Search Results (885)

Background and Objectives: Currently, the development of local drug delivery systems for the treatment of cancer patients is a pressing issue. Such systems allow for the targeted delivery of anticancer drugs directly to the tumor site, ensuring prolonged drug release or reducing the risk of recurrence after tumor removal, minimizing the impact on healthy tissues and thereby reducing the overall toxic load on the body. This work is devoted to evaluating the prospects of using scaffolds based on low-modulus titanium Ti-15Mo alloy with a biomimetic coating as a platform for the local administration of the cytostatic drug cisplatin into the patient’s body. Methods: Porous coatings were obtained by plasma electrolytic oxidation in an aqueous solution of sodium phosphate and calcium acetate with the addition of various components. The influence of coating parameters on the corrosion resistance of samples and on the antiproliferative effect of cisplatin-loaded scaffolds was evaluated. Human K562 hemoblastosis, HT116 intestinal cancer, and SKOV3 ovarian cancer cell lines were used as cell models. Results: It was shown that the addition of sodium phosphate (the PS type electrolyte) provides the formation of a coating with a developed system of interconnected pores characterized by an attractive combination of parameters: high porosity (17%), high pore size (3.9 μm), and considerable thickness (17.4 μm). This coating demonstrated the best corrosion resistance in a Ringer solution as compared to the other tested states. In addition, the PS coating loaded with cisplatin exhibited a pronounced cytotoxic effect on cancer cells. This effect was attributed to its ability to fix cisplatin on the surface, which slows down its release into the extracellular environment, increasing the time of its action, thereby contributing to a more effective (by more than 3 times) suppression of tumor cell proliferation compared to the action of the standard form of the drug in the form of a solution when changing the growth medium and subsequent incubation for 48 h. Conclusions: PS scaffolds made of low-modulus titanium alloy Ti-15Mo with a biomimetic surface in an electrolyte based on an aqueous solution of sodium phosphate and calcium acetate with the addition of sodium silicate can be used as an advanced platform for the local delivery of the cytostatic drug cisplatin, which makes them promising for application in orthopedic oncology. Full article

Cancer stem cells (CSCs) play a crucial role in colorectal cancer by sustaining intratumoral heterogeneity, therapeutic resistance, and metastatic potential. CD133 (PROM1) is among the most frequently used surface markers for CSC identification, whereas TRIM28, a versatile epigenetic regulator, has been implicated in controlling CD133 expression and stem-like features. In this study, we performed a detailed molecular and functional analysis of Caco2 colorectal cancer cell clones with individual knockouts of CD133 or TRIM28. Elimination of CD133 neither altered global gene expression, as confirmed by transcriptome profiling, nor affected key cellular properties. In contrast, loss of TRIM28 led to a marked reduction in CD133 protein abundance and induced extensive molecular and phenotypic remodeling. TRIM28 knockout was associated with broad transcriptomic changes involving more than 500 differentially expressed genes, decreased proliferative activity monitored by time-lapse imaging, and reduced sensitivity to paclitaxel, cisplatin, and curcumin. Furthermore, immune evasion molecules CD24 and CD47 (“don’t eat me” signals) were strongly upregulated in TRIM28-deficient cells, consistently confirmed by both RNA-Seq and flow cytometry analyses. At the same time, imaging flow cytometry and mitochondrial activity assays indicated that these effects were not due to major shifts in mitotic index or bioenergetic status. Altogether, our results demonstrate that TRIM28, rather than CD133, functions as a central regulator of CSC-associated phenotypes in colorectal cancer. These findings highlight the importance of epigenetic context in CSC biology and may inform the development of more effective therapeutic strategies. Full article

Bone metastases from osteosarcoma occur in only 10% of patients, and related preclinical models are lacking. A patient diagnosed with pelvic osteosarcoma developed a metachronous scapular metastasis and was treated with multi-agent chemotherapy and surgery. Patient-derived tissue fragments (PDTFs) were obtained from leftover material after diagnosis and biobanking. PDTFs were grown on chick chorioallantoic membrane, establishing an in vivo-like predictive model. Additionally, we obtained a patient-derived cell culture, OS-MET-R-092, which has been maintained in vitro for nearly one year. OS-MET-R-092 cells were authenticated based on short tandem repeats and on their morphology when grown on commercial 3D scaffolds. Using U-2 OS and SaOS-2 as controls, we characterized growth, clonogenic potential, ability to form spheroids, migration, osteogenic differentiation, and expression of related genes. OS-MET-R-092 cells showed a low proliferation rate, impaired differentiation potential, and migratory abilities comparable to SaOS-2, while expressing higher levels of some MMPs and CD44. Functionally, OS-MET-R-092 cells demonstrated a resistant phenotype to doxorubicin, cisplatin, gemcitabine, and docetaxel, corroborated by higher expression of chemo-resistance-related genes. Collectively, OS-MET-R-092 represents a valuable tool for studying bone metastasis from osteosarcoma across various experimental settings and serves as the foundational building block for composite and translatable 3D models. Full article

