Current Medicinal Chemistry - Volume 32, Issue 33, 2025

Oral cancers, with oral squamous cell carcinoma (OSCC) as the predominant type, have a significant impact on morbidity and mortality rates. Therefore, targeting the NFκB pathway shows promise in cancer therapy.

This study investigated the impact of two NFκB inhibitors, LY2409881 and MLN4924, on cell proliferation, apoptosis susceptibility, and in vivo tumorigenesis in OSCC cell lines CAL27 and SCC15.

The results revealed that both LY2409881 and MLN4924 effectively suppressed cell proliferation, induced apoptosis, and arrested the cell cycle at the G2/M phase—a phenomenon likely associated with the NFκB pathway. Furthermore, MLN4924 demonstrated potent inhibitory effects on cell proliferation at low μM concentrations, surpassing the effectiveness of LY2409881 as an inhibitor (All results: p<0.05).

These findings highlight the potential of LY2409881 and MLN4924 as novel therapeutic agents for OSCC, thereby offering new insights for the clinical management of this condition.

PTK7 (Protein Tyrosine Kinase 7), a member of the receptor protein tyrosine kinase family, was originally discovered in colon cancer cells. It plays a pivotal role in numerous developmental and physiological processes, particularly in the regulation of cell polarity. Despite accumulating evidence of PTK7's significant influence on tumor development, a comprehensive pan-cancer analysis of PTK7 has yet to be conducted.

We conducted a comprehensive analysis of PTK7's expression, prognostic value, and mutational patterns across various tumor types. We further explored the correlations between PTK7 expression and tumor stemness, immune-related genes, immune scores, and immune cell infiltration.

Enrichment analysis revealed PTK7's critical involvement in pan-cancer functions and processes, including the WNT pathway, Epithelial-Mesenchymal Transition (EMT), and cell polarity regulation. Additionally, we validated PTK7's expression in gastric cancer via immunohistochemistry.

Our study indicates that PTK7 holds promise as an ideal pan-cancer biomarker due to its involvement in tumor progression and tumor immunity.

The effectiveness of therapy is strongly impacted by the resistance of lung cancer cells to cisplatin. The objective of this research is to characterize the impact of ailanthone on cisplatin resistance in non-small cell lung cancer (NSCLC) and examine any potential in vivo and in vitro molecular pathways.

Following treatment of A549/DDP cells with ailanthone and cisplatin, cell survival and apoptosis were measured using flow cytometry and Cell Counting Kit-8 (CCK8) assays, respectively. mRFP-GFP-LC3 adenovirus transfection was used to track autophagy, and protein expression levels were analyzed by western blotting. Hematoxylin and eosin (H&E) staining was used after the organs of the mice were removed for in vivo investigations. In A549/DDP cells, ailanthone and cisplatin together induced autophagy and apoptosis in a dose and time-dependent manner (p< 0.05). After receiving combined treatment with ailanthone and cisplatin, the expression levels of cleaved caspase-3, Bcl-2, cleaved PARP, Beclin 1, LC3B-II were considerably elevated by inhibiting the PI3K/AKT/mTOR signaling pathway.

Our findings show that ailanthone, without causing adverse effects in vivo, greatly suppressed the growth of A549/DDP-grafted tumors and improved the anti-tumor efficaciousness of cisplatin.

According to this study, ailanthone may increase sensitivity to cisplatin and promote autophagy and death in NSCLC A549/DDP cells through the signaling pathway of PI3K/AKT/mTOR.

Skin melanoma is a potentially lethal cancer and ranks as the 17^th most common cancer worldwide. Overcoming resistance to advanced-stage melanoma is a significant challenge in its treatment. Parthenolide (PAR) is recognized as a potent anticancer small molecule, yet its potential in treating melanoma is poorly investigated.

Our objective was to investigate the apoptotic and anti-metastatic properties of PAR against the A2058 melanoma cells in vitro.

This study employed various assays, such as cytotoxicity, apoptosis, cell cycle analysis, reactive oxygen species (ROS) production, mRNA expressions, western blotting, gelatin zymography, and scratch assay. The synergy between PAR and dacarbazine, a chemotherapy drug for treating skin cancer, was also assessed.

Our study revealed that PAR significantly reduced the viability of A2058 cancer cells, demonstrating greater potency against cancer cells compared to normal L929 cells (IC50: 20 µM vs. 27 µM after 24 h). PAR increased ROS production, elevated mRNA expression of pro-apoptotic Bax and NME1 genes, and decreased expression of the MITF gene. PAR induced apoptosis and cell cycle arrest in A2058 cells, as evidenced by the increased proportion of cells in the late apoptotic phase and sub-G1 cell cycle arrest. MMP-2 and MMP-9 mRNA and protein expressions, gelatinase activity, and the migration of A2058 cells were also decreased by PAR, suggesting its potential to suppress cancer cell invasion.

