RESUMEN
Copper (II) complexes are promising in the development of new synthetic models for cancer treatment. In this context, we synthesized a new copper complex containing the pharmacophore group 1,4-dioxo-2-butenyl, the Bis(((Z)-4-((4-chlorophenyl) amino)-4-oxobut-2-enoyl)oxy) copper compound and we evaluated its antitumor activity in 4â¯T1 murine mammary adenocarcinoma cells and their toxicogenic effect in Swiss mice. The compound demonstrated cytotoxicity and genotoxicity to 4â¯T1 cells, and after cell cycle arrest in G1, which occurred by the increase in ATM and p21 expression, it induced the cells to apoptosis by increasing BAX and caspase-7. In vivo the compound was genotoxic in mice but did not show permanent damage, observed by the absence of increased micronucleus frequency, and did not induce changes in the biometric parameters of the animals. These results indicate that the new copper complex, described firstly in this work, presents therapeutic potential for breast cancer.
Asunto(s)
Antineoplásicos/farmacología , Complejos de Coordinación/uso terapéutico , Cobre/uso terapéutico , Adenocarcinoma/tratamiento farmacológico , Animales , Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Membrana Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayo Cometa , Cobre/química , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Ratones , Bazo/citología , Bazo/efectos de los fármacosRESUMEN
AIMS: Previous studies performed by our research group indicated that cytosporone analogues are capable of prevent or repair DNA damages. This work presents the evaluation of the activity of AMS35AA for metastatic murine melanoma cells (B16F10) in experimental model in vitro and, in pre-clinic assay of metastatic melanoma in vivo, using mice lineage C57BL/6. MAIN METHODS: In vitro assays were performed: MTT and comet assay, flow cytometry evaluation, gene expression assay by RT-PCR, qualitative evaluation of cell death using B16F10 cells. In vivo assays: micronucleus and comet assay, splenic phagocytosis, melanoma murine model and histopathological analysis, using mice lineage C57BL/6 (nâ¯=â¯20). KEY FINDINGS: In vitro results performed by MTT assay showed that AMS35AA is cytotoxic for B16F10 cells (pâ¯<â¯0.05). Based on comet assay the genotoxicity of the IC50 was determined (95.83⯵g/mL) (pâ¯<â¯0.05). These data were corroborated by flow cytometry analysis after the treatment with AMS35AA, which indicates the cellular death by apoptosis (pâ¯<â¯0.05) and increasing of ATR, p53, p21 and GADD45 gene expressions verified using RT-PCR. With respect to in vivo results, it was observed that AMS35AA did not show genotoxic activity. Data of tumor volume ex vivo indicate reduction of tumor for the treated animals with AMS35AA up to 15.84×, which is superior to Dacarbazina (50â¯mg/Kg, p.c.; i.p.). SIGNIFICANCE: In summary, the study showed that AMS35AA reveals relevant results regarding to cytotoxicity of B16F10 murine melanoma cells, inducing death by apoptosis via mitochondrial and/or mediated by DNA damages.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Benzofuranos/farmacología , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Melanoma Experimental/tratamiento farmacológico , Resorcinoles/química , Animales , Ensayo Cometa , Masculino , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Células Tumorales CultivadasRESUMEN
BACKGROUND/AIM: In recent years, the search for new anticancer experimental agents derived from natural products or synthetic analogues, such as resorcinolic lipids, has received increased attention. The present study aimed to evaluate the antitumor potential, describe the cell death mechanism and the effects of 3-Heptyl-3,4,6-trimethoxy-3Hisobenzofuran-1-one (AMS35AA) in combination with different chemotherapeutic agents in the MCF-7 cell line. MATERIALS AND METHODS: Analysis of cytotoxic, genotoxic, membrane integrity, cell death and gene expression induced by the compound was performed. RESULTS: The AMS35AA and its association with 5-FU demonstrated reduction of cell viability; increase of cell death; enhancement of genomic damage and accumulation of cells in G2/M phase. CONCLUSION: AMS35AA has potential for breast cancer treatment since it is capable of exerting cytotoxic and cytostatic effects in a breast cell line and also could be an adjuvant in cancer therapy when combined with 5-FU.