Chemosensitization and Molecular Docking Assessment of Dio-NPs on Resistant Breast Cancer Cells to Tamoxifen

Background: Diosgenin, a powerful compound found in fenugreek and Dioscorea villosa, has diverse pharmacological effects. This study examines the anticancer potential of diosgenin nanoparticles (Dio-NPs) against DMBA-induced breast cancer in mice in combination with tamoxifen. Methods: In the current investigation, characterization of Dio-NPs was performed, including their size, shape, zeta potential, UV-vis, and FT-IR spectra. Dio-NPs (120 mg/kg) and tamoxifen (2 mg/kg) were given to mice with DMBA-induced breast cancer, either alone or in combination, over 4 weeks. We measured inflammatory and oxidative stress markers, as well as gene expressions related to apoptosis, using ELISA and qRT-PCR. Additionally, molecular docking studies were conducted to assess the binding affinity of diosgenin with specific proteins. Molecular dynamics simulations were conducted on CDK4, AKT, and CDK6 proteins with diosgenin using GROMACS. The systems were solved, neutralized, and equilibrated under NVT and NPT ensembles. Simulations ran for 100 ns, and trajectories were analyzed for RMSD, RMSF, RG, SASA, and hydrogen bonds. Results: The IC50 of Dio-NPs against MCF-7 cells was 47.96 ± 1.48 µg/mL. Dio-NPs had a zeta potential of −21.8 ± 0.6 mV and a size of 56.85 ± 3.19 nm and were uniform and spherical. The LD50 of Dio-NPs was 2400 mg/kg. DMBA exposure increased WBCs, inflammatory markers, oxidative stress, and gene expression of CDK2, CDK4, CDK6, and Akt, while reducing Hb%, RBCs, PLTs, GSH, superoxide dismutase, and catalase levels. Dio-NPs and tamoxifen, both alone and combined, significantly reduced these effects. The combination treatment was more effective than individual treatments. Histological analyses supported these findings. Molecular docking showed diosgenin had a stronger binding affinity with the target proteins compared to tamoxifen. The simulations revealed that diosgenin effectively binds to CDK4, AKT, and CDK6, maintaining their stability and structural integrity. CDK4, AKT, and CDK6 showed consistent RMSD, RG, and SASA values, with moderate flexibility and stable hydrogen bonding patterns, suggesting their potential as therapeutic targets. Conclusions: Combining diosgenin and tamoxifen effectively inhibits breast cancer progression in DMBA-treated mice. This is primarily due to the reduction in expression of CDK2, CDK4, CDK6, and Akt proteins, which enhances the sensitivity of resistant breast cancer cells to tamoxifen.