ZnO nanoparticles enhance the cytotoxic effects of a chalcone-sulfonamide hybrid by impairing the autophagic flux and upregulating HIF-1α expression

<p> Colorectal cancer remains a leading cause of cancer-related deaths worldwide, highlighting the need for new treatment alternatives with higher selectivity and effectiveness. Molecular hybridization represents a cutting-edge strategy for the development of novel therapeutic agents. By integrating two pharmacologically active moieties into a single molecular framework, this approach can produce hybrids that not only retain the inherent bioactivities of their precursors but also exhibit superior pharmacological properties. The cytotoxic potential of chalcone-sulfonamides has been extensively described in literature, but their limited selectivity restricts the progression of the studies and, consequently, their use as therapeutic alternatives. Zinc oxide nanoparticles (ZnONPs), characterized by their facile synthesis and favorable biocompatibility, have been used as platforms to enhance drug delivery and selectivity. In this study, the cytotoxic effects of a combined system comprising ZnONPs and a chalcone-sulfonamide hybrid (ZnONPs-CSH99) were investigated against a colorectal cancer cell line (HCT-116). The ZnONPs-CSH99 combination displayed enhanced cytotoxicity and selectivity towards HCT-116, inducing cell cycle arrest at the G2/M phase, with no disturbances to cellular membrane integrity. Additionally, the treatment disrupted autophagic flux, as shown by the reduced expression of autophagy-related proteins and elevated levels of HIF-1α, suggesting a potential link between autophagy inhibition and cytotoxicity. No genotoxic effects were observed for the combination in <em>D. melanogaster</em> model, reinforcing its safety profile. Our results demonstrate that this combined treatment may represent a viable strategy to improve colorectal cancer therapy and to enable the progression of studies with potential anticancer molecules, contributing to the development of new treatment alternatives for the disease. </p>