Search Results (594)

Thyroid carcinomas are phenotypically heterogeneous malignancies. Advances in molecular and cellular technologies have revealed genetic, epigenetic, and nongenetic factors underlying this heterogeneity. Our study aimed to assess the impact of single and combined treatments with anticancer agents (Carboplatin, Doxorubicin, Paclitaxel, Avastin), natural compounds (Quercetin), and epigenetic modulators (suberoylanilide hydroxamic acid and 5-Azacytidine) on the expression of long noncoding RNAs, methylation regulators, and functional features in the human thyroid cancer cell line K1. Methods: Treated and untreated K1 cells were used throughout experiments to evaluate the drug-induced cytotoxicity, apoptosis, cell cycle distribution, cytokine release, gene expression, and global DNA methylation levels. Results: Some single- and combined-drug treatments modulated both cell cycle progression and apoptotic events, demonstrating anti-tumor activity of the tested compounds. Gene expression analysis showed treatment-specific regulation of target genes and lncRNAs, including both upregulation and downregulation across different drug combinations. All treatments resulted in increased global DNA methylation levels compared to the untreated controls. Several combinations significantly upregulated DNMT1 and DNMT3B, while concomitantly decreased EZH2 levels. Conclusions: These coordinated epigenetic changes highlight the therapeutic potential of combining epigenetic modulators with chemotherapeutic agents, suggesting a strategy to prevent or reverse treatment resistance and improve outcomes in thyroid cancer patients. Full article

Background: Doxorubicin (DOX) is a widely used chemotherapeutic agent, but its efficacy is often limited by cancer cell resistance. Although multiple DOX resistance mechanisms have been characterized, the global transcriptomic alterations underlying this phenomenon remain poorly understood. The aim of this work was to determine whether a common transcriptional response associated with DOX desensitization exists across tumor cells of different origins and to identify the core elements of this response. Methods: We performed an integrated bioinformatics analysis, including: analysis of independent transcriptomic datasets (comparing DOX-resistant neuroblastoma, breast, and cervical carcinoma cells to their DOX-sensitive counterparts), functional annotation of differentially expressed genes, reconstruction and topology analysis of gene networks, text mining, and survival analysis. The findings were validated through in vitro functional tests, RT-PCR, and analysis of the Cancer Therapeutics Response Portal and The Cancer Genome Atlas. Results: We showed that DOX resistance in cancer cells is associated with cytoskeletal reorganization, modulation of cell adhesion, cholesterol biosynthesis, and dysregulation of mTORC1, Wnt, and Gβγ signaling pathways. Network analysis identified a conserved regulome of 37 resistance-linked genes, with GJA1, SEH1L, TCF3, TUBA4A, and ZYX emerging as central hubs (mean degree: 8.7–19.7; mean fold change: 2.4–21.3). Experimental validation in DOX-resistant KB-8-5 cervical carcinoma cells and their sensitive counterparts (KB-3-1) confirmed enhanced cellular adhesion and reduced intracellular cholesterol levels associated with chemoresistance, supporting our in silico findings. A detailed follow-up analysis verified the upregulation of these hub genes in chemoresistant cells and their correlation with poor clinical outcomes across multiple cancer types. Conclusions: This integrative analysis identifies conserved transcriptomic signatures of DOX resistance and highlights hub genes GJA1, SEH1L, TCF3, TUBA4A, and ZYX with potential as predictive biomarkers and therapeutic targets. Targeting these pathways may help overcome chemoresistance and improve treatment outcomes in cancer patients. Full article

Background: Ewing sarcoma (EWS) is a rare cancer of the bone and soft tissue, most prevalent in children and young adults. The treatment of EWS has progressed relatively little in over 30 years. Survival rates for patients, particularly those with metastatic and/or relapsed disease remain poor, highlighting the urgent need for innovative treatment options. Methods: Here, we have explored the therapeutic potential of the oncolytic Maraba virus strain MG1 using various in vitro models of EWS, including established cell lines, doxorubicin-resistant derivatives, spheroid cultures and primary patient-derived Ewing sarcoma cell cultures. We examined the direct oncolytic activity of MG1 and its ability to stimulate the immune-mediated killing of EWS by human healthy donor peripheral blood mononuclear cells. Results: We show that MG1 undergoes productive replication and exerts direct oncolysis of established EWS cell lines, doxorubicin-resistant EWS cell lines and patient-derived Ewing sarcoma cell cultures more recently established from tumours. In contrast, primary mesenchymal stem cells (the likely cell of origin of EWS) were resistant to MG1, with IFN-I being a major determinant of tumour cell selectivity. MG1-treated PBMC produced IFN-I and killed EWS cells in vitro, in a natural killer (NK) cell-dependent manner. Conclusions: The ability of MG1 to kill EWS cells directly and stimulate NK cell cytotoxicity against this tumour suggests that MG1 may provide therapeutic benefit for EWS patients where the efficacy of conventional treatments is currently limited. Full article

