Anti-cancer agents in medicinal chemistry最新文献

Introduction: Breast cancer remains a leading cause of cancer-related mortality in women, primarily due to Breast Cancer Stem Cells (BCSCs), which contribute to tumor progression, metastasis, and resistance to conventional therapies. Vitex negundo Linn. (VN), a medicinal plant abundant in polyphenolic flavonoids such as luteolin (LT), has previously demonstrated anticancer potential. This study investigates the active metabolite profiling of VN targeting BCSCs and evaluates LT's therapeutic potential through in vitro and in silico approaches.

Methods: An integrated network pharmacology and computational approach identified VN metabolites targeting BCSCs, including CDK1, cyclin B1/B2, TOP1, GSK-3β, and PARP1. Mutational analysis in MCF-7 cells followed by luteolin (LT) treatment assessed its impact on stemness, gene expression, ROS generation, cell cycle, and apoptosis. Molecular docking and dynamics confirmed LT's strong binding to CDK1/Cyclin B.

Results: LT significantly reduced the properties of BCSCs by inhibiting the CDK1/Cyclin B complex and downregulating associated genes. It induced ROS-mediated apoptosis and altered cell cycle distribution, notably increasing G1 and S phase populations. Molecular modeling confirmed strong binding of LT to CDK1/Cyclin B, suggesting disruption of cell cycle regulation and self-renewal.

Discussion: LT binds strongly to CDK1 and Cyclin B proteins, suppressing their activity in MCF-7 cells. This disrupts gene expression linked to BCSC self-renewal, induces apoptosis, and causes cell cycle arrest. LT targeting CDK1/Cyclin B complexes offers promising therapeutic potential for future clinical development against BCSCs.

Conclusion: LT from VN shows promise as a therapeutic agent targeting CDK1/Cyclin B in ER+ breast cancer stem cells, supporting its potential for clinical development.

Introduction: Lapatinib, a novel targeted anti-tumor drug in clinical use, demonstrates notable potential for liver cancer treatment. However, its mechanism of action in liver hepatocellular carcinoma (LIHC) remains poorly understood. This investigation sought to clarify the function of secreted phosphoprotein 1 (SPP1) in LIHC and investigate the anti-tumor effects of lapatinib on SPP1 expression.

Methods: We analyzed data from normal liver and LIHC specimens obtained from The Cancer Genome Atlas (TCGA) and the GSE6764 dataset using R version 4.2.1. SPP1 protein expression in LIHC patients and its impact on patient prognosis were evaluated. Western blotting evaluated lapatinib-induced alterations in SPP1 protein levels in hepatoma cells. Cell Counting Kit-8 (CCK-8) assays measured lapatinib's impact on hepatoma cell growth and proliferation.

Results and Discussion: SPP1 level was notably elevated in LIHC specimens versus normal liver tissues (P < 0.01). The survival outcomes were notably inferior in cases displaying elevated SPP1 levels versus those with reduced levels (P < 0.05). CCK-8 analyses demonstrated that a decrease in SPP1 expression leads to a significant inhibition of growth and proliferation in the LIHC cell line HepG2, while lapatinib can inhibit the survival of liver cancer cells. Western blotting analyses revealed that lapatinib treatment reduced SPP1 expression in HepG2 cells, increased the ratio of BAX/Bcl2, and triggered apoptosis in cells.

Conclusion: These observations demonstrate that the expression of SPP1 is associated with disease progression and survival in patients with LIHC. Lapatinib exerts its anti-tumor effects in LIHC by downregulating SPP1 expression and promoting apoptosis in hepatoma cells.

Introduction: The polo-like kinase-1 (PLK1) plays a significant role in cell cycle regulation and proliferation; upon dysregulation, PLK1 activates different oncogenic pathways that lead to breast cancer. Therefore, targeting the PLK1 protein on the kinase domain prevents the possibility of tumor development.

Methods: A machine learning model was developed to screen small molecules against PLK1 using a cancer bioassay dataset. The binding affinity and structural integrity of the complex were assessed using molecular docking and dynamic studies. In vitro evaluation was then performed for the screened compound against the SKBR3 cell line.

