Influence of Bathophenanthroline in Cu-Naringenin complexes on 3D culture anticancer activity, antimetastatic properties and synergy with the antidepressant paroxetine

Abstract

Cancer is responsible for about 22.8 % of global deaths from noncommunicable diseases, with lung cancer the most diagnosed in 2022. Non-small cell lung cancer (NSCLC) accounts for 85-90 % of cases. Conventional treatments like chemotherapy have limitations, including low bioavailability and drug resistance. Drug repositioning, where existing medications are used for new purposes, has emerged as a promising approach. This study advances the understanding of antitumor effects of the copper-naringenin (Cu-Nar) complexes: CuNar, CuNarPhen, CuNarBatho [CuNarPhen and CuNarBatho feature CuNar containing phenanthroline (Phen) or bathophenanthroline (Batho)] in lung cancer cells (A549). Clonogenic assays in 2D cultures showed that CuNarBatho was the most effective complex in inhibiting colony formation. Likewise, in a 3D culture model, CuNarBatho disrupted tumor spheroids and demonstrated significant cytotoxicity, with an IC₅₀ value of 11.72 μM. The effect on metastatic processes was also studied, revealing that the complexes significantly reduced cell migration, adhesion, and invasion, particularly CuNarBatho. Zymography assays showed that this complex inhibited the activity of matrix metalloproteinases (MMP-2 and MMP-9), key enzymes involved in cancer metastasis. Additionally, the cytotoxic effects of the three complexes in combination with the antidepressant agent paroxetine, a selective serotonin reuptake inhibitor, were studied, and its inhibitory effect in A549 cells was also determined. When paroxetine and the copper complexes were combined, different degrees of synergy were observed, with CuNarBatho exhibiting the most impactful synergistic effect. These findings suggest that CuNarBatho has potential as a novel therapeutic strategy for lung cancer.

Keywords: Copper-complexes; Flavonoids; Metastasis; Paroxetine; Synergism; cancer.