Background: Multidrug resistance (MDR), primarily driven by P-glycoprotein (P-gp)-mediated drug efflux, presents a significant challenge in cancer therapy, contributing to chemotherapy failure and poor patient outcomes. Objectives: In this study, we explored the potential of manidipine (MA), a clinically approved calcium channel blocker, to reverse P-gp-mediated MDR through modulation of calcium signaling via nuclear factor of activated T cells 2 (NFAT2). Methods: Paclitaxel (PTX) resistance ABCB1-overexpressing cancer in vitro and in vivo were used for evualting the anti-MDR effects of MA, as well as the underlying mechanism with siRNA of NFAT2. Results: We found that MA at non-toxic concentrations (0.6–5.4 μM) significantly sensitize drug-resistant colorectal (HCT-8/T) and non-small cell lung (A549/T) cells to PTX, reducing its IC₅₀ by up to 1328-fold in vitro models. Mechanistically, MA inhibited P-gp efflux activity without altering its expression, as shown by an increased intracellular accumulation of doxorubicin and Flutax-2 (2.3- and 3.1-fold, respectively) and dose-dependent modulation of ATPase activity (EC₅₀ = 4.16 μM). Notably, MA reduced intracellular calcium levels (52% reduction, p < 0.001) and downregulated NFAT2, an oncogene overexpressed in resistant cells. In vivo, MA (3.5 mg/kg) synergizes with PTX to inhibit tumor growth by 68% (p < 0.001) in A549/T xenograft model, without an observable decrease in weight. Conclusions: In sum, all these results position MA as a novel NFAT2 inhibitor to overcome P-gp-mediated MDR via modulating calcium signaling, which points to further investigation for its clinical applications. Full article

Background/Objectives: To compare oncologic outcomes of second-line chemotherapy regimens in relapsed high-grade serous ovarian cancer (HGSOC) by platinum sensitivity. Methods: We retrospectively reviewed HGSOC patients treated at two centers (June 2003–December 2020), classified by platinum-free interval (6- and 12-month cut-offs). Outcomes were progression-free survival (PFS, primary) and objective response and disease control rates (secondary). Regimens administered to ≥10% of patients or with favorable outcomes were compared using multivariable Cox analyses. Results: Among 468 patients (41.2% sensitive, 32.9% partially sensitive, 25.9% resistant), platinum-sensitive patients were younger (p = 0.024), diagnosed earlier, and more likely to undergo primary debulking surgery (both p < 0.001), achieving best outcomes after second-line chemotherapy (median PFS 14.8 vs. 10.5 and 5.2 months, p < 0.001). In both sensitive groups, the most common regimens were taxane + platinum ± bevacizumab, followed by pegylated liposomal doxorubicin + carboplatin, which was associated with shorter PFS in platinum-sensitive patients (hazard ratio (HR) 1.67, p = 0.016). Second-line maintenance with bevacizumab or poly(ADP-ribose) polymerase inhibitors was associated with improved PFS in both groups (p < 0.001). In platinum-resistant patients, the omission of bevacizumab (HR 2.01, p < 0.001) and a primary treatment history without cytoreduction (HR 4.43, p = 0.044) were associated with inferior outcomes. Conclusions: In platinum-sensitive patients with a favorable prognosis, taxane + platinum regimens were most commonly used and outperformed PLD + carboplatin. Maintenance therapy also conferred a meaningful benefit. In platinum-resistant disease, bevacizumab use and prior cytoreductive surgery may improve outcomes, underscoring the importance of treatment selection and surgical approach. Full article