Results: The research findings highlighted the silymarin flavonoid to have a greater binding energy with PLK1 (-9.2 Kcal/mol) than other molecules (above -8.5 Kcal/mol). Additionally, the molecular dynamics simulation showed silymarin to be more stable, less flexible, and more compact with PLK1. Further, the binding free energy revealed silymarin to be more stable with PLK1 (-13.25 kcal/mol) than volasertib (-2.87 kcal/mol). The IC50 value of silymarin was found to be 95.76 μg/mL, inducing apoptosis on the SKBR3 cell line.

Discussion: Despite PLK1 being predicted as a potential oncogenic target, the treatment choices were limited. A cheminformatics approach was utilized for screening inhibitors against PLK1. The in silico and in vitro evaluations indicated that silymarin effectively inhibited the PLK1 protein in breast cancer.

Conclusion: These research findings established silymarin as a potential alternative drug targeting PLK1, which is highly expressed in HER2-positive breast cancer, and modulates the oncogenic processes not just in breast cancer, but also in other cancers.

Introduction: Cynara scolymus (Artichoke) is a medicinal plant of significant pharmacological importance, rich in phenolic acids and flavonoids. Therefore, the current research aimed to assess the anticancer properties and potential molecular pathways of Artichoke extract utilizing an HCC rat model induced by Carbon tetrachloride (CCl4).

Methods: Fifty male albino rats were randomly allocated into five groups: a negative control group (NCG), a positive control group (PCG), an Artichoke protective group (APG), an Artichoke treatment group (ATG), and a cisplatin treatment group (CTG). Blood and liver tissue samples were collected for biochemical and molecular analyses at the end of the experiment. We also performed histological examination of the liver and an immunohistochemistry assay for the significant tumor marker alpha-fetoprotein (AFP) and Nrf-2.

Results: Our data showed higher liver enzymes in PCG compared with NCG. Additionally, we also found a significant decrease in Nrf-2, CAT, SOD, caspase 3, and caspase 9 levels and up-regulation of AKT and PI3K in the PCG relative to the negative control group. On the other hand, our findings suggest that Artichoke extract holds protective and therapeutic potential for effectively treating HCC induced by CCl4, especially in the APG.

Discussion: Our findings imply that the impressive antioxidant, apoptotic, and anticancer capabilities of Artichoke extract are due to the combination of the phenolic acids and flavonoids. Consequently, it is advisable to incorporate artichoke as a dietary supplement for individuals with chronic liver conditions.

Conclusion: We conclude that the up-regulation of the Caspase 3 and Caspase 9 pathways and the suppression of PI3K/AKT signalling pathways may be the mechanisms behind the anti-tumor actions of artichoke extract.

Introduction: Estrogen receptor (ERα) is known to be a legitimate therapeutic target for the treatment of ER-positive breast cancer. Although selective estrogen receptor degraders (SERDs) like fulvestrant suppress ER signaling, their limited bioavailability challenges efficacy. Additionally, activating mutations in the ERα mediate resistance to endocrine therapy.

Methods: To elucidate the structural activity relationship within a chromene-based scaffold, we conducted pharmacophore mapping and Gaussian field-based 3D QSAR modelling. The most active analogue was docked into the ERα ligand binding domain (PDB ID: 6V8T) and then subjected to molecular dynamics simulations and molecular mechanics generalized born surface area (MM/ GBSA) binding-free energy calculations.

Results: The pharmacophore mapping produces a five-point hypothesis, of which HHHRR_1 achieved the highest survival score (6.423) with a fitness score close to 3. Using HHHRR_1, a Gaussian Field-based 3D QSAR model with strong internal predictivity (cross-validated q2 is 0.8) and an excellent external validation was developed (r2 is 0.94). Compound 18 demonstrated stable binding in the ERα pocket with a ΔGbind MM/GBSA value of -67.03 kcal/mol, outperforming fulvestrant with a ΔGbind MM/GBSA of -64.76 kcal/mol. These findings suggest compound 18 engages critical ERα interactions more effectively with the target.

Discussion: The integrated modelling approach, like pharmacophore mapping, 3D QSAR, docking, and molecular dynamics, elucidated molecular characteristics essential for potent ERα degradation. Compound 18, having superior binding affinities, implies that optimizing these features on a chromene scaffold can yield new oral SERDs with enhanced therapeutic potential.