The problem of acquiring chemoresistance by tumor cells is a growing concern for researchers as the effectiveness of diagnosis and treatment of primary tumors increases. To study the mechanisms of resistance, as well as to evaluate the effectiveness of new drugs, it is necessary to use adequate cell models. The review presents modern methods for obtaining chemoresistant cell lines used by researchers in such studies. It examines the most common cytostatics and targeted drugs, such as cisplatin, oxaliplatin, paclitaxel, doxorubicin, 5-fluorouracil, gemcitabine, gefitinib, bortezomib, erlotinib, and the monoclonal antibody cetuximab. Particular attention is paid to cell mechanisms activated due to drug resistance development and to methods of cell cultivation in the presence of drugs. The presented information provides an opportunity to discuss trends in the creation of chemoresistant cell lines for further research on resistance mechanisms and the development of new therapeutic strategies. Full article

Objectives: Pleural mesothelioma (PM) is a rare cancer that often develops after a decades-long latency period and confers a grim prognosis. Novel, biomarker-based therapeutic modalities are expected to improve the outcome of patients with advanced PM. CUDC-907 (fimepinostat) is a dual inhibitor that affects both histone deacetylases and PI3K enzymes. Its antitumor activity was described in several cancer types, but it has not yet been explored in PM. Materials and Methods: The sensitivity of 22 PM cell lines—including 18 models established in our laboratory—to cisplatin and CUDC-907 was determined using a cell viability assay. BAP1, PTEN, and c-Myc expression, as well as MYC copy number variation, were measured. The effect of combination treatment with cisplatin was assessed with cell viability, cell cycle, and 3D spheroid formation assays. Results: Most PM cell lines were sensitive to CUDC-907 treatment, and the CUDC-907 response was significantly higher in cell lines with higher c-Myc expression due to MYC copy number gain or amplification. Importantly, all cisplatin-insensitive cell lines were sensitive to CUDC-907. Combination treatment with cisplatin synergistically decreased cell viability and induced G2/M arrest or cell death. We tested cisplatin-sensitive P31WT and cisplatin resistant P31cis isogeneic pair and found that in both 2D and 3D assays the cisplatin-resistant cells showed a higher sensitivity to CUDC-907 single treatment. Combining CUDC-907 with cisplatin further decreased cell growth even in cisplatin-resistant cells. Conclusions: The majority of PM cell models are sensitive to CUDC-907, which may be a potent therapeutic agent in PM. Full article

Lacking effective therapeutics, cholangiocarcinoma (CCA) remains a deadly malignancy of the biliary tract. The Hippo pathway effector protein Yes-associated protein (YAP) is implicated in CCA pathogenesis and chemotherapeutic resistance; however, the oncogenic mechanisms underlying YAP regulation remain incompletely understood. An enhanced understanding of YAP and its role in CCA may uncover novel therapeutic targets and better define resistance pathways. Human CCA cells and murine syngeneic CCA models were utilized to explore the molecular relationship of YAP and protein tyrosine phosphatase 1B (PTP1B). Previous work in CCA has demonstrated that YAP interacts with multiple protein tyrosine phosphatases, including SHP2 and PTP1B. We observed that PTP1B pharmacologic inhibition was associated with increased cell proliferation and YAP target gene expression, while genetically enforced overexpression of PTP1B was associated with a decrease in YAP activation. Treatment of CCA cells in vitro and syngeneic, orthotopically implanted CCA murine tumors in vivo with standard cytotoxic chemotherapy, gemcitabine/cisplatin, had enhanced efficacy in the setting of PTP1B overexpression. These findings demonstrate that pYAP^Y357 can be modulated through protein tyrosine 1B phosphatase activity, and reducing pYAP^Y357 through enhanced phosphatase levels can sensitize CCA to chemotherapy. Full article

