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

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.

Efeito modulador do Firocoxib (Previcox®) sobre a ação carcinogênica da doxorrubicina por meio do teste de tumores epiteliais (ETT) em Drosophila melanogaster / Modulatory effect of Firocoxib (Previcox®) on the carcinogenic action of doxorubicin through the epithelial tumor teste (TTE) in Drosophila melanogaster

Introdução: a superexpressão da COX-2 relaciona-se com o aumento da produção de fatores de crescimento vascular e como consequência, com o desenvolvimento tumoral. O Firocoxib é um anti-inflamatório não esteroidal utilizado para inflamação associada à osteoartrite em cães. É o inibidor mais seletivo da COX-2, reduzindo eficientemente a ação desta enzima. Estudos indicam os benefícios do Firocoxib na terapia antineoplásica. Objetivo: este trabalho objetivou avaliar o efeito modulador do Firocoxib sobre a ação da doxorrubicina (DXR) por meio do teste de tumores epiteliais (ETT) em Drosophila melanogaster. Metodologia: foram preparadas três concentrações de Firocoxib: 2,5; 5 e 10 mg/mL, utilizadas isoladamente e em associação à doxorrubicina. O tratamento ocorreu com larvas de D. melanogaster descendentes do cruzamento de fêmeas wts/TM3 com machos mwh/mwh. Resultados: os resultados sugerem que o Firocoxib possui atividade moduladora sobre a ação carcinogênica da DXR, pois houve redução significativa nas frequências tumorais dos indivíduos tratados com diferentes concentrações de Firocoxib em cotratamento com a doxorrubicina quando comparadas à frequência tumoral do controle positivo. Conclusão: conclui-se que, nas presentes condições experimentais, o Firocoxib reduziu a frequência de tumores induzidos pela doxorrubicina em D. melanogaster.

Introduction: COX-2 overexpression is related to increased production of vascular growth factors and, as a consequence, to tumor development. Firocoxib is a non-steroidal anti-inflammatory drug used for inflammation associated with osteoarthritis in dogs. It is the most selective inhibitor of COX-2, efficiently reducing the action of this enzyme. Studies indicate the benefits of Firocoxib in anticancer therapy. Objective: this study aimed to evaluate the modulatory effect of Firocoxib on the action of doxorubicin (DXR) by means of the epithelial tumor test (ETT) in Drosophila melanogaster. Methodology: three concentrations of Firocoxib were prepared: 2.5; 5 and 10 mg/mL, used alone and in association with doxorubicin. The treatment occurred with D. melanogaster larvae descended from the crossing of wts/TM3 females with mwh/mwh males. Results: the results suggest that Firocoxib has modulating activity on the carcinogenic action of DXR, as there was a significant reduction in tumor frequencies in individuals treated with different concentrations of Firocoxib in co-treatment with doxorubicin when compared to the tumor frequency of the positive control. Conclusion: it is concluded that, under the present experimental conditions, Firocoxib reduced the frequency of tumors induced by doxorubicin in D. melanogaster.