Conclusion: Based on the results of pharmacophore mapping, docking, molecular simulation, and 3D QSAR studies, we have designed a new set of chromene scaffold-based derivatives as potent SERDs along with their predicted activity.

Background: Solid lipid nanoparticles (SLNs) are submicron carriers with great promise in revolutionizing cancer therapy. They offer a potential solution to the side effects of conventional anticancer drugs, such as systemic toxicity and non-specific distribution. Taxanes, a widely used class of anticancer agents, have been increasingly incorporated into nano-lipid formulations (NLFs) to enhance their therapeutic index.

Objective: Designing optimal SLN formulations with enhanced drug loading capacity (DLC%), entrapment efficiency (EE%), and controlled drug release profiles is a significant challenge in pharmaceutical nanotechnology. This review, the first of its kind, systematically explores the key factors influencing EE%, DLC%, and the release behavior of Taxane-loaded SLNs. It provides a comprehensive and updated perspective, equipping you with the latest knowledge in this field.

Methods: This narrative review adopts a comprehensive approach to examine the formulation variables that affect EE%, including lipid type, drug properties, surfactants, co-surfactants, emulsifiers, and conjugates. It also outlines the critical parameters that influence drug release, such as particle size, co-loaded drugs, types of lipids and emulsifiers, surface modifiers, release media, and environmental conditions, including pH. The review process involved thoroughly analyzing existing literature and studies in pharmaceutical nanotechnology.

Results: Numerous studies demonstrate that EE% is significantly affected by the physicochemical properties of both the drug and lipid matrix and the choice and concentration of surfactants (e.g., Poloxamer, Tween-80, Solutol HS-15, lecithin). Certain modifications, such as conjugation with Hyaluronic acid, Chitosan derivatives, and PEGylation, tend to lower EE% but improve targeted release. Incorporation of compounds like α-lipoic acid, Ketoconazole, or co-loaded PTX and DTX results in a slower drug release profile. Conversely, siRNA incorporation often accelerates drug release. The release rate is also modulated by environmental pH and the nature of the lipid carriers. Ideal SLN formulations demonstrate high EE% and DLC% along with sustained and controlled release of Taxanes.

Conclusion: Multiple formulation and environmental factors influence EE%, DLC%, and the drug release behavior of Taxane-loaded SLNs. Understanding these variables is not just important, but it is the key to rationalizing effective and stable nano-lipid formulations in cancer therapy. It is a fascinating and crucial area of study that demands our attention.

Introduction: Prostate cancer is a leading cause of cancer-related mortality in men worldwide, and the treatment of metastatic castration-resistant prostate cancer (mCRPC) remains a major clinical challenge. CD24, a glycosylated cell surface protein, plays a critical role in tumor progression and immune evasion. This review focuses on the role of CD24 in prostate cancer pathogenesis, particularly its interaction with mutant p53, and explores potential therapeutic implications.

Methods: Through a systematic search of the PubMed, Web of Science, and Embase databases (2015-2025), using the following structured search terms: (CD24 OR "CD24 antigen") AND ("prostate cancer" OR "prostatic neoplasms") AND ("mutant p53" OR "TP53 mutation") AND ("targeted therapy" OR immunotherapy), relevant studies were identified and screened according to PRISMA guidelines.

Results: CD24 overexpression was significantly associated with high Gleason scores, metastasis, and poor prognosis. Mechanistically, CD24 promotes tumor progression by destabilizing p53 through the disruption of ARF-NPM interactions and by synergizing with mutant p53. Preclinical studies indicate that therapies targeting CD24, such as CAR-T cells and nanoparticle-based drug delivery systems, demonstrate potent anti-tumor effects.

Discussion: The CD24-p53 axis is amplified in mCRPC and interacts with androgen receptor signaling, while tumor microenvironment factors further enhance treatment resistance.

Conclusion: CD24 and mutant p53 represent promising therapeutic targets in metastatic castration-resistant prostate cancer (mCRPC). Translating these targeting strategies into clinical practice may help overcome current therapeutic challenges and improve patient outcomes.

