Repurposing doxorubicin and digoxin as novel treatment options for Pulmonary Arterial Hypertension (PAH)

Pulmonary arterial hypertension (PAH) is a severe vascular disorder characterised by the constriction of small blood arteries in the lungs, which leads to right heart failure and premature death. The condition is defined by abnormal proliferation and death of pulmonary artery smooth muscle cells (PASMCs) and endothelial cells (PAECs). Mutations in the type II receptor for bone morphogenic protein (BMPRII) are responsible for most of the inherited disease and familial forms. There is no treatment for this disorder hence novel therapeutic interventions are needed. The primary objectives of this research are to investigate the underlying mechanisms which contribute to the disease pathogenesis and identify novel therapeutic strategies. Accordingly, the effects of anti-cancer drugs; doxorubicin and digoxin and the three genes; ABL1, ERK1 and IGF1R were investigated on TGFβ and BMP signalling in PAH. These compounds promoted BMPRII signalling and suppressed TGFβ signalling, inhibiting excessive PASMCs proliferation. The genes modulated both pathways in HEK293T cells. Furthermore, the reformulation of nano-liposome with epigallocatechin gallate (EGCG) compound and its therapeutic potential were investigated. The newly formulated compound significantly inhibited the TGFBRII-mediated signalling in HEK293T cells. To the best of my knowledge, this is the first comprehensive report investigating the underlying disease mechanisms and outlining the potential of repurposing doxorubicin and digoxin in PAH. These results may have experimental and clinical applications not only in PAH but also in other BMP and TGFβ-associated disorders.

URI

https://bradscholars.brad.ac.uk/handle/10454/20841

Type

Thesis

Qualification name

PhD