However, the tumor microenvironment (TME) significantly influences the therapeutic efficacy of MMC. Among the key regulators within the TME, the complement system and the coagulation pathway play a crucial role in modulating immune responses to cancer therapies, including MMC. This article explores the interaction between platinum nanoparticles (PtNPs) with human serum (HS) of NMIBC patients (T1 and Ta subtypes) at three different points: before the chemotherapy instillation of MMC (t₀) and three (t₃) and six months (t₆) after the treatment with MMC. This novel nanoproteomic strategy allowed the identification of a TME proteomic signature associated with the response to MMC treatment. Importantly, two proteins involved in the immune response were found to be deregulated across all patients (T1 and Ta subtypes) during MMC treatment: prothrombin (F2) downregulated and complement component C7 (C7) upregulated. By understanding how these biomarker proteins interact with MMC treatment, novel therapeutic strategies can be developed to enhance treatment outcomes and overcome resistance in NMIBC. Full article

The development of novel platinum-based anticancer agents remains a critical objective in medicinal inorganic chemistry, particularly in light of resistance and toxicity limitations associated with cisplatin. In this study, the synthesis, structural characterization, quantum chemical analysis, and cytotoxic evaluation of four new acetylplatinum(II) complexes (cis-[Pt(COMe)₂(PASO₂)₂], cis-[Pt(COMe)₂(DAPTA)₂], trans-[Pt(COMe)Cl(DAPTA)₂], and trans-[Pt(COMe)Cl(PASO₂)]: 1–4, respectively) bearing cage phosphine ligands PASO₂ (2-thia-1,3,5-triaza-phosphaadamantane 2,2-dioxide) and DAPTA (3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane) are presented. The coordination geometries and NMR spectral features of the cis/trans isomers were elucidated through multinuclear NMR and DFT calculations at the B3LYP/6-311++G(d,p)/LanL2DZ level, with strong agreement between experimental and theoretical data. Quantum Theory of Atoms in Molecules (QTAIM) analysis was applied to investigate bonding interactions and assess the covalent character of Pt–ligand bonds. Cytotoxicity was evaluated against five human cancer cell lines. The PASO₂-containing complex in cis-configuration, 1, demonstrated superior activity against thyroid (8505C) and head and neck (A253) cancer cells, with potency surpassing that of cisplatin. The DAPTA complex 2 showed enhanced activity toward ovarian (A2780) cancer cells. These findings highlight the influence of ligand structure and isomerism on biological activity, supporting the rational design of phosphine-based Pt(II) anticancer drugs. Full article

The pharmacological treatment of cholangiocarcinoma (CCA) is often hampered by tumor resistance. Improving our understanding of this issue is crucial for developing strategies that can overcome drug refractoriness. We have established and characterized two novel human cell sublines derived from extrahepatic CCA EGI-1 cells that are resistant to cisplatin and 5-fluorouracil (5-FU). Migration and proliferation were analyzed using holographic microscopy. The expression of genes involved in drug uptake and efflux was determined by RT-qPCR. Cross-resistance to commonly used antitumor drugs was assayed using the MTT test. EGI-1 sublines resistant to cisplatin (CR) or 5-FU (FR) exhibited more than a three-fold increase in resistance to cisplatin and 5-FU, respectively, and showed reduced proliferation, migration, and colony-formation rates, along with an altered cell cycle compared to wild-type cells, while retaining tumorigenic capacity. The analysis of the transportome showed downregulation of uptake transporters and upregulation of the export pumps MRP3/4. EGI-1 cells with acquired resistance to 5-FU demonstrated cross-resistance to irinotecan and gemcitabine, while cisplatin-resistant cells showed decreased sensitivity to 5-FU and platinum derivatives. These resistant cell lines offer valuable models for investigating the molecular basis of chemoresistance in CCA, providing a robust platform for the development and evaluation of novel therapeutic strategies. Full article

Cisplatin was the first metal-based anticancer drug introduced into clinical use. It is a “small” molecule, but it represented a very “big” discovery. Since it was introduced on the market, it has not been withdrawn, despite being not free of side effects, owing to its peculiarity of being highly effective in the treatment of cancer. Anticancer activity of the platinum-based complexes was discovered with this molecule; since then, several other platinum-based drugs have been developed and tested in preclinical studies against cancer cells; however, only a few of them reached clinical trials, and their side effects are not much less than cisplatin. Despite the constraints of drug resistance and side effects, chemotherapy remains a fundamental strategy in cancer treatment. Nowadays, cisplatin remains one of the most-used anticancer agents in treating lung, colon, ovary, testicles, bladder, cervix, and many more cancers, although cisplatin resistance represents a major hurdle in cancer treatment. Will there ever be another drug that can overcome the side effects of cisplatin but at the same time be able to block tumors as does cisplatin? Full article

