Search Results (574)

Background/Objective: Persistent infection with human papillomavirus type 16 (HPV-16) is the principal cause of cervical high-grade squamous intraepithelial lesions (cHSIL) and cervical cancer, yet the established treatments remain limited to ablative or excisional procedures that carry reproductive risk and do not eliminate the underlying infection. We report the preclinical development of ARV-2001, a messenger RNA (mRNA)–lipid nanoparticle (LNP) immunotherapeutic encoding mutated, non-oncogenic HPV-16 E6 and E7 fused to a SARS-CoV-2 spike S2 subdomain enriched in human CD4 helper epitopes, formulated in a novel cholesterol-derived ionizable lipid (ARV-T1). Methods: Interactions of ARV-2001-expressed antigens with p53 and retinoblastoma (Rb) were evaluated in human cervical carcinoma cell line C33A, in lentiviral constructs in primary human keratinocytes, and in soft-agar colony-formation assays. ARV-2001 was administrated by intramuscular (IM) or intradermal (ID) injection in naive mice or in the TC-1 tumor models. Tumor size and survival were monitored over time and tumor-infiltrated lymphocytes were characterized by flow cytometry. Intracellular cytokine staining and Elispot were used to evaluate immunogenicity. Results: In vitro, the mutated E6/E7–S2 antigen lost the ability to degrade p53, to deregulate the retinoblastoma (Rb) pathway, and to support anchorage-independent growth, suggesting abrogation of oncogenic activity. The S2 domain and imiquimod administration each augmented antitumor activity and intratumoral CD8⁺ T-cell infiltration while reducing myeloid-derived suppressor cells in the syngeneic HPV-16 E6/E7 TC-1 tumor models. In addition, ID administration of ARV-2001 into TC-1 tumor-bearing mice was superior to IM administration in terms of both tumor growth inhibition and survival. ID vaccination with ARV-2001 in mice consistently elicited a more potent E6/E7-specific T-cell response than the same dose given IM. Dose-escalation studies showed a dose-dependent T cell response against E6/E7 in ID-injected mice. Conclusions: This study supports future human evaluation of intradermally administrated ARV-2001 for treatment of HPV-16+ cHSIL in clinical trials. Full article

HMGB-1 is an alarmin representative of DAMP playing a central role in immunogenic cell death (ICD), a necessary condition in the dialog established between dying tumor cells and the immune system during some anticancer therapies. Therefore, early screening for ICD inducers represents a major priority in drug development today. In this work, we investigated the effect elicited by the clinical-grade CIGB-300 peptide, which impairs Protein Kinase CK2-mediated phosphorylation and other CK2 signaling connected kinases. Here, HMGB-1 extracellular release was investigated in an 18-cell line panel from blood malignancies, uterine-cervical cancer and NSCLC treated with CIGB-300 at equipotent doses (IC₅₀) over 24 h. Interestingly, CIGB-300 treatment upregulated the HMGB-1 protein levels at the culture supernatant in most of the cell lines (p = 0.01) and fold-change increases ≥ 2 were associated with intrinsic cell line sensitivity towards CIGB-300’s cytotoxic effect. However, the HMGB-1 release by CIGB-300 was context-specific with clear induction on blood and uterine-cervical cancer cells and a diffused response pattern in NSCLC. Importantly, CIGB-300 treatment of blood cancer patients enrolled in a Phase I study induced plasma HMGB-1 alarmin in 4 out of 7 subject who received the entire treatment plan. Altogether, our data reveal for the first time that CIGB-300 treatment is able to induce extracellular HMGB-1 release in vitro and in vivo which could be indicative of ICD induction in some kinds of tumors; furthermore, the induction of extracellular HMGB-1 alarmin as a putative CIGB-300 response biomarker merits further investigation. Full article

Background/Objectives: Cervical cancer (CC) is the most clinically significant HPV-associated malignancy. Platinum-based chemotherapies produce drug resistance and serious adverse effects. Drug repurposing and combinations are promising approaches to improve the antitumor response. Here, we evaluated the antineoplastic potential of loratadine and simvastatin alone and in combination with cisplatin and gefitinib in HPV-positive CC cells. Methods: HeLa and SiHa CC cells were treated with loratadine, simvastatin, cisplatin, gefitinib, or their combinations. Metabolic activity was assessed using the MTT assay to determine drug inhibitory concentrations (IC₂₀, IC₅₀) from concentration–response curves. Apoptosis was assessed by Annexin V-FITC/PI flow cytometry. Clonogenic survival and migratory capacity were evaluated using colony formation and wound-healing assays, respectively. Tumor formation was evaluated in vivo using the chick chorioallantoic membrane model. Results: Metabolic activity decreased in a concentration-dependent manner following drug treatment in both cell lines. Several combination regimens at IC₂₀ significantly improved reductions in metabolic activity and increases in apoptosis compared with monotherapies or two-drug combinations. Notably, some three-drug combinations, with or without cisplatin, had similar effects to the quadruple regimen. Combination treatments also reduced clonogenic survival and migratory capacity, as well as tumor formation and cancer cell dissemination in vivo. Conclusions: Drug combinations at relatively low concentrations (IC₂₀) significantly enhanced the anticancer effects on CC cells in in vitro and in vivo settings. These findings support the potential of drug repurposing and combination strategies as promising approaches to decrease adverse side effects while improving therapeutic efficacy for the benefit of CC patients. Full article