These results, along with the synergic effect with dacarbazine, indicated that PAR may have the potential to be a therapeutic drug for melanoma by triggering apoptosis and suppressing invasion and migration.

Resveratrol (RES) is a phytochemical bioactive compound with suggested therapeutic benefits.

The current work aimed to evaluate the anti-inflammatory effect of RES against palmitate (PA) induced lipotoxicity in raw 264.7 macrophages cell line.

The cells viability was assessed by lactate dehydrogenase assay. Then the effects of RES and PA on nitric oxide (NO), triglyceride (TG) content, and cytokines release were studied. The effect of RES and PA on the treated cells bioenergetics and redox status was evaluated via different assays.

The results showed that at doses of 10 and 20 µM, RES dramatically increased the vitality of PA-exposed macrophages with dramatic significant decrease in the release the proinflammatory cytokines TNF-α, HMGB-1, IL-1β, and IL-6 and their coding genes expression with marked improvement in the cells phagocytic capacity. In addition, RES dramatically lowered the levels of NO and TG in PA-stimulated macrophages. In addition, PA markedly decreased mitochondrial complexes I and III activities with decreased mitochondrial membrane potential and lowered ATP production with induction of oxidative stress. RES was shown to mitigate the effect of PA on macrophages bioenergetics and the oxidative damage and counteracted PA effect on genes linked to oxidative damage, such as Nrf2, Ho-1, NF-κB p65, SOD1, and SOD2.

RES could reduce PA-induced lipotoxicity in macrophages via enhancing their viability and counteracting the excess release of cytokines through alleviating PA-induced bioenergetic disruption and oxidative damage with a suggested positive impact of RES on obesity related illnesses caused by triggered cellular inflammation.

Elevated glucose can have a detrimental effect on the function and healing process of periodontal cells in inflammatory conditions. Hesperidin (HPN), a bioflavonoid found abundantly in citrus fruits, has numerous biological benefits, including regenerative and anti-inflammatory properties. The current in vitro study aimed to assess the impact of HPN on the proliferation, wound healing, and functionality of periodontal cells in optimal and elevated glucose conditions.

Human periodontal ligament cells (HPDLCs) were cultured in optimal glucose (1g/L) (OG) and high glucose (4.5 g/L) (HG) conditions. XTT, wound healing, ALP, and calcium release assays were conducted with or without HPN in the culture media.

The statistical analysis revealed that adding different concentrations of HPN (2, 4, 10, or 100 µM) had no significant effect on the viability of HPDLCs under both OG (p=0.436) and HG conditions (p=0.162) compared to the control. However, in the HG condition, the addition of 100 µM HPN resulted in a statistically significant increase in wound closure (p=0.003). Furthermore, in the HG condition, the addition of 100 µM HPN significantly increased ALP activity in the non-osteogenic media (p=0.001) and significantly increased calcium release within the osteogenic media (p=0.016).

The findings of this study suggest that HPN provides beneficial effects, facilitating repair and mineralization in HPDLCs under HG conditions.

This study involves several recently synthesized Schiff base derivatives of hydrochlorothiazide (3a-3e), characterized by advanced spectroscopic techniques including Fourier transform infrared (FTIR), ¹H-, ¹³C-NMR (Nuclear magnetic resonance), and High-resolution electrospray ionization mass spectrometry (HR-ESI-MS).

Hydrochlorothiazide (HCTZ, 2 mM) was mixed with 2 mM aldehydes in ethanol (20 mL) in the presence of glacial acetic acid, and the product was stirred with the help of a magnetic stirrer under the specified conditions. Keeping in mind the importance of imine derivatives against DPPH radical, the synthesized compounds were evaluated for antioxidant activity (in vitro) using DPPH assay and diuretic activity (in vivo) by Lipschitz method. All derivatives demonstrated notable antioxidant activity, exhibiting 52-86% inhibition.

The compounds 3a-3e also displayed remarkable diuretic effects in an in vivo model at a dose of 50 mg/kg. The computational studies of all the newly synthesized compounds were interpreted for the diuretic activity at the molecular level against human renal outer medullary potassium channel (ROMK1, PDB: ID) protein present on the nephron involved in diuresis indicating all compounds showed significant interactions at all receptors.

As the derivatives were more active than drugs in some regards; therefore, these derivatives will be beneficial and open new windows for research and additional pharmacological screening could be planned as part of the project's extension.