Pancreatic ductal adenocarcinoma (PDAC) is a highly heterogeneous cancer with a severe stromal reaction mediated by pancreatic stellate cells (PSCs), leading to increased resistance to chemotherapy and radiotherapy. Following a repurposing concept, this preclinical study investigates the potential of approved drugs, known to be modulators of cellular copper transport, in combination with cisplatin for therapeutic approaches in PDAC. Two major strategies were pursued: (i) inhibiting copper transporters ATP7A and B with tranilast (TR) and omeprazole (OM) to block the cellular copper and, potentially, also cisplatin efflux, and (ii) using the chelator elesclomol (ES) to elevate intracellular copper and cisplatin levels. Human cell lines PanC-1 (PDAC), HPaSteC (PSC), and their co-culture, as well as the hepatocellular carcinoma cell line HepG2 as a reference model, were used. In addition to an analysis of the expression of copper transport proteins, the dynamics of cellular copper uptake and transport were monitored using a [⁶⁴Cu]CuCl₂ radiotracer approach. In vitro, all drugs enhanced cellular copper uptake and/or reduced copper efflux. Moreover, all drugs contributed to the enhanced cellular anticancer activity of cisplatin, with ES being the most effective compound. The results suggest that the targeted modulation of copper transport mechanisms may offer novel adjuvant approaches for the treatment of PDAC. Full article

The increasing resistance to chemotherapeutic agents in lung cancer significantly contributes to its high mortality. Natural compounds such as acetyl-11-keto-β-boswellic acid (AKBA) have emerged as promising adjuncts to standard therapies. This study investigated the synergistic apoptotic and cytotoxic effects of AKBA in combination with cisplatin (Cis) on A549 non-small-cell lung cancer (NSCLC) cells. Cell viability, apoptosis, and gene expression were evaluated using MTS assay, Annexin V-FITC/PI staining, caspase activity, RT-qPCR, and ELISA, complemented by molecular docking (AKBA–p53) and molecular dynamics (AKBA–p53 and Cis–p53) analyses. Combined AKBA + Cis treatment significantly enhanced apoptosis and reduced cell viability compared to monotherapies (p < 0.001), accompanied by upregulation of p53 and caspase-3 and suppression of NF-κB. In silico results further supported direct and stable binding of p53, particularly with AKBA. These findings indicate that AKBA synergizes with Cis to potentiate apoptotic and anti-inflammatory responses in NSCLC and may provide a novel dose-sparing strategy with improved therapeutic efficacy, warranting further in vivo validation. Full article

Supportive agents, such as vitamin B12 (cobalamin, B12) and granulocyte colony-stimulating factor (G-CSF), are widely used during chemotherapy; however, their direct effects on tumor biology are not well understood. We evaluated the impact of pharmacological B12 and G-CSF, alone or in combination with cisplatin, on hormone receptor-positive (MCF-7) and triple-negative (MDA-MB-231) breast cancer cells, conducting in vitro assays of cell viability, cytotoxicity, caspase activation, mitochondrial membrane potential, and cytolytic protein expression. Neither B12 nor G-CSF alone induced cytotoxicity; instead, both promoted proliferation in a dose- and time-dependent manner. When combined with cisplatin, they consistently attenuated drug-induced cytotoxicity, suppressed caspase-3/-8/-9 activation, preserved mitochondrial integrity, and reduced perforin/granzyme expression, exhibiting stronger effects in MCF-7 cells. G-CSF markedly increased proliferation (>130% at 50 ng/mL), while B12 modestly enhanced viability and mitigated cisplatin-induced damage, particularly in triple-negative cells. These findings indicate that B12 and G-CSF can impair cisplatin efficacy by blunting apoptotic signaling and mitochondrial injury in different breast cancer subtypes. These preclinical findings warrant prospective, biomarker-driven in vivo and clinical studies to delineate the clinical contexts in which B12 and G-CSF can be safely integrated into supportive care without compromising antitumor efficacy. Full article

