Interactions of hop xanthohumols with model membranes and their toxicity to cancer and erythrocytes cells.

Prenylated hydroxychalcones (xanthohumols) are hop-derived flavonoids with promising anticancer activity; however, their membrane interactions and structure-activity relationships remain incompletely understood. Here, xanthohumol C (XHC) and its semi-synthetic derivatives, 1″,2″-dihydroxanthohumol C (DHXHC) and 1″,2″-dihydroxanthohumol K (DHXHK), were evaluated for cytotoxic, pro-apoptotic, and membrane-modulating effects in comparison with xanthohumol (XH). In vitro antiproliferative activity against eleven human and one murine cancer cell lines yielded IC50 values in the micromolar range, with XHC showing the highest activity toward epidermoid carcinoma, urinary bladder carcinoma, and glioblastoma cells. Apoptosis induction was confirmed in MCC-13 Merkel carcinoma cells. Hemolytic activity toward human erythrocytes was concentration-dependent in the range of 10-100 μM, with XHC classified as toxic at 100 μM, while DHXHC and DHXHK were only slightly toxic. Membrane interactions were studied using fluorescence spectroscopy in cancer cell-mimicking lipid membranes. At low micromolar concentrations (0.5-5 μM), XHC and DHXHC increased DPH anisotropy, indicating membrane stiffening, while Laurdan generalized polarization decreased, consistent with enhanced interfacial hydration. In contrast, DHXHK showed negligible membrane effects. These results suggest that differences in molecular structure, including planarity, may contribute to the observed variation in membrane interactions and cytotoxic effects among xanthohumol derivatives.