Search Results (2,995)

Background/Objectives: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the BCR–ABL fusion gene, whose constitutive tyrosine kinase activity drives leukemogenesis. Although tyrosine kinase inhibitors (TKIs) have revolutionized treatment, drug resistance and leukemic stem cell persistence remain major challenges. Natural compounds such as polyphenols have shown potential in modulating key oncogenic pathways in CML. Results: Polyphenols such as resveratrol, quercetin, curcumin, and epigallocatechin gallate (EGCG) demonstrated significant antiproliferative and pro-apoptotic effects in CML cell lines, including imatinib-resistant models. These effects were mediated through the modulation of signaling pathways, including PI3K/Akt, STAT5, and MAPK; inhibition of BCR–ABL expression; induction of oxidative stress; and the enhancement of apoptosis via mitochondrial and caspase-dependent mechanisms. Some polyphenols also showed synergistic activity with TKIs, potentiating their efficacy and overcoming resistance. Conclusions: Preclinical evidence supports the role of polyphenols as potential adjuvants in CML therapy, particularly in drug-resistant contexts. Their pleiotropic molecular actions and low toxicity profile make them promising candidates for integrative oncology. Nonetheless, clinical translation requires further investigation through well-designed trials assessing efficacy, safety, and pharmacokinetics. Full article

Objectives: This study analyzed the antiproliferative potential of Eugenia uniflora L. leaf extracts against cervical cancer and non-cancerous cell lines. Methods: The extracts were prepared by maceration using hexane (EUH), dichloromethane (EUD), and ethyl acetate (EUA). Their cytotoxic potential was evaluated through MTT assays, wound healing assays, and flow cytometry. To identify classes of secondary metabolites, total phenolic and flavonoid contents were quantified using spectrophotometric methods, and individual metabolites were tentatively identified by LC-MS/MS. Results: EUH, EUD. and EUA exhibited cytotoxicity in HeLa cells, with IC₅₀ values of 63.03 μg/mL, 33.79 μg/mL, and 38.38 μg/mL, respectively. Due to their lower IC₅₀ values, the EUD and EUA fractions were selected for further investigation. EUA and EUD inhibited cell migration at all the time points tested and altered the cell cycle. Twenty-eight compounds were tentatively identified in E. uniflora L. leaf extracts based on the interpretation of their fragmentation patterns and molecular formulas obtained from mass spectrometry. Conclusions: The EUD and EUA extracts appear to modulate the metabolism of cervical cancer cells, leading to cell cycle arrest and inhibition of cell migration. Flavonoids and other phenolic compounds are likely responsible for these observed biological effects. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, with limited effective therapeutic options due to late diagnosis, aggressive progression, and rapid development of drug resistance. In pursuit of novel treatments, this study reports the design, synthesis, and biological evaluation of a new series of topsentin derivatives, featuring a 1,2,4-oxadiazole core. The newly synthesized derivatives were screened for antiproliferative activity against multiple PDAC cell lines (SUIT-2, Patu-T, and PANC-1), identifying several compounds with potent growth-inhibitory effects, particularly on SUIT-2 and Patu-T cells. Further studies demonstrated that these compounds also significantly inhibited cell migration and reduced clonogenic potential, with IC₅₀ values in the micromolar range. The results suggest that these marine-inspired 1,2,4-oxadiazole derivatives effectively target key hallmarks of PDAC, including proliferation, migration, and colony formation, supporting their further development as promising candidates for overcoming drug resistance and metastatic progression in pancreatic cancer. Full article

Background/Objectives: Cadherin-6 (CDH6), also known as K-cadherin, is a type II classic cadherin molecule that plays an important role in the embryonic development of the kidney but has very limited expression in adult tissues. It is overexpressed in several human malignancies, primarily in ovarian cancer, renal cell carcinoma, as well as, less frequently, cholangiocarcinoma, uterine serous carcinoma, glioma, lung, pancreatic and thyroid cancers. The characteristic of limited expression in normal tissues, high expression in tumor tissues, and rapid internalization upon antibody binding makes CDH6 a well-suited antibody-drug conjugate (ADC) target. Methods: We developed a novel CDH6-targeting ADC, CUSP06, consisting of a proprietary humanized antibody selective for CDH6, a protease cleavable linker, and an exatecan payload, with a drug-to-antibody ratio (DAR) of 8. We further characterized the pharmacological activities of CUSP06 in multiple in vitro and in vivo models. Results: CUSP06 was selectively bound to cell surface CDH6 and was efficiently internalized into CDH6-positive ovarian cancer cells, and led to the induction of DNA damage and apoptosis of CDH6-positive cancer cells. CUSP06 exhibited strong antiproliferative activity against several CDH6-positive cancer cell lines and demonstrated strong bystander cell killing effect in the cell mixing experiments in vitro. CUSP06 exhibits excellent in vivo antitumor efficacy in CDH6-high or -low cell line-derived xenograft (CDX) or patient-derived xenograft (PDX) models from human ovarian, renal and uterine cancers, as well as cholangiocarcinoma. CUSP06 demonstrated a favorable safety profile in GLP-compliant toxicology studies in Sprague Dawley rats and cynomolgus monkeys. Conclusions: The preclinical data highlighted the therapeutic potential of CUSP06 in multiple CDH6-positive human cancers. Full article

