The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2018

Combination sulfasalazine and metformin are additive in reducing placental secretion of antiangiogenic factor sFlt   (#342)

Fiona Brownfoot 1 , Stephen Tong 1 , Ping Cannon 1 , Vi Nguyen 1 , Natalie Hannan 1 , Roxanne Hastie 1 , Tu'Uhevaha Joy Lino 1
  1. University of Melbourne, Heidelberg, VIC, Australia

Introduction

Preeclampsia is associated with increased placental secretion of antiangiogenic factors sFlt-1 and sENG and a reduction in angiogenic proteins placental growth factor secretion (PlGF) and vascular endothelial growth factor (VEGF). We have identified two medications, safe in pregnancy, that mitigate key aspects of preeclampsia in vitro. We have demonstrated metformin and sulfasalazine independently reduce placental sFlt-1 secretion and vessel dysfunction.

 

In this study we investigate the possibility of combining these medications to reduce the dose required to mitigate key aspects of preeclampsia; sFlt-1 and sENG secretion and PlGF and VEGF expression, using primary human tissues.

 

Methods

Metformin and sulfasalazine, at low doses individually and in combination, were administered to primary trophoblasts and placental explants and sFlt-1 secretion assessed. At the mRNA level there are two sFlt-1 splice variants; the primate and placental specific isoform sFlt-1 e15a and the predominately vascular isoform sFlt-1 i13. Both were measured following combination treatment. In addition the expression of angiogenic factors PlGF and VEGFα were assessed.

 

Results

Combining low-dose metformin and sulfasalazine additively decreased sFlt-1 secretion from primary trophoblast compared to either drug alone. Similarly, an additive decrease in sFlt-1 e15a and i13 was identified following combination treatment. In placental explants, combination treatment also additively decreased sFlt-1 secretion.

 

Low dose sulfasalazine potently upregulated PlGF expression in primary trophoblasts and this was maintained with the addition of metformin. Metformin and sulfasalazine individually increased VEGFα, and this effect was additive when the two drugs were combined.

 

Conclusion

Combination metformin and sulfasalazine additively reduced sFlt-1 secretion and the expression of its splice variants, sFlt-1 e15a and i13. Furthermore, in combination metformin and sulfasalazine upregulate angiogenic factor VEGFα. Therefore we conclude that they might be promising combination therapeutics that could reduce the burden of this devastating disease.