Oral Presentation ESA-SRB-NZSE-CaSR 2026 in conjunction with ENSA

Metformin and Ingenol Mebutate Combination Therapy as a Potential Treatment Strategy for Preeclampsia  (143765)

Dilara Dassanayake 1 2 , Wini Vudiniabola 1 2 , Manju Kandel 1 2 , Tuong-Vi Nguyen 1 2 , Ping Cannon 1 2 , Stephen Tong 1 2 , Lucy Bartho 1 2 , Tu'uhevaha Kaitu'u-Lino 1 2
  1. Obstetrics, Gynaecology and Newborn Health, University of Melbourne , Heidelberg, VIC, Australia
  2. Mercy Perinatal , Mercy Hospital for Women, Heidelberg, VIC, Australia

Background: Preeclampsia is a pregnancy complication characterised by placental dysfunction and maternal endothelial dysfunction. The only cure is delivery of the placenta with limited treatment options available. Ingenol Mebutate (IM), identified through high-throughput screening, and Metformin, have been shown to have vasoprotective properties. Therefore, this study explored whether combining these drugs could rescue features of preeclampsia in vitro.  

Methods: The effects of IM and Metformin combination therapy were investigated in primary cytotrophoblasts (24 and 48 hours) and human umbilical vein endothelial cells (HUVECs) (24 hours) using 0.01uM or 0.1uM IM, 1000uM Metformin, 0.1uM IM + 1000uM Metformin (high-dose combination) and 0.01uM IM + 1000uM Metformin (low-dose combination). HUVECs were treated with 1ng/mL TNFα to model endothelial dysfunction. Endothelial dysfunction markers were tested in HUVECs (ET-1, ICAM1, VCAM1); cytoprotective markers (GCLC, HMOX-1, PDSS1, TXN) and sFlt-1 variant expression (e15a, i13) were assessed in HUVECs and primary cytotrophoblasts using qRT-PCR. sFlt secretion in the media was measured via ELISA.   

Results: In HUVECs, both combination treatments significantly reduced ET-1 expression compared to Metformin (n=5, p<0.0001). VCAM1 expression was reduced relative to Metformin (n=5, p<0.01), although there were no changes to leukocyte adhesion.  

Combination treatments significantly increased HMOX-1 expression at 48-hours, but did not change PDSS1, TXN and GCLC expression in primary cytotrophoblasts (n=5, p<0.05). In HUVECs, both combination treatments significantly increased GCLC (n=5, p<0.05) and PDSS1 (n=5, p<0.01). Low-dose combination significantly increased TXN (n=5, p<0.05) and HMOX-1 (n=5, p<0.01) and high-dose combination significantly increased HMOX-1 (n=5, p<0.05).  

We observed reduced sFlt-1 secretion in primary cytotrophoblasts with low-dose combination after 24-hours (n=5, p<0.05), but no effect on sFlt-1 mRNA expression.  

Conclusion: Our findings suggest that combination therapy of Metformin and IM may act synergistically to improve endothelial cell health and reduce sflt-1 secretion, supporting its potential as a therapeutic strategy for preeclampsia management.