Breast cancer threatens the health of women worldwide. However, the use of chemotherapy for breast cancer is prone to generating side effects and drug resistance. Therefore, identifying natural compounds with anticancer activity is a better solution to the problem of drug resistance. Oleanolic acid (OA), a kind of pentacyclic triterpenoid, is widely studied and used in the field of oncology. It has biological activity against breast cancer and has few side effects on normal cells. OA can be used as a frame for chemical modification to synthesize new compounds for the development of new drugs. At present, some OA derivatives with anti-breast cancer biological activity have been proven clinically, while others have emerged as candidates. This review aims to provide a comprehensive understanding of the mechanisms of oleanolic acid and its derivatives on breast cancer from previous studies.

Introduction/objective: Radiotherapy (RT) is a standard cancer treatment that may be associated with problems such as ineffectiveness and side effects. This study investigated ginsenosides' radiosensitizing and radioprotective properties and their metabolites during RT.

Methods: This study searched databases including PubMed/MEDLINE, Scopus, Embase, and Cochrane Library for articles before January 28, 2025. After specifying the inclusion and exclusion criteria, relevant articles were imported into EndNote software and screened. Then, the data were recorded in tables and analyzed.

Results: After the screening process, 28 articles were included. Ginsenosides exhibited radioprotective effects in normal tissues by reducing oxidative stress, preserving mitochondrial integrity, enhancing DNA repair, modulating inflammatory pathways, and supporting hematopoiesis. Key compounds such as Rg1, Rg3, and Rh2 promoted tissue regeneration and protected against radiation-induced organ damage. In tumour cells, ginsenosides enhance radiosensitivity by increasing reactive oxygen species (ROS), disrupting mitochondrial function, inducing DNA damage and cell cycle arrest, and promoting apoptosis. They also inhibited tumour progression via nuclear factor kappa B (NF-κB) suppression and immune activation, reducing angiogenesis and metastasis. These dual actions suggest their potential to improve radiotherapy outcomes.

Discussion: Ginsenosides revealed dual roles as radioprotective and radiosensitizing agents, highlighting their potential in improving RT outcomes. However, the limited clinical data and lack of ginseng extract studies indicate the need for future clinical studies to establish optimal dosing, safety, and relevance for humans.

Conclusion: The findings of both in vivo and in vitro studies indicated that ginsenosides enhance RT and provide protective effects against the harmful impacts of ionizing radiation.

Introduction: The emergence of acquired resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors (EGFR-TKIs) presents a significant barrier to effective treatment in lung adenocarcinoma. This study investigates the antitumor efficacy of FN-1501 and its potential synergistic interaction with Almonertinib (Alm) to combat this resistance.

Methods: The impact of FN-1501 on lung adenocarcinoma and its synergistic effects with Almonertinib (Alm) were assessed through flow cytometry, Western blot analysis, CCK-8 assays, and clonogenic formation assays. Additionally, transcriptome analysis and network pharmacology were employed to elucidate the functional mechanisms by which FN-1501 may reverse EGFR-TKI acquired resistance.

Results: FN-1501 demonstrated the ability to inhibit cell proliferation, induce apoptosis, and arrest the cell cycle. The combination of Alm and FN-1501 restored sensitivity in resistant cell lines. Mechanistic investigations indicated that this combination triggered ferroptosis via the FOXO1-mediated upregulation of NCOA4. In vivo experiments showed that the Alm+FN-1501 combination significantly inhibited tumor growth compared to either treatment alone.

Discussion: These results provide compelling evidence that targeting ferroptosis pathways could be a viable approach to overcoming resistance to EGFR-TKIs. The FOXO1/NCOA4 axis emerges as a critical component in this process, enhancing our understanding of the mechanisms underlying resistance. While these findings are promising, further research is needed to evaluate toxicity, pharmacokinetics, and the applicability of this strategy in a broader context of resistance. Identifying predictive biomarkers could help refine patient selection for this treatment approach.

Conclusion: FN-1501 exhibits significant antitumor activity and, when combined with Alm, effectively reverses EGFR-TKI resistance by inducing ferroptosis, highlighting its potential for clinical application.