Background: Metabolic reprogramming enables cancer cells to adapt to energetic stress and sustain proliferation. Simultaneous inhibition of glycolysis and mitochondrial respiration has emerged as a promising strategy to overcome metabolic plasticity. This study evaluated the antiproliferative effects of the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) alone and in combination with metformin in human cancer cell lines. Methods: Human cervical carcinoma (HeLa), lung adenocarcinoma (A549), colorectal adenocarcinoma (HT-29), and normal lung fibroblasts (MRC-5) were treated with 2-DG or metformin individually, or with metformin in the presence of a fixed concentration of 2-DG (1 mM). Cell viability was assessed using the sulforhodamine B assay after 24 and 48 h. IC₅₀ values were calculated by nonlinear regression, Dose Reduction Index (DRI) analysis evaluated sensitization to metformin, and molecular docking was performed to investigate interactions with selected metabolic targets. Results: Both 2-DG and metformin inhibited cell proliferation in a concentration- and time-dependent manner. HeLa cells were the most sensitive to glycolytic inhibition, while A549 and HT-29 cells showed moderate susceptibility. Co-treatment with 2-DG significantly enhanced metformin activity, reducing its IC₅₀ in HeLa cells from 6.04 to 2.00 mM after 24 h and from 2.28 to 1.56 mM after 48 h. DRI analysis demonstrated increased sensitivity to metformin in all cancer cell lines, particularly HT-29 and A549, whereas normal MRC-5 fibroblasts remained comparatively less affected. Molecular docking revealed favorable binding of both 2-DG and metformin to proteins involved in cellular energy metabolism. Conclusions: Combined inhibition of glycolysis and mitochondrial respiration potentiates the antiproliferative effects of metformin, increases metabolic vulnerability in cancer cells, and is supported by molecular docking evidence of interactions with metabolic targets, while showing limited toxicity toward normal fibroblasts. These findings support dual metabolic targeting as a promising therapeutic strategy and warrant further mechanistic and in vivo studies. Full article

The primary aim of this review is to summarize current evidence from clinical and pre-clinical studies on endogenous molecular biomarkers associated with radiosensitivity and radioresistance in cervical cancer, including patients treated with photon-based radiotherapy, cervical cancer cell lines, and xenograft models, and to evaluate the association of these biomarkers with radiotherapy response, residual disease, recurrence and survival, and experimental measures of radiosensitivity. A systematic literature review was conducted for studies published over the last 10 years that evaluated associations between genomic, epigenetic, or protein biomarkers and radiotherapy response or survival outcomes in cervical cancer. Eligible studies included in the current analysis summarize clinical, translational, and pre-clinical studies in correlation with photon-based radiotherapy. Research focusing exclusively on non-coding RNAs, exogenous radiosensitizers, or non-photon modalities was excluded. In total, 112 studies were identified, and 46 of them met the inclusion criteria. The identified biomarkers clustered into several key biological processes: DNA damage response and cell cycle regulation, cancer stemness, hypoxia and microenvironment, epigenetic and transcriptional regulation, and signaling pathways, including exosome-mediated communication. Most markers were linked to radioresistance and adverse outcomes, whereas a smaller subset was associated with increased radiosensitivity. A limited group of biomarkers was linked to clinical outcomes such as local control, residual disease, or survival, and emerging multi-marker protein signatures suggested that combinatorial approaches may outperform single-marker strategies. Radiosensitivity in cervical cancer is regulated by a network of biological pathways. Validated, integrated biomarker panels that capture DNA repair proficiency, stemness, hypoxia adaptation, and key signaling pathways are needed to improve risk stratification and enable biomarker-guided radiosensitization. Full article

