Medicina - Synergistic in vivo antitumor effect of 2?-nitroflavone and safingol combination

Congreso

Resumen *

The sphingosine kinase 1 (SphK1)/sphingosine-1-phosphate (S1P) axis has been widely studied in cancer research due to its role in modulating sphingolipid metabolism, which determines cell survival or death. In this sense, the development of SphK1 inhibitors has emerged as a promising strategy due to their ability to increase pro-apoptotic ceramide and decrease oncogenic S1P levels. In addition, it has been reported that certain flavonoids exert antitumor activity through an increase 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 vitro in breast tumor cells. In this work, we studied the effects of the 2NF and safingol combination in an in vivo syngeneic LM3 breast cancer murine model. Animals were treated with either vehicle, 2NF (0.7 mg/kg), safingol (0.5 mg/kg) or the combination of these drugs three times per week for two weeks. Results showed that the single administration of 2NF reduced tumor volume by 38% (p<0.05), whereas safingol had no significant effect compared to control mice. However, the co-administration of both drugs diminished tumor volume by ~80% (p<0.0001). We also studied the mechanism underlying these effects by performing western blot assays in tumor lysates. Pro-apoptotic Bax and cleaved PARP proteins were increased (p<0.01) and anti-apoptotic Bcl-xL and Bcl-2 were diminished (p<0.05) in samples from mice treated with both drugs, compared to those treated with each compound alone or vehicle. The combination also reduced PCNA immunofluorescence staining in tumor sections. Drug doses did not have any toxic effect, since neither mice weight nor hematoxilin-eosin-stained tissues showed differences between treatments. In summary, results suggested the potential benefit of combining an antitumor flavonoid with a regulator of sphingolipid metabolism to promote an enhanced cell death response. Información suministrada por el agente en SIGEVA