Background/Objectives: This study aimed to determine whether the expression levels of GPAT4 and SLC7A11 are associated with survival outcomes and platinum resistance in epithelial ovarian cancer (EOC) patients. Methods: We analyzed the medical records of EOC patients. EOC samples obtained during surgery were stained for GPAT4 and SLC7A11. Cox regression and Kaplan—Meier analyses were performed to assess the impact of GPAT4 and SLC7A11 expression on overall survival (OS). Results: We found that GPAT4 and SLC7A11 expression levels were greater in platinum-resistant ovarian cancer tissues than in platinum-sensitive ovarian cancer tissues. High expression of both GPAT4 and SLC7A11 was associated with an increased risk of platinum resistance compared with low expression of both factors. High expression of both SLC7A11 and GPAT4 was independently correlated with poor OS, highlighting the significance of this integrated metric as a prognostic factor in ovarian cancer. The GPAT inhibitor (GPAT-IN-1) and an SLC7A11 inhibitor (erastin) attenuated platinum resistance in ovarian cancer cells, and their combined application increased cytotoxicity. Furthermore, the combination of GPAT-IN-1, erastin, and cisplatin significantly improved the chemotherapeutic effects on platinum-resistant ovarian cancer cells. Conclusions: High expression of both SLC7A11 and GPAT4 is related to platinum resistance in EOC patients. The high expression of both SLC7A11 and GPAT4 serves as an important independent prognostic factor and indicates potential therapeutic targets for patients with platinum-resistant EOC. Full article

Multidrug-resistant (MDR) biofilm infections characterized by densely packed microbial communities encased in protective extracellular matrices pose a formidable challenge to conventional antimicrobial therapies and are a major contributor to chronic, recurrent and device-associated infections. These biofilms significantly reduce antibiotic penetration, facilitate the survival of dormant persister cells and promote horizontal gene transfer, all of which contribute to the emergence and persistence of MDR pathogens. Metal nanoparticles (MNPs) have emerged as promising alternatives due to their potent antibiofilm properties. However, conventional synthesis methods are associated with high costs, complexity, inefficiency and negative environmental impacts. To overcome these limitations there has been a global push toward the development of sustainable and eco-friendly synthesis approaches. Recent advancements have demonstrated the successful use of various plant extracts, microbial cultures, and biomolecules for the green synthesis of MNPs, which offers biocompatibility, scalability, and environmental safety. This review provides a comprehensive overview of recent trends and the latest progress in the green synthesis of MNPs including silver (Ag), gold (Au), platinum (Pt), and selenium (Se), and also explores the mechanistic pathways and characterization techniques. Furthermore, it highlights the antibiofilm applications of these MNPs emphasizing their roles in disrupting biofilms and restoring the efficacy of existing antimicrobial strategies. Full article

Ovarian cancer is the most lethal gynecologic malignancy, which causes 313,959 new cases and 207,252 deaths worldwide annually. The lack of specific symptoms, together with no effective screening tools, results in 75% of patients receiving their diagnosis at an advanced stage. The combination of cytoreductive surgery with platinum-based chemotherapy plays a pivotal role in the treatment of advanced epithelial ovarian cancer, but patients still experience poor long-term survival because of frequent relapses and chemotherapy resistance. The treatment landscape has evolved because bevacizumab and Poly-ADP Ribose Polymerase inhibitors now serve as frontline and maintenance therapies for homologous recombination-deficient tumors. Treatment decisions for recurrent disease depend on platinum sensitivity assessment, which determines the appropriate therapeutic approach, while targeted agents deliver significant benefits to specific patient groups. The development of antibody-drug conjugates such as mirvetuximab soravtansine and immunotherapy, including checkpoint inhibitors and cancer vaccines, demonstrates promising investigative potential. The precision of therapy improves through the use of emerging biomarkers and molecular profiling techniques. The future management of this disease may change because of innovative approaches that include adoptive cell therapy, cytokine therapy, and oncolytic viruses. The progress made in ovarian cancer treatment still faces challenges when it comes to drug resistance, survival improvement, and life quality preservation. The development of translational research alongside clinical trials remains essential to bridge treatment gaps while creating personalized therapies based on molecular and clinical tumor characteristics. Full article