We herein report the anticancer activity and molecular docking studies of a series of amide derivatives of two nonsteroidal anti-inflammatory drugs (mefenamic acid and ibuprofen). The hypothesis of drug repurposing has been successfully employed to explore the promising anticancer activity of analogs of known anti-inflammatory agents. The compounds have been tested for their inhibitory potential against cervical cancer cell lines by MTT assay using 5-fluorouracil as the reference standard. Among the compounds screened, 3aa [2-(2,3-dimethylamino)phenyl)(1H-indol-1-yl)methanone] and 3ad [2-(2,3-dimethylphenylamino)phenyl)(9H-carbazol-9-yl)methanone] displayed good potency of less than 25 µg/mL half-maximal inhibitory concentration (IC₅₀). The docking analysis has confirmed that molecule 3aa effectively binds to the active site of the target protein CDK2, with a docking score of −9.21 Kcal/mol and a binding energy of −46.44 Kcal/mol, involving a hydrogen bond with Ile 10. The molecule 3ad also exhibited a good glide score of −6.78 Kcal/mol with the binding energy of −45.90 Kcal/mol. As many of the tested compounds displayed promising potency against cervical cancer cell lines, our investigation revealed the importance of drug repurposing in the development of lead molecules in medicinal chemistry. Full article

The underexplored Passerini–Smiles reaction (PSR), a variant of the 3-component Passerini reaction (3CPR), was successfully employed to create a tailored library of phenoxy-indoline carboxamide derivatives based on a fragment-based hybrid drug design strategy. Under mild conditions, inexpensive and commercially available isatin was utilized as a privileged carbonyl core, combined with electron-deficient phenols to establish a highly functionalized framework. Post-Passerini–Smiles transformations leveraged this strategic layout to provide a step-economical route to a complementary library of three-dimensional spirooxindole hybrids derived from the PS adducts. This study reinforces the relevance of combining structural hybridization with multicomponent reaction strategies in the discovery of potential anticancer active pharmaceutical ingredients (APIs). Both libraries were evaluated against six human solid-tumor cell lines, including non-small cell lung carcinoma, cervical and colon adenocarcinoma, and breast and pancreatic cancers. The most active compound 4gaa exhibited GI₅₀ values below 10 μM for most of the tested cancer cell lines. Full article

Antiproliferative activity of pyrrolo[3,4-d]isoxazolines and pyrrolo[2,1-a]isoquinolines derived from them was studied against human erythroleukemia (K562), cervical carcinoma (HeLa), and melanoma (Sk-mel-2) cell lines in vitro by MTS assays followed by study of their effect on actin cytoskeleton and cell motility by confocal microscopy, and apoptotic activity by flow cytometry. Most effective among the screened compounds were bicyclic hydroxylactams 6–9 with a pyrrolo[3,4-d]isoxazoline structure; they showed IC₅₀ values ranging from 12 to 36 μg/mL for all tested cancer cell lines with selectivity indexes up to 12 (as compared to the embryonic kidney HEK293T cell line). Loss of stress fibers with diffuse redistribution of granular actin throughout the cytoplasm in up to 25% of treated cells and a decrease in filopodia-like protrusions up to 69% were observed by confocal microscopy during an actin cytoskeleton study. Such cytoskeletal changes and the proposed altered cell motility were confirmed by scratch-test (revealed a three-fold decrease in cell motility). Full article

Cancer therapy remains limited by drug resistance and poor selectivity, while inflammation-driven tumor progression further complicates treatment outcomes. Antimicrobial peptides (AMPs) have emerged as promising therapeutic alternatives due to their multifunctional properties. In this study, we investigated the anticancer and immunomodulatory activities of KI17, a rationally designed peptide derived from GL18, a peptide fragment identified from the talisin protein of Talisia esculenta. KI17 exhibited dose-dependent antiproliferative effects against murine and human melanoma (B16F10-Nex2, SK-MEL-2, A375) and cervical cancer (HeLa) cell lines, while displaying reduced cytotoxicity toward non-tumoral BV-2 microglial cells, resulting in a favorable selectivity index. Mechanistic analyses revealed that KI17 induces morphological alterations, mitochondrial dysfunction, caspase activation, and late-stage apoptosis, together with G0/G1 cell cycle arrest accompanied by accumulation of the Sub-G0 population, indicating coordinated regulation of cell death and cell cycle progression. KI17 effectively suppressed lipopolysaccharide (LPS)-induced microglial activation, markedly reducing pro-inflammatory cytokine and nitric oxide production without compromising cell viability. These biological activities are consistent with the peptide’s optimized physicochemical features, including increased cationicity, amphipathicity, and α-helical folding. Overall, our findings demonstrate that KI17 combines selective anticancer activity with potent immunomodulatory effects, highlighting its potential as a bioinspired peptide for further preclinical development in cancer therapy. Full article

