Speciation of Tetracycline and Its Zn2+ Complexes in Aqueous Solution and Their Antiproliferative Activity in Non-Small Lung Cancer Cells

Tetracycline (TC), the primary member of the tetracyclines, is a widely used broad-spectrum antibiotic that has also attracted interest for its nonantibiotic biological effects, including anticancer activity. The aim of this study is to assess the acid-base behavior of TC, its ability to form complexes with Zn2+ under various conditions, and to demonstrate that such species enhance the antitumor activity of TC in non-small cells lung cancer (NSCLC). The speciation study on TC and its Zn2+ complexes was performed in aqueous NaCl solutions at different temperatures (15 ≤ t/ °C ≤ 45) and I = 0.15 mol L-1 via potentiometric, UV-vis spectrophotometric, and 1H NMR titrations. The protonation and formation constants of the species were calculated, and their temperature dependence was evaluated, along with the sequestration capacity of TC toward Zn2+. The speciation results were essential to identify the most suitable Zn2+/TC ratio and experimental conditions to ensure significant complex formation for the in vitro cytotoxicity studies in A549 cells. The biological results showed that Zn2+ complexation significantly affected the cytotoxicity of TC, enhancing its antiproliferative activity compared to the free ligand.