The side effects of conventional cancer treatments, such as chemotherapy, radiotherapy, etc., worsen the quality of life of patients. Therefore, it is necessary to explore the possibilities of creating new drugs containing natural products with low toxicity. The experimental scientific pharmacological research of rose preparations in Bulgaria began in the first half of the 20th century. Bulgarian rose essential oil (BREO) is qualified by GC FID analysis. To study the effect of the BREO, we used HCT-8 and HT-29 tumor cell lines. As a model of healthy tissue, we used the non-tumorigenic cells MCF-12F. Cells were treated with twofold increasing concentrations of BREO from 7.5 µg/mL to 1000 µg/mL. The NRU test and MTT assay were used for evaluation of the safety, antiproliferative activity and colony formation assay. Our results showed low cytotoxicity (CC₅₀ = 629.72 ± 22.38 μg/mL) and high level of photosafety (PIF = 0.92) of BREO. The antiproliferative activity test shows that the BREO has an IC₅₀ = 290.45 ± 10.79 μg/mL for the HT-29 cells. In the normal cell line MCF-12F, this effect is lower (IC₅₀ = 383.90 ± 34.75 μg/mL). Furthermore, colony forming assay showed a significant reduction in IC₅₀ value (IC₅₀ = 163.79 ± 10.25 μg/mL) in HT-29 cells. The in silico experiments confirmed the potential of the BREO for antiproliferative effect and further activation of different pathways leading to apoptosis. Full article

Background/Objectives: Oxidative stress is a pathophysiological factor that causes challenging issues in the treatment of several diseases, including gastric ulcer, inflammatory diseases, and adenocarcinomas. V. paradoxa and P. biglobosa are African plants whose parts are used for treating diseases, including gastrointestinal pathologies. This study aimed to characterize the gastroprotective, antioxidant, and anti-inflammatory activities of V. paradoxa and P. biglobosa stem bark extracts based on various solvents. Methods: The phytochemical screening and antioxidant evaluation were performed using radical scavenging (ABTS and DPPH) and reduction (FRAP and APM) methods. The anti-inflammatory activity was performed through an egg albumin denaturation model. The toxicological evaluation was performed on Artemia salina and female Wistar rat models, and the gastroprotective activity was carried out on an ethanolic-induced gastric ulcer rat model. Results: The results reported that V. paradoxa stem bark extracts contain catechin, epicatechin, ferulic acid, apigenin-7-gluc, and hesperidin, while P. biglobosa bark contains chlorogenic acid, catechin, caffeine, epicatechin, and cichoric acid. In the DPPH assay, the lowest scavenging capacities were 1.8 ± 0.21 mmol AAE/mg of dry extract (V. paradoxa, 97% ethanol) and 11.43 ± 0.208 mmol AAE/mg of dry extract (P. biglobosa, 50% ethanol). Similarly, for ABTS, the lowest scavenging capacities were 0.9726 ± 0.03952 mmol AAE/mg of dry extract (V. paradoxa, methanol with 1% HCl) and 1.3 mmol AAE/mg of dry extract (P. biglobosa, 97% ethanol), indicating strong antioxidant capacity. In the FRAP assay, both species reached a maximum reducing power of 2.39 mMol AAE/mg of dry extract (methanolic extract for V. paradoxa; methanol + 1% HCl for P. biglobosa). For APM, the 97% ethanolic extracts again showed the highest total antioxidant capacities: 31.78 ± 1.481 mMol AAE/mg (V. paradoxa) and 31.21 ± 0.852 mMol AAE/mg (P. biglobosa). The stem bark extracts of both V. paradoxa and P. biglobosa were revealed to be harmless in the Artemia salina as well as the rat model. The extracts of V. paradoxa as well as P. biglobosa exerted a stronger gastroprotective effect than omeprazole, a commonly used reference molecule. Conclusions: These extracts, rich in compounds exhibiting strong antioxidant, anti-inflammatory, and gastroprotective activities, surpassed omeprazole in ulcer protection in rat models. Their safety was confirmed in both Artemia salina and rodent assays. Future studies will explore their immunomodulatory, antiproliferative activities in vitro and in vivo and, specifically, the efficacy of isolated compounds in gastric adenocarcinoma models to assess these plants’ anticancer potential and elucidate their underlying mechanisms. Full article

