Glioblastoma (GB) therapy is challenged by tumor heterogeneity and multidrug resistance (MDR), highlighting the need for effective therapies. This study aimed to explore the combined anticancer effects of Sunitinib (SNB) and Fenofibrate (FEN) on U87 cells.

U87 cells were exposed to SNB, FEN, or their combination for 24 h, followed by evaluations of cell viability, migration, and clonogenic survival using MTT, scratch, and colony formation assays. Intracellular reactive oxygen species (ROS) were quantified via the 2^′, 7^′-dichlorofluorescein assay, while mitochondrial membrane potential (MMP) was assessed using JC-1 red/green fluorescence. Molecular docking was performed to investigate SNB and FEN interactions with multiple molecular targets, including topoisomerase II (TOP-II), c-Jun N-terminal kinase (JNK), histone deacetylase 2 (HDAC2), cyclooxygenase-2 (COX-2), matrix metalloproteinase-9 (MMP-9), cytochrome P450 3A4 (CYP3A4), glutathione peroxidase 4 (GPX4), glutathione S-transferase (GST), heme oxygenase-1 (HO-1), and 5-lipoxygenase (5-LOX).

The results demonstrated that both SNB and FEN significantly reduced U87 cell viability, migration, and clonogenic potential, with the combination treatment exhibiting synergistic cytotoxicity. SNB alone markedly increased ROS levels, while FEN, individually or in combination, reduced oxidative stress. Although SNB diminished mitochondrial membrane potential, co-treatment with FEN restored MMP values close to control levels. Docking analyses revealed that SNB displayed strong affinities for TOP-II, JNK, and HDAC2, whereas FEN preferentially interacted with MMP-9, COX-2, CYP3A4, and GPX4, suggesting complementary mechanisms targeting oxidative stress, inflammation, and programmed cell death regulation.

The combination of SNB and FEN represents a promising multi-targeted therapeutic approach against GB. SNB and FEN combination capable of modulating and reprogramming key molecular pathways involved in GB progression and MDR.

Prostate cancer (PCA) is the second most widespread cancer among men globally, with a rising mortality rate. Enzyme-responsive lipid nanoparticles (ERLNs) are promising vectors for the selective delivery of anticancer agents to tumor cells. The goal of this study is to fabricate ERLNs for dual delivery of gefitinib (GF) and simvastatin (SV) to PCA cells.

ERLNs loaded with GF and SV (ERLNGFSV) were assembled using bottom-up and top-down techniques. Subsequently, these ERLN cargoes were coated with triacylglycerol, and phospholipids and capped with chitosan (CS). The ERLNGFSV, and CS engineered ERLNGFSV (CERLNGFSV) formulations were characterized for particle size (PS), zeta potential (ZP), and polydispersity index (PDI). The biocompatibility, and cytotoxicity of the plain and GF plus SV-loaded ERLN cargoes were assessed using erythrocytes and PC-3 cell line. Additionally, molecular docking simulations (MDS) were conducted to examine the influence of GF and SV on succinate dehydrogenase (SDH), glutathione peroxidase-4 (GPX-4), and 5α-reductase (5α-RD).

These results showed that plain, ERLNGFSV, and CERLNGFSV cargoes have a nanoscale size and homogeneous appearance. Moreover, ERLNGFSV and CERLNGFSV were biocompatible, with no detrimental effects on erythrocytes. Treatment with GF, SV, GF plus SV, ERLNGFSV, and CERLNGFSV significantly reduced the viability of PC-3 cells compared to control cells. Particularly, the blend of GF and SV, as well as ERLNGFSV and CERLNGFSV augmented PC-3 cell death. Also, treating PC-3 cells with free drugs, their combination, ERLNGFSV, and CERLNGFSV formulations elevated the percentage of apoptotic cells. MDS studies demonstrated that GF and SV interact with the active sites of SDH, GPX-4, and 5α-reductase.

This study concludes that SVGF combination and ERLNs loading induce particular delivery, and synergism on PC-3 death through action on multiple pathways involved in cell proliferation, and apoptosis, besides the interaction with SDH, GPX-4, and 5α-RD. Therefore, GFSV-loaded ERLN cargoes are a promising strategy for PCA treatment. In vivo studies are necessary to confirm these findings for clinical applications.