Producción CyT
Medicina - Mechanism of 2´-nitroflavone and safingol antitumor synergistic combination in mammary cancer cells
Congreso
Fecha:
2022Editorial y Lugar de Edición:
Fundacion Revista MedicinaResumen *
Sphingosine kinase 1 (SphK1), a lipid kinase overexpressed in some mammary tumor cells, regulates the balance between proapoptotic ceramides and prosurvival sphingosine-1-phosphate. Furthermore, SphK1 inhibitors prevent catabolism of ceramides, contributing to tumor cell death. It has been reported that certain flavonoids exert antitumor activity through an increment in ceramide levels. Previously, we demonstrated that the synthetic flavonoid 2´-nitroflavone (2NF) and the SphK1 inhibitor safingol synergistically inhibited cell proliferation and induced apoptosis in LM3 murine mammary tumor cells. In this work, we examined the modulation of JNK and ERK 1/2 MAPK transduction pathways. Results showed that after 1h of incubation with both compounds, the levels of p-JNK and p-ERK1/2 MAPKs were significantly increased (2,3 ± 0,3 fold, p<0,05; 1,5 ± 0,1 fold, p<0,01, respectively). Moreover, the antiproliferative effect of the combination was reverted when cells were preincubated with JNK SP600125 or ERK1/2 PD98059 inhibitors. Additionally, we studied the antitumor efficacy of 2NF combined with safingol in human mammary MDA-MB-453 cancer cells and also found a synergistic reduction of cell growth after treatment with 5 µM 2NF and 0,625 µM safingol. Analysis by Compusyn software showed Combination Index values of 0,63 ± 0,08 (48 h) and 0,73 ± 0,06 (72 h). Ethidium bromide and acridine orange staining revealed that safingol potentiated the apoptosis induced by 2NF in these cells. When we evaluated the expression of Bax proapoptotic protein, results obtained by Western blot showed a 3,6 ± 0,4 fold increment after cell incubation with both 2NF and safingol for 24 h (p<0.001). Taken together, these results demonstrated that the combination of 2NF and safingol induced a synergistic antitumor effect in mammary cancer cells, probably mediated by the activation of JNK and ERK1/2 MAPKs pathways. Información suministrada por el agente en SIGEVAPalabras Clave
nitroflavonesynergistic antitumor actionmammary cancer cellssafingol