Ribosomal proteins have long been recognized as vital components of ribosomes that are involved in protein synthesis. However, emerging evidence indicates that some ribosomal proteins exhibit extraribosomal functions. In this study, we investigated the role of the ribosomal protein S4 X-linked (RPS4X) in the regulation of the Skp1–Cullin1–F-box (SCF) ubiquitin ligase complex and apoptosis. We found that RPS4X expression interfered with SCF complex formation by disrupting the interaction between Cullin1 and Skp1. This disruption suppressed ubiquitination of multiple SCF complex substrates, including the anti-apoptotic proteins myeloid cell leukemia 1 (MCL1) and HS1-associated protein X1 (HAX1). Stabilization of MCL1 and HAX1 by RPS4X led to increased resistance of HeLa cells to doxorubicin-induced apoptosis. These findings suggest that RPS4X contributes to the regulation of protein homeostasis and apoptotic pathways by modulating SCF complex activity, providing new insights into the extraribosomal roles of ribosomal proteins. Full article

Histone deacetylase inhibitors (HDACis) induce the expression of multidrug resistance (MDR) pumps and can even display the MDR phenotype in cell lines. This is the first report to include the profiles of ATP-binding cassette (ABC) transporters in intrinsically expressed HeLa cells as well as those acquired due to a 5 mM valproic acid (VPA) treatment. Expression of ABC transporters related to the MDR phenotype was analyzed by RT-PCR in untreated HeLa cells and HeLa cells treated with 5 mM VPA. The ABCB5 protein was identified in HeLa cells by immunocytochemistry. HeLa cell treatment with 5 mM VPA increased ABCB1 expression and triggered the de novo expression of ABCB5 in mRNA and protein. Despite the expression of ABCB5 and the overexpression of ABCB1, VPA reduced the growth rate by 20%, delayed doubling time by 25%, and decreased the number of living cells per well to 50% after 72 h. Pretreatment with VPA for 24 h followed by cotreatment with doxorubicin (DOX) sensitized HeLa cells to DOX. However, for the de novo expression of ABCB5, HeLa cells did not acquire the MDR phenotype from the 5 mM VPA treatment. The ABCB5 isoform induced by VPA treatment probably lacks MDR activity. 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

Background: Breast cancer is the most common cancer among women. Although doxorubicin (DOX) is widely used in its treatment, its dose-dependent toxicity and the development of drug resistance reduce its therapeutic efficacy. Therefore, this study aims to identify a novel anticancer agent that is more effective than DOX, inhibits cancer cell growth, and is less toxic to healthy cells. Methods: The cytotoxic effects of DOX and 2S-series molecules were evaluated on human (MDA-MB-231) and mouse (4T1) TNBC breast cancer cell lines and healthy breast epithelial (hTERT) cells using MTT assays at 48 and 72 h to screen functional similarities and possible differences upon drug/inhibitor treatment. Apoptosis and cell cycle analysis were analyzed by flow cytometry. Gene expression profiles were assessed by qPCR, and binding interactions with Hsp90 were examined via molecular docking. Results: 2S-5 exhibited IC₅₀ values of 6.21 µM (MDA-MB-231) and 7.04 µM (4T1), while 2S-13 showed IC₅₀ values of 7.73 µM and 8.21 µM, respectively. Both compounds demonstrated selective cytotoxicity against cancer cells. Gene expression and pathway analysis revealed that 2S-13 modulated the PI3K-Akt, MAPK, apoptosis, and HIF-1 pathways, showing broader modulation than DOX. Conclusions: 2S-13 appears to be a promising drug candidate, particularly in the MDA-MB-231 cell line. However, the current findings are limited to in vitro models. Further in vivo studies and pharmacokinetic analyses are required to validate its therapeutic potential, assess long-term efficacy and safety, and explore its resistance profile and molecular mechanisms in more detail. Full article