Background/objectives: Melanoma is one of the deadliest forms of malignant cancers; ultraviolet radiation exposure together with genetic mutations, such as BRAF, represent the main risk factors and are involved in metastatic dissemination. Previous studies demonstrated the anti-emetic and anti-proliferative effects of the flavonoid genistein and the turmeric curcumin in cancers. This study aimed at investigating the anticancer effects of curcumin, genistein and their association in melanoma cells. Methods: Human A375 and CHL-1 cell lines were cultured and treated with different concentrations of curcumin or genistein or curcumin + genistein for 24 h according to IC50. Results: Genistein and curcumin induced cell death, as demonstrated by MTT assay and FDA/PI staining. The anti-apoptotic protein Bcl-2 was significantly reduced after curcumin and curcumin + genistein treatment, but unexpectedly not with genistein alone. Curcumin and genistein significantly increased DNA fragmentation, thus indicating apoptosis induction. Moreover, comet assay confirmed that curcumin and genistein stimulated cell death, as quantified by measuring the displacement between the ‘comet head’ and the resulting ‘tail’. FAK protein expression was significantly reduced by genistein and curcumin in CHL-1 cells and after the treatment with genistein + curcumin in the most aggressive A375 cells. These anti-proliferative effects were confirmed by scratch assay and phospho-p38 reduction. Moreover, both curcumin and genistein alone and in association inhibited cell adhesion, thus indicating that these nutraceuticals could reduce invasion and metastasis. Conclusion: The obtained results provided new insights for the anticancer effects of genistein and curcumin, which could be used to improve therapeutic adherence and drug response. Full article

In this study, extraction conditions were optimized to maximize the biological activities of extracts obtained from Paralepista flaccida, an edible mushroom species. Extraction processes were carried out using an ultrasonically assisted system, and two different optimization approaches were used as follows: Response Surface Methodology (RSM) and Artificial Neural Network–Genetic Algorithm (ANN-GA). The antioxidant potentials of the optimized extracts were evaluated using DPPH, FRAP, TAS, TOS, and OSI parameters; anticholinesterase activities were measured against AChE and BChE enzymes; and antiproliferative activities were investigated in A549, MCF-7, and DU-145 human cancer cell lines. In addition, phenolic contents were determined by LC-MS/MS analysis. The findings revealed that the extracts obtained by the RSM method exhibited a superior biological profile compared to ANN-GA extracts in terms of antioxidant, anticholinesterase, and antiproliferative activities. The high cytotoxicity observed, particularly in the MCF-7 line, supports the anticancer potential of this extract. These results demonstrate that optimization strategies are crucial for increasing not only extract yield but also biological functionality. Full article

Continuing our search for bioactive compounds in species from the Juncaceae family, we investigated Juncus tenuis. The structures of five previously undescribed phenanthrenes—tenuins A–E (1–5)—and 14 known phenanthrenes (6–19), along with other components, were isolated and characterized using nuclear magnetic resonance and high-resolution mass spectrometry measurements. The antiproliferative activity of all of the isolated phenanthrenes was evaluated against the human colorectal adenocarcinoma cell lines COLO 205 (doxorubicin-sensitive) and COLO 320 (doxorubicin-resistant), as well as a non-tumorigenic human fibroblast cell line (CCD-19Lu), using the MTT viability assay. Diphenanthrenes 4, 5, and 19 showed the most potent antiproliferative effects, with IC₅₀ values ranging from 7.60 to 17.32 μM; however, these compounds lacked selectivity toward cancer cells. To explore potential chemosensitizing properties, the synergistic effects of the phenanthrenes with the anticancer drug doxorubicin were also examined in the COLO 320 cells. Notably, compound 2 exhibited very strong synergism (CI = 0.021), indicating a highly potent interaction. These findings highlight J. tenuis as a valuable source of phenanthrenes and demonstrate the synergistic anticancer potential of natural phenanthrenes with doxorubicin, offering promising prospects for overcoming multidrug resistance in colorectal cancer therapy. Full article

