Year

2017

Degree Name

Doctor of Philosophy

Department

School of Biological Sciences

Abstract

Identification of proteins whose expression and/or activities are upregulated in clinical neoplasias provides insight into the mechanisms underlying carcinogenic transformation and malignancy. Validation of such proteins as biomarkers through correlation to patient outcomes can provide novel targets for the development of selective anticancer therapies. Therapeutics that target phenotypic alterations common to a variety of cancers could have a broad impact on the treatment of cancer as a whole. Increased invasive capability accompanying upregulated proteolytic activity is widely recognized as a critical determinant of metastatic potential and is commonly observed in progressive disease. The urokinase plasminogen activator (uPA) is a key contributor to cell invasiveness through the activation of plasminogen and downstream proteases. These proteolytic actions endow cancerous cells with the ability to degrade extracellular matrix and basement membrane components, facilitating their invasive spread. uPA and its cognate cell-surface receptor (uPAR) are of prognostic relevance in a variety of aggressive cancers where their overexpression predicts adverse patient outcomes and metastatic potential.

A second phenotype observed in virtually all cancers is the reversal of transmembrane pH gradients relative to healthy tissues. Alkalinization of the intracellular pH (pHi) and the concomitant acidification of the extracellular space create a permissive environment that promotes further dysregulated growth, insensitivity to apoptotic checkpoints and increased motility and invasiveness that propel transformed cells towards malignancy and metastasis. The Na+/H+ exchanger isoform 1 (NHE1) is upregulated in a wide variety of tumours and is a primary contributor to the cancer-specific reversal of transmembrane pH gradients. Hyperactivation of NHE1 is an early event in oncogene-driven carcinogenesis and has been shown to be essential for maintenance of transformed phenotypes and growth of tumour xenografts in mice. Amiloride, a commonly prescribed oral potassium-sparing diuretic, presents a unique opportunity for medicinal chemistry optimization into dual-targeting uPA/NHE1 inhibitors as anticancer therapeutics as it is a moderate inhibitor of both targets and shows robust anticancer side activities in vivo.

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