Malignant bone and soft tissue tumors are often resistant to conventional treatment, and treatment options for unresectable and metastatic cases are limited. L-type amino acid transporter 1 (LAT1) is overexpressed in several malignancies, including sarcomas, making it an attractive target for targeted alpha therapy. In this study, we investigated the therapeutic efficacy of LAT1-targeted alpha therapy using a novel modified 3-astatin-211 Astato-α-methyl-L-tyrosine (²¹¹At-AAMT) for bone and soft tissue sarcomas. LAT1 expression and the specificity of LAT1-mediated uptake of ²¹¹At-AAMT were evaluated in bone and soft tissue sarcoma cell lines. Antiproliferative effects were assessed using cell viability and colony formation assays. DNA damage was assessed using immunostaining with phosphorylated histone γH2AX. In vivo efficacy of ²¹¹At-AAMT, determined using xenograft mouse models, was compared with that of doxorubicin. LAT1 was highly expressed in all cell lines, especially MP-CCS-SY and MG-63 cells. ²¹¹At-AAMT uptake was LAT1-dependent and significant in all cell lines. It inhibited cell proliferation in a dose-dependent manner, comparable to that of doxorubicin. In xenograft models, a single administration of ²¹¹At-AAMT significantly inhibited tumor growth without systemic toxicity, whereas doxorubicin caused weight loss. Histopathological analysis showed reduced cell density, inhibited proliferation, and extensive DNA damage in tumors treated with ²¹¹At-AAMT, whereas LAT1 expression was maintained in residual tumor tissues. LAT1-targeted alpha therapy with ²¹¹At-AAMT demonstrated antitumor efficacy comparable to that of first-line chemotherapy for osteosarcoma and soft tissue sarcoma. Sustained LAT1 expression suggests the potential for repeated or combination treatments, highlighting its promise as a novel therapy for advanced, treatment-resistant sarcomas. Full article

Esophageal squamous cell carcinoma (ESCC) accounts for the majority of esophageal cancers worldwide, with a poor prognosis and increasing resistance to conventional treatments. Faced with these limitations, nanoparticles (NPs) are attracting growing interest as innovative therapeutic agents capable of improving specificity and efficacy and reducing systemic toxicity. This study critically examines the pharmacological effects, mechanisms of action, and toxicity profiles of different metallic or organic nanoparticles tested on ESCC cell lines. Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 guidelines were followed by a meticulous literature search of Google Scholar, Web of Science, PubMed/Medline, and Scopus databases to achieve this goal. The results show that the anti-tumor properties vary according to the type of nanoparticle (copper(II) oxide (CuO), silver (Ag), gold (Au), nickel(II) oxide (NiO), nano-curcumin, etc.), the synthesis method (chemical vs. green), and the biological activity assessment method (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Bromodeoxyuridine (BrdU), Cell Counting Kit-8 (CCK8) assays, etc.). NPs derived from green synthesis, such as those based on Moringa oleifera, Photinia glabra, or pomegranate bark, exhibit moderate cytotoxic activity (50% inhibitory concentration (IC₅₀) between 92 and 500 µg/mL) but show good tolerance on normal cells. In contrast, chemically synthesized NPs, such as Cu(II) complexes with 1,3,5-benzenetricarboxylic acid (H₃btc) or 1,2,4-triazole (Htrz), show lower IC₅₀ (34–86 µM), indicating more marked cytotoxicity towards cancer cells, although data on their toxicity are sometimes lacking. In addition, multifunctional nanoparticles, such as gold-based nano-conjugates targeting Cluster of Differentiation 271 (CD271) or systems combined with doxorubicin, show remarkable activity with IC₅₀ below 3 µM and enhanced tumor selectivity, positioning them among the most promising candidates for future clinical application against ESCC. The most frequently observed mechanisms of action include induction of apoptosis (↑caspases, ↑p53, ↓Bcl-2), oxidative stress, and inhibition of proliferation. In conclusion, this work identifies several promising nanoparticles (silver nanoparticles derived from Photinia glabra (PG), gold-based nano-immunoconjugates targeting CD271, and silver–doxorubicin complexes) for future pharmaceutical exploitation against ESCC. However, major limitations remain, such as the lack of methodological standardization, insufficient in vivo and clinical studies, and poor industrial transposability. Future prospects include the development of multifunctional nanocomposites, the integration of biomarkers for personalized targeting, and long-term toxicological assessment. 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

