Comparative Mechanistic Insights into Quercetin-Loaded Selenium Nanoparticles and Cisplatin in HCT116 Cells

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, with rising incidence, treatment resistance, and chemotherapy-induced toxicity underscoring the need for safer, more effective therapeutic strategies. Nanotechnology offers a promising approach through targeted drug delivery and enhanced therapeutic efficacy. This study investigates the anticancer potential of quercetin-loaded selenium nanoparticles (Qu-SeNPs) against HCT116 colorectal cancer cells and directly compares their effects with cisplatin (CP). To our knowledge, this is the first study to systematically compare the mechanistic actions of Qu-SeNPs and CP in CRC cells. Comprehensive physicochemical characterization using UV-vis spectroscopy, FTIR, TEM, EDX, zeta potential, and DLS confirmed successful synthesis of stable, well-dispersed Qu-SeNPs, exhibiting a characteristic peak at 410 nm. MTT assays demonstrated that Qu-SeNPs reduced HCT116 cell viability in a dose-dependent manner, with an IC₅ ₀ of 51.19 μg/mL, compared to CP (IC₅ ₀ = 17.6 μg/mL). Morphological analysis revealed distinct apoptotic features in Qu-SeNP-treated cells. In vitro drug release profiles showed rapid CP release under both neutral and acidic conditions, while Qu-SeNPs exhibited a pH-responsive, sustained release pattern. ROS kinetics analysis showed that CP caused a sharp early ROS spike at 6 h, plateauing between 24 and 48 h. In contrast, Qu-SeNPs resulted in a gradual, sustained increase in ROS over 48 h, indicating ongoing oxidative stress. Cell cycle analysis demonstrated that CP induced S and G2/M-phase arrest, consistent with checkpoint-mediated DNA repair, whereas Qu-SeNPs significantly augmented the sub-G0/G1 population, indicating apoptosis induction and checkpoint bypass. Apoptosis assays, comet assay, and DNA fragmentation confirmed extensive cell death with Qu-SeNPs, accompanied by upregulation of Bax and cleaved caspase-3, confirming mitochondrial apoptotic activation. Western blotting revealed that CP significantly upregulated Nrf-2, suggesting activation of antioxidant defenses, while Qu-SeNPs did not induce Nrf-2, implying that persistent ROS overwhelmed cellular antioxidant responses. Collectively, Qu-SeNPs promote checkpoint bypass and sustained ROS-mediated apoptosis while failing to activate Nrf-2 expression, suggesting a more effective strategy for overcoming treatment resistance compared to CP. In conclusion, Qu-SeNPs demonstrate potential anticancer effects against CRC in vitro; however, further in vivo investigations are needed to confirm their effectiveness and safety profile.