Copper(II) Complex Containing 4-Fluorophenoxyacetic Acid Hydrazide and 1,10-Phenanthroline: A Prostate Cancer Cell-Selective and Low-Toxic Copper(II) Compound

Abstract

Prostate Cancer (PCa) is the second leading cause of cancer-related deaths among men worldwide. The treatment of advanced cases is based on chemotherapy, which lacks specificity and efficacy, due to severe side effects and resistance to the traditional drugs. Copper complexes have shown antitumoral efficacy and low toxicity, being considered a promising class of metal-based drugs for the treatment of malignant neoplasms. Thus, the present study aimed to evaluate the cellular effects of a copper(II) complex with 4-fluorophenoxyacetic acid hydrazide and 1,10-phenanthroline (1) on PCa cell lines, as well as the mutagenic/recombinogenic and anticarcinogenic potential of 1 in Drosophila melanogaster. PNT-2 (non-tumorigenic), LNCaP (hormone-responsive PCa) and PC-3 (androgen-independent PCa) cells were cultured, and cytotoxicity was assessed using the MTT assay. The expression levels of the proliferation markers Ki-67 and Cyclin D1 were analyzed by flow cytometry. Furthermore, the Somatic Mutation and Recombination Test (SMART) and the Epithelial Tumor Test (ETT) were performed. Complex 1 was selective to LNCaP cells, significantly reducing Ki-67 and Cyclin D1 expression levels. Sub-toxic concentrations of complex 1 were defined by the toxicity test in D. melanogaster, and no mutagenic/recombinogenic/carcinogenic effects were observed. Anticarcinogenic potential was observed in D. melanogaster, suggesting modulating activity of the complex 1 against Doxorubicin, a drug used as control by its carcinogenic properties. Therefore, complex 1 is a possible starting point for the development of new antitumor agents for the treatment of PCa.

Cuproptosis: Mechanism, role, and advances in urological malignancies

“…In addition to common copper chelators, various new drugs based on copper chelation have been developed and have been shown to be effective in preliminary studies. [75][76][77] Chen et al synthesized a nanoparticle that combined copper with diethyldithiocarbamate, an active metabolic component of DSF. The nanoparticle exhibited good anticancer activity against paclitaxel-resistant PC cells 61 (Figure 4C).…”

A Ternary Copper (II) Complex with 4-Fluorophenoxyacetic Acid Hydrazide in Combination with Antibiotics Exhibits Positive Synergistic Effect against Salmonella Typhimurium

“…The copper complex [Cu(4-FH)(phen)(ClO 4 ) 2 ] (DRI-12) was previously evaluated for its physicochemical properties, cytotoxicity in tumours [21], selectivity and non-mutagenicity in tests with Drosophila melanogaster (in press) [22], as well as its antimycobacterial activity [20]. These studies revealed that DRI-12 has high potency and low toxicity, which makes it a promising compound to fight cancer and microorganisms.…”

“…Moreover, copper is an essential trace element with importance for the functioning of several enzymes involved in energy metabolism, respiration and DNA synthesis in the cell, which make it very attractive for the development of safe and effective drugs [17][18][19]. Thus, DRI-12 was recently prepared [20] as a selective copper (II) complex containing 4-fluorophenoxyacetic acid hydrazide and 1,10-phenanthroline, and it has shown DNA-cleaving and pro-apoptotic properties in cancer cells, as well as selectivity and non-mutagenicity in tests with Drosophila melanogaster [21,22].…”