BQ323636.1 (BQ) is a splice variant of NCOR2. Its overexpression is associated with endocrine therapy and chemoresistance in estrogen receptor-positive (ER+ve) breast cancer. This study investigates how BQ overexpression drives doxorubicin (DOX) resistance by enhancing androgen receptor (AR) signaling and non-homologous end joining (NHEJ). BQ overexpressed breast cancer cell lines (MCF-7, T-47D, BT-549, MDA-MB-453), showed increased AR activity (ARE-luciferase assay) and demonstrated DOX resistance (EC50 > 10-fold with DHT, p < 0.05), as assessed via cell viability, TUNEL, and comet assays. RNA-sequencing (GSE295979, GSE2048) revealed the involvement of AR signaling. BQ upregulated cell cycle-related kinase (CCRK), stabilizing KU70, a key NHEJ protein, resulting in enhanced NHEJ activity (EJ5-GFP assay, p < 0.01). Co-immunoprecipitation confirmed the interaction between CCRK and KU70, and CCRK was found to modulate the protein stability of KU70. AR inhibition with bicalutamide in BQ overexpressing cells reversed DOX resistance. Xenograft models validated AR-dependent DOX resistance. In ER+ve breast cancer patient samples, high CCRK expression correlated with DOX resistance (p = 0.002) and metastasis (p = 0.001). Kaplan–Meier analysis showed poorer overall survival (p < 0.001) and disease-specific survival (p < 0.001) in cancers with high CCRK. Cox-regression analysis showed that high CCRK was a poorer prognostic factor of overall survival (p < 0.001; RR 3.056, 95% CI 1.661, 5.621, AR (p < 0.001; RR 3.420, 95% CI 1.783, 6.562), and disease-specific survival (p < 0.001; RR 2.731, 95% CI 1.472, 5.067). The BQ-AR-CCRK-KU70 axis represents a novel mechanism of DOX resistance in ER+ve breast cancer, suggesting AR or CCRK inhibition as a potential therapeutic strategy. Full article

Drug resistance remains a major obstacle in cancer treatment despite advances in therapeutic regimens. To address this, we explored the potential of Doxorubicin (Dox) delivery in poly (lactide-co-glycolic acid) (PLGA) nanoparticles to enhance Diffuse large B-cell lymphoma (DLBCL) cell death. This research investigates the potential of Doxorubicin and advanced delivery methods. We used PLGA nanoparticles with Oleyl cysteineamide (OCA); its amphiphilic nature enables interfacial anchoring and thiol surface functionalization of PLGA NPs. Compared to PLGA-NPs, PLGA-OCA-NPs enhance immunity and induce tumor cell death. They also show significant apoptotic cell death and induced immune responses in DLBCL mouse models. Dox-conjugated PLGA-OCA-NPs (DOX-OCA) exhibit significant in vitro and in vivo anticancer activity compared to free DOX, showing remarkable antitumor effects with reduced systemic toxicity in mouse models. Our findings underscore the promising potential of PLGA-OCA-NPs in DLBCL treatment, offering a hopeful future in cancer therapy. This innovative delivery system offers enhanced immune responses and effectively addresses toxicity concerns, marking a significant step forward in cancer therapy. Full article

Background/Objectives: Doxorubicin (DOXO) is effective against various types of cancer; however, it is associated with hepatotoxicity that may eventually lead to liver fibrosis, limiting its clinical use. Aurora kinase A (AURKA) has emerged as a crucial regulator of essential cellular processes and a promising target to overcome tumors resistant to some anticancer drugs, including DOXO. However, the potential beneficial effect of targeting AURKA on DOXO-induced toxicities has not been explored yet. Therefore, the current study aimed to explore the potential protective effect of the AURKA-selective inhibitor alisertib on DOXO-induced hepatotoxicity in mice and address the possible underlying mechanism. Methods: Mice were treated with alisertib (10 and 20 mg/kg) daily for five consecutive days and challenged with DOXO (20 mg/kg, i.p.) once on day two. Results: Our findings revealed that alisertib significantly reduced biomarkers of liver dysfunction and oxidative stress elevated by the DOXO challenge. Interestingly, alisertib suppressed DOXO-induced IL-17A upsurge along with NF-κB and STAT3 activation. Alisertib also suppressed the upregulated expression of HIF-1α and VEGF-A as well as PERK activation associated with the DOXO challenge. Moreover, alisertib counteracted DOXO-induced TGF-β1 and α-SMA overexpression in the liver. These beneficial effects of alisertib were further reflected in the histopathological findings, which indicated the ability of alisertib to ameliorate DOXO-induced hepatic necroinflammation and fibrosis. Conclusions: Alisertib mitigates DOXO-induced hepatotoxicity in mice via targeting the IL-17A/NF-κB and IL-17A/STAT3/HIF-1α/VEGF-A signaling pathways, attenuating oxidative stress, inflammation, ER stress, and fibrosis. Full article