Restenosis is the main cause of failure after stent implantation during angioplasty. The localized, sustained delivery of an antirestenotic drug may reduce smooth muscle cell (SMCs) proliferation and thereby limit neointimal hyperplasia. The aim of this study was to develop degradable sirolimus-eluting polymer coatings that can be applied on bioresorbable polymer-based scaffolds via an ultrasonic coating system. This is a novel approach because the detailed analysis of the coating procedure on bioresorbable polymeric scaffolds with the use of an ultrasonic system has not been reported thus far. It has been observed that the ultrasonic technique facilitates formation of a smooth coating, well-integrated with the scaffold. However, the drug dose is affected by the concentration of the coating solution and the number of layers. Therefore, these parameters can be used for tailoring the drug dose and release process. Although all types of the developed coatings provided sirolimus elution for at least 3 months, a more uniform, diffusion-controlled release profile was observed from coatings obtained from the 1.0% polymeric solution. The released drug showed antiproliferative activity against vascular SMCs, without any hemolytic or thrombogenic effects. The results of the study may be advantageous for further progress in the development and medical translation of polymeric vascular scaffolds with antirestenotic activity. Full article

Chilean Schinus molle has been used in traditional medicine for effects such as antibacterial, antifungal, anti-inflammatory, analgesic, antiviral, antitumoral, antioxidant, antispasmodic, astringent, antipyretic, cicatrizant, cytotoxic, diuretic, among others. In this study, we evaluated the pharmacological potential of Schinus molle seed essential oil extract (SM_EO) through in vitro and in silico approaches. In vitro, the antioxidant potential was analyzed, and antitumor activity was evaluated in non-tumor and human epithelial tumor cell lines. Caenorhabditis elegans was used as a model for evaluating toxicity, and the chemical composition of the SM_EO was analyzed using gas chromatography–mass spectrometry. The oil contained four major monoterpenes: α-phellandrene (34%), β-myrcene (23%), limonene (13%), and β-phellandrene (7%). Based on quantum mechanical calculations, the reactivity of the molecules present in the SM_EO was estimated. The results indicated that α- phellandrene, β-phellandrene, and β-myrcene showed the highest nucleophilic activity. In addition, the compounds following these as candidates for antioxidant and antiproliferative activities were α-phellandrene, β-phellandrene, ρ-cymene, sabinene, caryophyllene, l-limonene, and α-pinene, highlighting β-myrcene. Based on ADME-Tox properties, it is feasible to use these compounds as new drug candidates. Moreover, the antibacterial activity MIC value obtained for B. cereus was equivalent to 2 μg/mL, and for Y. enterocolitica, S. enteritidis, and S. typhimurium, the MIC value was 32.5 μg/μL. SM_EO could selectively inhibit the proliferation of human epithelial mammary tumor MCF7 cells treated with SM_EOs at 64 and 16 ug/mL—a significant increase in BCL-2 in a dose-dependent manner—and showed low toxicity against Caenorhabditis elegans (from 10 to 0.078 mg·mL⁻¹). These findings suggest that SM_EO may be a potential source of bioactive compounds, encouraging further investigation for applications in veterinary medicine, cosmetics, and sanitation. Full article

Triple-negative breast cancer (TNBC) is a highly aggressive and therapeutically challenging subtype of breast cancer due to its lack of estrogen receptors, progesterone receptors, and HER2 (Human epidermal growth factor receptor 2) expression, which severely limits available treatment options. Recently, Simvastatin—a widely used HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitor for hyperlipidemia—has garnered interest for its potential anticancer effects. This study investigates the therapeutic potential of Simvastatin in triple-negative breast cancer (TNBC). The results demonstrate that Simvastatin significantly inhibits the proliferation of TNBC cells, particularly MDA-MB-231, in a dose- and time-dependent manner. Mechanistically, Simvastatin primarily induces G1 phase cell cycle arrest to exert its antiproliferative effects, with no significant evidence of apoptosis or necrosis. These findings support the potential repositioning of Simvastatin as a therapeutic agent to suppress TNBC cell growth. Further analysis shows that Simvastatin downregulates cyclin-dependent kinase 4 (CDK4), a key regulator of the G1/S cell cycle transition and a known marker of poor prognosis in breast cancer. These findings highlight a novel, apoptosis-independent mechanism of Simvastatin’s anticancer action in TNBC. Importantly, given that many breast cancer patients also suffer from hyperlipidemia, Simvastatin offers dual therapeutic benefits—managing both lipid metabolism and tumor cell proliferation. Thus, Simvastatin holds promise as an adjunctive therapy in the treatment of TNBC and warrants further clinical investigation. Full article