Folate receptor alpha (FRα), a glycosylphosphatidylinositol-anchored glycoprotein encoded by the FOLR1 gene, plays a crucial role in folate transport during cell growth and development. While minimally expressed in most normal adult tissues, FRα is frequently overexpressed in several epithelial malignancies, particularly in high-grade serous ovarian carcinoma. An immunohistochemical (IHC) evaluation of FRα expression using the VENTANA FOLR1 (FOLR1-2.1) RxDx Assay is now approved as a companion diagnostic for selecting patients eligible for mirvetuximab soravtansine, an FRα-targeted antibody–drug conjugate. Clinical trials such as SORAYA and MIRASOL have demonstrated significant clinical benefit in platinum-resistant epithelial ovarian cancer patients with high FRα expression (≥75% of tumor cells with moderate to strong membrane staining). This review summarizes the biological significance of FRα in ovarian cancer progression, its predictive value for targeted therapy, and the technical aspects of IHC assessment, including scoring interpretation and pre-analytical variables. We also discuss heterogeneity in FRα expression across histological subtypes and tumor sites, as well as the impact of archival versus fresh tissue. Understanding FRα expression patterns across histologic subtypes and tissue samples is critical for optimizing clinical decision-making and expanding the role of FRα-targeted therapies in gynecologic oncology. Full article

Emergent cancer drug resistance and further metastasis can mainly be attributed to altered expression levels and functional activities of multiple genes of cancer cells under chemotherapy. In response to challenge with anticancer drugs, enhanced ceramide glycosylation catalyzed by glucosylceramide synthase (GCS) confers drug resistance and enrichment with cancer stem cells. p53 mutations, which gain function in tumor progression, are prevalently extant in ovarian cancers. Via integrated gene expression assessments, we characterized GCS-responsive genes in ovarian cancer cells treated with dactinomycin. NCI/ADR-RES cells dominantly expressed a p53 mutant (7 aa deleted in exon-5) and displayed anti-apoptosis; however, silencing GCS expression rendered these cells sensitive to dactinomycin-induced apoptosis. Microarray analyses of NCI/ADR-RES and its GCS transfected sublines found that elevated GCS expression or ceramide glycosylation was associated with altered expression of 41 genes, notably coding for ABCB1, FGF2, ALDH1A3, apolipoprotein E, laminin 2, chemokine ligands, and IL6, with cellular resistance to induced apoptosis and enrichment with cancer stem cells, promoting cancer progression. These findings were further corroborated through integrated genomic analyses of ovarian cancer from The Cancer Genome Atlas (TCGA) and cancer resistance to platinum-based chemotherapy. Altogether, our present study indicates that altered ceramide glycosylation can modulate expression of these GCS-responsive genes and alter cancer cell attributes under chemotherapy. Full article

Neuroendocrine transformation in non-small-cell lung cancer (NSCLC) is an uncommon but clinically significant resistance mechanism to targeted therapy, immunotherapy, and chemotherapy. This phenomenon, primarily observed in adenocarcinoma (ADC) with EGFR mutations under tyrosine kinase inhibitor (TKI) treatment, leads to histological transformation into small-cell lung cancer (SCLC), commonly associated with an aggressive clinical course and poor prognosis. Standard platinum–etoposide chemotherapy provides only transient disease control, highlighting the urgent need for improved therapeutic strategies. Early identification of transformation through biopsy, liquid biopsy, or biomarkers like neuron-specific enolase (NSE) and pro-gastrin-releasing peptide (pro-GRP) may allow for early intervention. As targeted therapies continue to develop, understanding the molecular drivers of neuroendocrine transformation is crucial for optimizing treatment. Further research into novel treatment approaches, including combination therapies with TKIs, chemotherapy, immunotherapy, and epigenetic modulators, is required to improve outcomes for these patients. Full article

We developed a novel biodegradable poly(lactic-co-glycolic acid) (PLGA) polymer chemically modified with paclitaxel (PTX) to form a PLGA-PTX hybrid. Pre-modification of PTX enhanced its loading in PLGA-PTX nanoparticles (NPs). Background/Objectives: PTX is one of the most effective chemotherapy agents used in cancer therapy. The primary mode of PTX’s action is the hyperstabilization of microtubules leading to cell growth arrest. Although highly potent, the drug is water insoluble and requires the Cremophor EL excipient. The toxic effects of the free drug (e.g., neurotoxicity) as well as its solubilizing agent are well established. Thus, there is strong clinical rationale and need for exploring alternative PTX delivery approaches, retaining biological activity and minimizing systemic effects. Methods: The PTX modification method features reacting the C-2′ and C-7 residues with a linker (succinic anhydride) to produce easily accessible carboxyl groups on the PTX for enhanced coupling to the hydroxyl group of PLGA. The PLGA-PTX hybrid, formed via esterification reaction, was used to formulate lipid-coated PLGA-PTX NPs. As proof of concept, the PLGA-PTX NPs were tested in ovarian cancer (OvCA) models, including several patient-derived cell lines (PDCLs), one of which was generated from a platinum-resistant patient. Results: The PLGA-PTX NPs critically remained stable in water and serum while enabling slow drug release. Importantly, PLGA-PTX NPs demonstrated biological activity. Conclusions: We suggest that this approach offers both a new and effective PTX formulation and a possible path towards the development of a new generation of OvCA treatment. Full article