In this study, novel electrospun polymer mats based on biocompatible poly(lactic acid) (PLA) and hydrophilic poly(ethylene glycol) (PEG) were successfully fabricated for the co-delivery of two natural polyphenols, quercetin (QUE) and rosmarinic acid (RA). Scanning electron microscopy (SEM) revealed the formation of defect-free, continuous nanofibers with high interconnected porosity. By mimicking the structural features of the native extracellular matrix, these nanofibrous platforms facilitate pronounced combined antioxidant and anticancer action. X-ray diffraction (XRD) analysis confirmed that the rapid solvent evaporation during electrospinning induced a physical state transformation, converting both QUE and RA from their native crystalline structures into an amorphous dispersion within the polymer fibrous materials, thereby optimizing their potential bioavailability. The obtained hybrid fibrous materials possessed good mechanical properties. Moreover, the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay demonstrated that the incorporation of PEG enhanced matrix hydrophilicity, allowing the four-component PLA/PEG/QUE/RA mats to achieve the highest antioxidant efficiency (98.1%), suggesting an enhanced, complementary radical-neutralization pathway. Furthermore, in vitro biological assessments against human cervical carcinoma cell line (HeLa) and normal murine embryo fibroblasts BALB/3T3 demonstrated prominent anticancer activity, while noncancerous cells were significantly less affected. The dual-loaded PLA/PEG/QUE/RA fibrous mats induced significant cell shrinkage, chromatin condensation, and apoptotic cell death in HeLa cells, while normal BALB/3T3 fibroblasts retained cell membrane integrity and displayed higher resistance. Modeled after the native extracellular matrix, these bioinspired materials demonstrate significant antioxidant and anticancer activity, highlighting their potential for applications in localized cancer therapy, wound management, and tissue engineering. Full article

This study investigates the phytochemical and pharmacological profiles of Crinum asiaticum L. var. anomalum Baker from Vietnam. Phytochemical screening identified diverse secondary metabolites, including polyphenols, flavonoids, and alkaloids. Gas chromatography–mass spectrometry analysis of the n-hexane fractions revealed 19 major compounds. While all extracts showed moderate antioxidant activity, the chloroform fraction exhibited superior antidiabetic potential via α-amylase inhibition (IC₅₀ = 83.13 ± 6.67 µg/mL). Furthermore, at non-cytotoxic concentrations (3.13 to 50 µg/mL), this fraction effectively rescued mouse β-TC6 insulinoma cells from thapsigargin. In anti-inflammatory assays, the n-hexane fraction significantly suppressed nitric oxide production in RAW 264.7 macrophages (IC₅₀ = 53.12 ± 1.63 µg/mL). Notably, the extracts displayed remarkable selective anticancer activity, particularly the chloroform fraction against HeLa cervical and HepG2/Huh-7 hepatoma cell lines. In silico ADMET and Lipinski’s Rule of Five analyses confirmed that the key bioactive constituents possess favorable pharmacokinetic profiles and drug-likeness. These findings demonstrate C. asiaticum L. var. anomalum Baker as a promising natural source for developing multitarget therapeutic agents against inflammation, diabetes, and cancer. Full article

Cervical cancer is a malignant disease that affects women worldwide and is associated with both high incidence and a high mortality rate. miR-34 is a direct transcriptional-target of p53 and is downregulated in several types of cancers. 1,4-Naphthoquinones (NQs) have anticancer properties and have been used to modulate miR-34 expression. We tested (3-chloro-NQ-2-yl)-alanine (ANQCl), -methionine (MNQCl), -glycine (GNQCl), -phenylalanine (FNQCl), -asparagine (NNQCl), and (1,4-napthoquinon-2-yl)-asparagine (NNQ) in immortal and tumorigenic cells, both HPV-positive and -negative, simulating precancerous and cancerous status to observe the response of the p53-miR-34 system, migration and invasion. A dose–response was achieved to determine the IC50 of the compounds in SiHa, CaLo, C33-A and HaCaT cells. HaCaT cell migration inhibition was more potent than in SiHa, CaLo, and C33-A cells, while invasion hindrance was more evident in the tumorigenic SiHa, CaLo and C33-A. NNQCl, GNQCl, ANQCl and FNQCl compounds induced p53 overexpression in SiHa and CaLo cells. Compound ANQCl in SiHa and FNQCl in CaLo induced miR-34a overexpression, probably via p53. Migration and invasion of most compounds decreased independently of p53-miR-34. NQ-amino acids exert effect on cell proliferation, migration and invasion in cervical cancer cells, suggesting their potential use in the field of cancer treatment. Full article