Background: Metastatic melanoma is a highly aggressive malignancy with poor prognoses and frequent resistance to conventional chemotherapy. Approximately 40% of melanoma cases carry the BRAF^V600E mutation, for which vemurafenib, a selective BRAF^V600E inhibitor, is approved. Despite initial clinical benefits, vemurafenib often leads to drug resistance and relapse, highlighting the need for improved therapeutic strategies. Objectives, methods: In this study, we designed, synthesized, and characterized five novel vemurafenib analogs—RF-86A, RF-87A, RF-94A, RF-94B, and RF-96B—with the aim of enhancing anti-proliferative and anti-metastatic effects against human melanoma cells. Results: All compounds induced apoptosis in BRAF^V600E-mutated A375 cells, with RF-86A displaying the lowest IC₅₀ value among the series, comparable to that of vemurafenib. Moreover, RF-86A exhibited the highest selectivity index, as determined using HEK293T cells as a non-tumorigenic control. Additionally, migration assays and gelatin zymography demonstrated that the analogs, unlike vemurafenib, significantly inhibited matrix metalloproteinases MMP-2 and MMP-9, key enzymes involved in tumor invasion and metastasis. Conclusions: These findings suggest that structural modifications to the vemurafenib scaffold may improve therapeutic efficacy and offer a promising strategy to overcome acquired resistance. Full article

Cancer is one of the most lethal diseases of this century. Unfortunately, many anticancer agents have harsh side effects or fail to work against cancer any longer due to tolerance. Dihydropyrimidinones are promising structures containing a pyrimidine ring. Targeting Eg5 is their most well-known activity. Inhibition of this enzyme gives them the privilege of strong cytotoxic activity with less side effects. Phenyl ring is a group that can be found in the majority of organic molecules and possesses preferable pharmacokinetic and pharmacodynamic characteristics. This review studies DHPM derivatives that are substituted with a phenyl ring and possess antiproliferative ability by inhibiting Eg5. The compounds are able to inhibit different cancer cell lines, and some are more potent than the standard drug. The biological results are in accordance with the docking studies. Full article

Background: The increased incidence of malignant melanoma is observed in patients with Parkinson’s disease. Methods: The anti-proliferative effects of carbidopa and rasagiline on four human malignant melanoma cell lines (A375, SK-MEL28, FM55P and FM55M2) were determined in MTT assay. The interaction profiles of rasagiline in combinations with cisplatin (CDDP) and mitoxantrone (MTX) in four human melanoma cell lines (A375, SK-MEL28, FM55P and FM55M2) were assessed by means of the isobolographic analysis in the MTT test; Results: Rasagiline, but not carbidopa, produced clear-cut anti-proliferative effects on various melanoma cell lines. The median inhibitory concentrations (IC₅₀ values) of rasagiline in the MTT were 280.69 µM for A375, 402.89 µM for SK-MEL28, 349.44 µM for FM55P, and 117.45 µM for FM55M2, respectively. The experimentally-derived selectivity index for rasagiline ranged from 8.22 to 28.18. Flow cytometry assay revealed, in two melanoma cell lines (FM55P and A375), a significant increase in the number of cells in the G0/G1 (up to 76.48% and 75.46% for cell lines, respectively), accompanied by a decrease in the percentage of cells in the S phase (decrease to 9.91% and 10.83% for cell lines, respectively), which may indicate potential cytostatic properties of rasagiline. The combinations of rasagiline with CDDP (at the fixed-ratio of 1:1) exerted either antagonistic interactions (p < 0.05) in the A375 and SK-MEL28, or additive interactions, with a tendency toward antagonism in the FM55P and FM55M2 cell lines in the MTT test. In contrast, the combinations of rasagiline with MTX (ratio of 1:1) produced either synergistic interaction (p < 0.05) in the FM55P cell line or additive interactions with a tendency toward synergy in the FM55M2, SK-MEL28, and A375 cell lines in the MTT test. Conclusions: Rasagiline combined with MTX exerted the most desirable synergistic interactions in relation to the anti-proliferative effects in four malignant melanoma cell lines, as assessed isobolographically. In contrast, rasagiline should not be combined with CDDP during the treatment of malignant melanoma due to the antagonistic interactions in the MTT assay. Full article