Search

Simple Summary: Besides their antibacterial effects, fluoroquinolones possess other valuable properties such as immunomodulatory and anticancer activities. These features make fluoroquinolones ideal compounds for 'drug repositioning'. In the last decades, fluoroquinolone derivatives with improved anticancer effects have been synthesized. We have previously shown that certain ciprofloxacin and norfloxacin derivatives were more potent anticancer agents than their precursors. For this study, the mechanisms of action of the most active among these derivatives were evaluated in a panel of tumor cell lines, including particularly untreatable cancer forms (e.g., triple-negative breast cancer). The tested compounds exerted several well-known fluoroquinolone effects, like cell cycle arrest, apoptosis induction, migration, and topoisomerase II inhibition, along with rather unexplored mechanisms for fluoroquinolones, namely, alternative cell death and histone deacetylase inhibition. Our results delve deeper into the anticancer mechanisms of fluoroquinolone derivatives that, given their known tolerability, could represent a valid therapeutic option, even in poorly treatable tumors. Antibacterial fluoroquinolones have emerged as potential anticancer drugs, thus prompting the synthesis of novel molecules with improved cytotoxic characteristics. Ciprofloxacin and norfloxacin derivatives, previously synthesized by our group, showed higher anticancer potency than their progenitors. However, no information about their mechanisms of action was reported. In this study, we selected the most active among these promising molecules and evaluated, on a panel of breast (including those triple-negative) and bladder cancer cell lines, their ability to induce cell cycle alterations and apoptotic and necrotic cell death through cytofluorimetric studies. Furthermore, inhibitory effects on cellular migration, metalloproteinase, and/or acetylated histone protein levels were also evaluated by the scratch/wound healing assay and Western blot analyses, respectively. Finally, the DNA relaxation assay was performed to confirm topoisomerase inhibition. Our results indicate that the highest potency previously observed for the derivatives could be related to their ability to induce G2/M cell cycle arrest and apoptotic and/or necrotic cell death. Moreover, they inhibited cellular migration, probably by reducing metalloproteinase levels and histone deacetylases. Finally, topoisomerase inhibition, previously observed in silico, was confirmed. In conclusion, structural modifications of progenitor fluoroquinolones resulted in potent anticancer derivatives possessing multiple mechanisms of action, potentially exploitable for the treatment of aggressive/resistant cancers. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) relies on the combined action of a photosensitizer (PS), light at an appropriate wavelength, and oxygen, to produce reactive oxygen species (ROS) that lead to cell death. However, this therapeutic modality presents some limitations, such as the poor water solubility of PSs and their limited selectivity. To overcome these problems, research has exploited nanoparticles (NPs). This project aimed to synthesize a PS, belonging to the BODIPY family, covalently link it to two NPs that differ in their lipophilic character, and then evaluate their photodynamic activity on SKOV3 and MCF7 tumor cell lines. Physicochemical analyses demonstrated that both NPs are suitable for PDT, as they are resistant to photobleaching and have good singlet oxygen (1O2) production. In vitro biological analyses showed that BODIPY has greater photodynamic activity in the free form than its NP-bounded counterpart, probably due to greater cellular uptake. To evaluate the main mechanisms involved in PDT-induced cell death, flow cytometric analyses were performed and showed that free BODIPY mainly induced necrosis, while once bound to NP, it seemed to prefer apoptosis. A scratch wound healing test indicated that all compounds partially inhibited cellular migration of SKOV3 cells. [ABSTRACT FROM AUTHOR]