Pharmacological Reports最新文献

Background: Glioblastoma (GBM) is the most aggressive and frequent primary malignant brain tumor and remains highly resistant to existing therapies. Snake-venom disintegrins possess potent anticancer activities, yet their pharmacological potential against GBM is not fully explored. In this work, we aimed to evaluate the therapeutic potential of the disintegrin CC8 from Cerastes cerastes snake venom, toward the development of a novel anti-GBM drug.

Methods: The effects of CC8 on the viability and proliferation of human GBM cell lines U87, U251, LN229, and LN18 were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and crystal violet assays. Apoptosis induction was examined by annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis of pro- and anti-apoptotic gene expression. The effect of CC8 on cell-extracellular matrix (ECM) interactions was evaluated through adhesion assays and integrin-blocking antibodies. GBM cell infiltration potential was further explored using cell invasion assays and spheroid-based migration models.

Results: CC8 significantly reduced the viability of U87, LN18, and LN229 cells and inhibited the proliferation of U87, whereas U251 cells showed resistance up to 200 nM. CC8 induced caspase-dependent apoptosis, as evidenced by downregulation of BCL2 apoptosis regulator (BCL2) and upregulation of BCL2-associated X, apoptosis regulator (BAX), caspase 3 (CASP3), and caspase 8 (CASP8) expression. CC8 also disrupted cell adhesion to fibrinogen (Fg) and fibronectin (Fn) through integrin interference. Furthermore, it markedly decreased GBM cell invasion and reduced U87 spheroid migration.

Conclusions: These findings identify CC8 as a promising venom-derived candidate for GBM drug development, with potential to improve therapeutic outcomes for this aggressive and treatment-resistant cancer.

Clinical trial number: Not applicable.

Background: The convergence of microbial infections and cancer risk in inflammatory skin diseases demands novel, multi-functional therapeutics. This challenge is exacerbated by the rise in antimicrobial resistance and the lack of approved drugs for pathogens like human adenovirus (HAdV).

Methods: Here, we investigated a series of isoxazole derivatives to identify lead candidates with combined antibacterial, antiviral, and anticancer properties for dermatological applications. The tests performed include antibacterial agar diffusion assay, antiviral quantitative suspension test, in silico and in vitro assays such as MTT, Rho-123, DCF-DA, Griess, as well as ELISA tests (Caspase-3, IL-6, TNF-α, COX), and detection of apoptosis in a microchip.

Results: Our study identified compound MO3 with significant antibacterial action against Staphylococcus aureus and the zoonotic pathogen Staphylococcus pseudintermedius. In antiviral assays, MO10 and MO7 demonstrated exceptionally high virucidal potency against HSV-1 (100-fold greater than the threshold) and AdV-5 (10-fold greater than the threshold), respectively, while remaining non-toxic to human fibroblasts. Critically, MO10 also exhibited multi-modal anticancer effects in melanoma, inducing NO-mediated apoptosis, reducing pro-inflammatory cytokines, and acting in strong synergy with doxorubicin to enhance its chemotherapeutic effect.

Conclusion: In conclusion, this work validates specific isoxazole derivatives as highly promising candidates for development: MO3 for resistant bacterial infections, MO7 for otherwise untreatable adenovirus infections, and MO10 as a dual-action agent against HSV-1 and an adjunct to melanoma chemotherapy.