The high cost of platinum (Pt) catalysts impedes the widespread commercialization of proton exchange membrane fuel cells (PEMFCs). Reducing Pt loading will increase local oxygen transport resistance ($R_{\mathrm{Pt}}^{{\mathrm{O}}_2}$) and decrease performance. Due to the oxygen transport resistance, the reactants in the cathode catalyst layer (CCL) are not evenly distributed. The gradient structure can cooperate with the unevenly distributed reactants in CL to enhance the Pt utilization. In this work, a one-dimensional gradient CCL model considering $R_{\mathrm{Pt}}^{{\mathrm{O}}_2}$ is established, and the optimal gradient structure is optimized by combining the artificial neural network (ANN) model and the genetic algorithm (GA). The optimal structure parameters of non-gradient CCL are l_CL equal to 8.86 μm, r_C equal to 36.82 nm, and I/C equal to 0.48, with the objective of maximum current density (I_max); l_CL equal to 4.24 μm, r_C equal to 36.60 nm, and I/C equal to 0.76, with the objective of maximum power density (P_max). For the gradient CCL, the best gradient distribution enables Pt loading to increase from the membrane (MEM) side to the gas diffusion layer (GDL) side and the ionomer volume fraction to decrease from the MEM side to the GDL side. Full article

Lung adenocarcinoma (LUAD) is a leading cause of cancer-related mortality, with heme metabolism playing a critical role in tumor progression and treatment resistance. This study investigates the clinical implications of heme metabolism in LUAD, focusing on its link to ferroptosis and drug sensitivity. Using multi-omics data from TCGA-LUAD, GEO databases, and a single-cell RNA-seq cohort, we identified two molecular subtypes based on heme metabolism-related genes. We further developed a prognostic panel, termed the heme metabolism risk score (HMRS), using LASSO and multivariate Cox regression analyses. The HMRS panel effectively stratified patients into high- and low-risk groups, with high-risk patients showing enhanced tumor proliferation, suppressed ferroptosis, and resistance to chemotherapy. Single-cell analysis revealed elevated heme metabolism risk in epithelial cells correlated with tumor progression. Drug sensitivity predictions were validated in platinum-based chemotherapy cohorts, confirming HMRS as a robust prognostic tool. ABCC2 was identified as a key regulator of ferroptosis and cisplatin resistance, with in vitro experiments demonstrating that ABCC2 knockdown enhanced cisplatin-induced ferroptosis. These findings highlight HMRS as a critical tool for patient stratification and ABCC2 as a promising therapeutic target to overcome cisplatin resistance. Full article

Most women with ovarian cancer (OC) develop resistance to platinum chemotherapy, posing a significant challenge to treatment. Matrix metalloproteinase 3 (MMP3) is overexpressed in High-Grade Serous Ovarian Cancer (HGSOC) and is associated with poor survival outcomes; however, its role in platinum resistance remains underexplored. We evaluated the baseline and cisplatin-induced MMP3 transcript and protein levels in cisplatin-resistant OC cells, revealing significantly higher MMP3 levels in cisplatin-resistant cells than in cisplatin-sensitive cells. siRNA-mediated MMP3 knockdown in cisplatin-resistant OC cells significantly reduced viability, proliferation, and invasion, and these effects were further enhanced when combined with cisplatin treatment, indicating a possible synergistic impact on reducing cancer cell aggressiveness; however, chemical MMP3 inhibition did not replicate these effects. RNA sequencing of MMP3-siRNA-treated cisplatin-resistant HGSOC cells revealed 415 differentially expressed genes (DEGs) compared to the negative control, with an additional 440 DEGs identified in MMP3-siRNA HGSOC cells treated in combination with cisplatin. These DEGs were enriched in pathways related to cell cycle regulation, apoptosis, metabolism, stress response, and extracellular matrix organization. Co-immunoprecipitation-coupled mass spectroscopy (IP-MS) identified MMP3-interacting proteins that may contribute to cell survival and chemoresistance in cisplatin-resistant OC. While MMP3-siRNA monotherapy did not reduce tumor growth in vivo, its combination with cisplatin significantly inhibited tumor growth in a cisplatin-resistant HGSOC xenograft model. These findings underscore the multifaceted role of MMP3 in cisplatin resistance, suggesting its involvement in critical cellular processes driving chemoresistance and highlighting the challenges associated with direct MMP3 targeting in therapeutic strategies. Full article