Non-small cell lung cancer (NSCLC) accounts for over 80% of lung cancer cases and remains challenging to treat due to high recurrence and mortality rates. While cisplatin (CDDP) is a first-line chemotherapy for NSCLC, its clinical utility is limited by toxicity, drug resistance, and inadequate tumor suppression. Plant-derived extracts have shown promise as complementary therapies, offering potential benefits including enhanced efficacy and reduced treatment side effects. The aqueous extract of Actinidia eriantha Benth. root (WE-AER) exhibits significant antitumor activity, though its mechanisms in NSCLC remain unclear. This study demonstrates WE-AER’s potent anti-NSCLC effects through multiple mechanisms. In vitro, WE-AER dose-dependently inhibited A549 cell growth (74.74% inhibition, IC50 = 210.38 µg/mL) by inducing apoptosis via TGF-β/FOXO/mTOR pathway modulation. In vivo, WE-AER suppressed tumor growth and angiogenesis while activating immune responses and reducing inflammation in mouse models, with excellent biosafety. These findings elucidate WE-AER’s anticancer mechanisms and support its potential as a novel herbal therapy for NSCLC. Full article

Osteosarcoma (OS), the most common primary malignant bone tumor, arises in highly mechanosensitive tissue and exhibits marked heterogeneity and resistance to conventional therapies. While molecular drivers have been extensively characterized, the role of mechanical stimuli in OS progression remains underexplored. Here, we identify the transient receptor potential vanilloid 1 (TRPV1) channel as a key regulator of mechanotransduction and drug responsiveness in OS cells. Using uniaxial cyclic stretch, we show that aggressive U-2 OS cells undergo TRPV1-dependent perpendicular reorientation, unlike the inert SAOS-2 cells. Confocal microscopy, immunohistochemistry, and atomic force microscopy reveal that nanomolar concentrations of capsaicin—a well-characterized TRPV1 agonist—chemically mimic this mechanical phenotype, altering metastatic traits including adhesion, edge architecture, migration, nuclear-to-cytoplasmic ratio, and sensitivity to doxorubicin and cisplatin. TRPV1 activation, whether mechanical or chemical, induces subtype-specific effects absent in healthy hFOB osteoblasts. Notably, it differentially regulates nuclear localization of the proto-oncogene Src in U-2 OS versus SAOS-2 cells. Corresponding changes in Src and acetylated histone H3 (acH3) levels support a role for TRPV1 in modulating the Src–acH3 mechanosignaling axis. These effects are tumor-specific, positioning TRPV1 as a mechanosensitive signaling hub that integrates mechanical and chemical cues to drive epigenetic remodeling and phenotypic plasticity in OS, with potential as a therapeutic target in aggressive, drug-resistant subtypes Full article

Cholangiocarcinoma (CCA) and pancreatic ductal adenocarcinoma (PDAC) are aggressive malignancies with limited therapeutic options and poor prognoses. In recent years, microRNAs (miRNAs) have gained attention as key molecular regulators involved in tumor progression, chemoresistance, and metastasis. This review explores the diagnostic, prognostic, and therapeutic potential of miRNAs in CCA and PDAC, emphasizing their shared and distinct molecular pathways and their utility in the context of precision oncology. Several dysregulated miRNAs, most notably miR-21 and miR-155, are overexpressed in both cancers and contribute to activation of oncogenic pathways such as PI3K/AKT signaling, epithelial–mesenchymal transition, and inflammatory cascades. miR-21, in particular, is associated with resistance to gemcitabine and cisplatin. In contrast, tumor-suppressive miRNAs such as miR-34a and miR-145 are often downregulated, and their restoration using synthetic mimics has demonstrated promising antitumor effects in preclinical studies. Moreover, circulating miRNAs show potential as non-invasive biomarkers for early detection and disease monitoring. Advanced delivery platforms, including nanoparticles and exosome-based systems, are being developed to improve the stability and tumor specificity of miRNA-based therapeutics. miRNAs represent a promising class of molecules in the diagnosis, stratification, and treatment of CCA and PDAC. Their dual role as biomarkers and therapeutic agents positions them at the intersection of molecular pathology and personalized medicine. Further multicenter clinical trials and mechanistic studies are needed to validate their clinical applicability and to refine delivery strategies for targeted miRNA modulation. Full article