The continuous expression of HPV oncogenes E6 and E7 contributes to the maintenance of the cervical cancer (CC) phenotype by altering gene expression programs involved in tumor progression and aggressiveness. MicroRNAs (miRNAs) have emerged as critical regulators of gene expression in CC, including miR-218-5p, which has been described as a tumor suppressor. In this study, we investigated the impact of HPV-16 oncoproteins E6 and E7 on the regulation of miR-218-5p expression and its target gene PIK3C2A, as well as their functional and clinical relevance in CC. We found that miR-218-5p expression is significantly reduced in HPV-16-positive CC cell lines, while PIK3C2A expression is increased. Silencing the expression of the E6/E7 oncogenes in Ca Ski cells restored miR-218-5p levels and reduced PIK3C2A expression. Conversely, overexpression of the E6 and E7 oncogenes in C-33 A cells significantly decreased miR-218-5p expression and increased PIK3C2A expression. Functional assays performed on C-33 A cells expressing E6 and E7 revealed that ectopic expression of miR-218-5p suppresses cell proliferation and migration, effects that are partially mediated by PIK3C2A. Bioinformatics analysis showed that low miR-218-5p expression and high PIK3C2A expression are associated with reduced overall survival in patients with cervical cancer. Our findings identify the miR-218-5p/PIK3C2A axis as a novel regulatory pathway modulated by HPV-16 oncoproteins E6 and E7 that contributes to CC cell proliferation and migration. Furthermore, miR-218-5p and PIK3C2A emerge as potential prognostic biomarkers in CC. Full article

Gelatin functionalized with methacrylate (GelMA), norbornene (GelNB), and phenol (GelPH) has been studied as a precursor for crosslinkable biomaterials in tissue engineering. Cytocompatibility is usually assessed post-hydrogel formation, but cells briefly encounter soluble precursors during preparation and residual functional groups that may remain post-gelation. However, the biological effects of these uncrosslinked derivatives remain poorly understood. This study systematically investigated the impact of functional group chemistry on cellular responses under uncrosslinking conditions. Four cell lines, including fibroblasts (BALB/3T3), cervical cancer cells (HeLa), mesenchymal stem cells (UE7T-13), and neuronal cells (PC-12), were exposed to soluble GelMA, GelNB, and GelPH at matched polymer concentrations and degrees of functionalization (~50%). The results showed no overt cytotoxicity. The detectable differences were subtle and strongly cell type-dependent. HeLa and PC-12 cells showed no clear differences from untreated controls in most parameters. BALB/3T3 fibroblasts showed mainly GelMA-associated differences in mitochondrial activity, proliferation, and morphology. In the UE7T-13 cells, GelMA-treated cells showed the largest deviations from controls across the readouts examined, including mitochondrial activity, cell area, phenotype-related gene expression, and some osteogenic markers, while GelPH was intermediate and GelNB was comparable to controls. These findings underscore the importance of considering residual precursor effects in gelatin-based biomaterial design. Full article

Background/Objectives: Transition metal complexes of imidazoles exhibit a variety of biological activities. This makes them promising metal-based drugs for use in medicine. The aim of this research is to investigate the complexes of zinc(II) with N-vinyl, N-allyl, and N-propargylimidazoles, represented by the formula [ZnL₂Cl₂], as potential drug candidates. Methods: Structural studies of the obtained complexes were performed using single-crystal X-ray diffraction analysis, IR and NMR spectroscopy. DFT calculations were used to determine structural, electronic and thermochemical parameters of the complexes. QSAR analysis was performed using PASS. The wound-healing and antihypoxic activities were studied in vivo using models of wounds and acute hypoxia of various origins. The antimicrobial activity of the complexes was evaluated against Staphylococcus aureus Wood 46, Escherichia coli M-17, and the yeast fungus Candida albicans 927. The cytotoxic activity was tested using several cell lines, including monkey kidney (Vero) cells, human cervical cancer cells (Hep2C and HeLa), human lung carcinoma (A549), and human embryonal rhabdomyosarcoma (RD). Results: New complexes of N-allylimidazole and N-allyl-2-methylimidazole with ZnCl₂ were synthesized and characterized. All the studied complexes possess diverse biological activities. While the antimicrobial activity was modest, a distinct antifungal activity was observed. The cytotoxicity of the complexes was found to be mainly in relation to Hep2c and RD cell lines. Conclusions: Based on the results of QSAR analysis and experimental findings, the diverse biological activities of the compounds indicate that they are promising lead structures for further optimization in drug development. Full article