Despite advances in cancer treatment, head and neck squamous cell carcinoma (HNSCC) remains a serious clinical problem due to tumor aggressiveness, tumor resistance to therapy, and treatment toxicity. The combination of photodynamic therapy (PDT) with chemotherapy is a promising approach to improve efficacy while reducing side effects. For the first time, the possibility and antitumor effect of the combined use of PDT and chemotherapy with intra-arterial administration of chlorin e6 (Ce6) and cisplatin in patients with HNSCC were assessed. Two patients with locally advanced HNSCC received intra-arterial administration of Ce6 (at a dose of 0.5 mg/kg) and cisplatin (at a dose of 50 mg/m²) via a catheter into the tumor-feeding artery followed by laser irradiation. Ce6 distribution, tumor response, and treatment efficacy were assessed by fluorescence diagnostics, confocal microscopy, and histopathological analysis. Intra-arterial administration of the photosensitizer (PS) and chemotherapeutic agent ensured high selectivity of their tumor accumulation. Fluorescence diagnostics showed rapid and selective Ce6 accumulation in the tumor and PS photobleaching after PDT. For a patient with three PDT sessions, there is a significant acceleration of the Ce6 spread from the tumor-feeding artery throughout the tumor bed with each therapy session. This is a good sign of a tumor stroma density decrease. The combined use of PDT and chemotherapy with intra-arterial administration of Ce6 and cisplatin is safe and feasible, with preliminary evidence of local cytotoxicity treatment for HNSCC, allowing targeted drug delivery to the tumor. This is the first report of the combined use of PDT and chemotherapy with selective intra-arterial administration of a PS and a chemotherapeutic drug for the treatment of cancer. Full article

Cancer, a leading global cause of death responsible for nearly 10 million deaths annually, demands innovative therapeutic strategies. Intrinsic cytotoxicity and biocompatibility of zinc oxide nanoparticles (ZnO-NPs) have rendered them promising nanoplatforms in oncology. We herein systematically review their applications for targeted cancer chemotherapy, with a focus on physicochemical properties, drug delivery mechanisms, and interactions with the tumor microenvironment (TME). We searched PubMed, SCOPUS, and Web of Science from inception through December 2024 for peer-reviewed preclinical studies on cancer models. Results were qualitatively synthesized. Quality was assessed with the SYRCLE risk of bias tool. Among 20 eligible studies, ZnO-NPs were frequently functionalized with ligands to enhance tumor targeting and minimize systemic toxicity. Chemotherapeutic agents (doxorubicin, 5-fluorouracil, docetaxel, cisplatin, gemcitabine, and tirapazamine) were loaded into ZnO-based carriers, with improved anticancer efficacy compared to free drug formulations, particularly in multidrug-resistant cell lines and in vivo murine xenografts. The mildly acidic TME was exploited for pH-responsive drug release, premature leakage reduction, and improvement of intratumoral accumulation. Enhanced therapeutic outcomes were attributed to reactive oxygen species generation, zinc ion-mediated cytotoxicity, mitochondrial dysfunction, and efflux pump inhibition. Deep tumor penetration, apoptosis induction, and tumor growth suppression were also reported, with minimal toxicity to healthy tissues. ZnO-NPs might constitute a versatile and promising strategy for targeted cancer chemotherapy, offering synergistic anticancer effects and improved safety profiles. Future studies emphasizing long-term toxicity, immune responses, and scalable production could lead to clinical translation of ZnO-based nanomedicine in oncology. Full article

Non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer-related mortality, with resistance to chemotherapy representing a major therapeutic challenge. In this study, we investigated the effects of conventional chemotherapeutics, Cisplatin and 5-fluorouracil (5-FU), in combination with small molecule inhibitors (SMIs) targeting the PI3K/AKT signaling pathway, on NSCLC cell viability. Two NSCLC cell lines, H460 (large cell lung carcinoma) and A549 (adenocarcinoma), both characterized by constitutive activation of PI3K/AKT signaling, were evaluated. A normal human lung fibroblast cell line, MRC-5, was used as a non-cancer control to assess selectivity and exclude cytotoxic effects. Dose–response analyses were performed to determine the optimal concentrations of Cisplatin, 5-FU, the AKT inhibitor MK2206, and the PI3K inhibitor BKM120, both as monotherapies and in combination treatments. We identified a synergistic combination of 5-FU and BKM120 that significantly reduced viability and induced apoptosis in NSCLC cells while sparing MRC-5 cells. Mechanistic studies revealed that apoptosis induction was mediated through the apoptotic pathway regulated by the Bcl-2 family and activation of caspase-3 and caspase-6. These findings highlight the therapeutic potential of combining PI3K/AKT inhibitors with conventional chemotherapy to overcome resistance mechanisms in NSCLC. Full article