Dr Erica Baker
BSc (Honours), PhD
Position: NHMRC Senior Research Fellow, Associate Professor, Physiology
Affiliation: University of Western Australia, Department of Physiology
Phone: +61 (08) 6488 393
Our research has been primarily in iron metabolism, characterising the processes of iron uptake, intracellular metabolism of iron and iron mobilization and investigating the regulatory of mechanisms involved in these processes in health and disease. Iron is essential for life. It is incorporated into enzymes and proteins required for important cellular processes such as oxygen transport, cell proliferation and energy production. However, free iron is toxic and the iron in the body is primarily bound in a non toxic form to the plasma iron transport protein, transferrin or the storage iron protein, ferritin. In iron overload, iron is present in the plasma as non-transferrin bound iron (NTBI) and inside the cell as a putative labile iron pool. Both these iron forms have the capacity to promote tissue damage due to free radical production. Such decompartmentalised iron may be involved in the pathology of several diseases including primary and secondary iron overload diseases (haemochromatosis, thalassaemia) and several disorders including ischaemia, atherosclerosis, arthritis and neurodegeneration. Our early work involved defining the transferrin to cell cycle of iron delivery to erythroid and placental cells and characterisation of the transferrin molecule by a variety of techniques, including crystallography. Various stages of the receptor-mediated endocytosis of transferrin were identified.
Our research focus later shifted to the liver. Processes of iron uptake and mobilization from liver cells were investigated in the perfused liver and isolated hepatocytes in culture. These processes are of great importance physiologically as the liver is the main storage compartment for iron and also because, in diseases of iron overload, iron accumulates to toxic levels in the parenchymal cells of the liver with subsequent pathological changes. My interest in iron chelation therapy arose from these studies. Liposome-entrapped chelators and iron-transporting ionophores were explored as a new approach to iron chelation therapy with some success. Further studies concentrated on characterising various classes of chelators to identify those which targeted hepatocytes more specifically. The use of hepatocytes in culture was developed as a chelator screen and many chelators were assessed. Several compounds were outstanding, including, desferrithiocin (DFT) which showed great promise in in vitro and in vivo studies, but was shown to be toxic as the iron-complex, ferrithiocin, and therefore unsuitable for long term chelation therapy. Several other chelators were promising including deferiprone (L1; 1,2-dimethyl-3,hydroxypyrid-4-one) and an extensive in vivo trial was undertaken in an animal model, the guinea-pig. Deferiprone was effective in reducing iron in iron-loaded animals but there was some toxicity. It was concluded that the relationship between drug dose and iron status is critical in avoiding toxicity and must be monitored rigorously as cellular iron is depleted. Toxicity of deferiprone is believed to be related to its bidentate nature, allowing the formation of unstable 1:1 and 2:1 iron-complexes preceding the formation of the 3:1 complex in which iron is unreactive and cannot generate free radicals. The results of recent extensive clinical trials are controversial, for eg. one trial showed an actual increase in liver fibrosis with deferiprone. We have assessed a group of tetradentate and hexadentate analogues of deferiprone (K Raymond, University of California, Berkeley) of which several are as active as deferiprone at low, clinically attainable concentrations, where deferiprone is most toxic.
Another major interest is in the iron metabolism of cancer cells, many of which have a high iron requirement due to their rapid proliferation. Two processes of iron uptake were identified in melanoma cells, including a second endocytotic process which is most active at physiological concentrations of transferrin, well above the level of saturation of the transferrin receptors. Another cancer cell, the hepatoma cell, has also been shown to have two mechanisms of transferrin-iron uptake, allowing unregulated uptake of iron at physiological levels of transferrin. The potential of iron chelators as antineoplastic agents has been investigated in detail in a range of structural classes of chelators including the aminocarboxylates, ortho-substituted phenolates, hydroxypyridinonates, hydroxamic acids and ferrous chelators. Several compounds including DTPA have shown outstanding promise in inhibiting the proliferation of hepatoma cells. DTPA is of particular interest because it is unique within the aminocarboxylate class in showing antineoplastic activity and because of its specificity towards hepatoma cells compared with the proliferating Swiss-3TC mouse fibroblast cells, breast and prostate cancer cells and normal hepatocytes. It is also of interest because it has been used safely clinically as the calcium or zinc-complex in the treatment of thalassaemia in cases where the patient is unable to tolerate desferrioxamine. Other lines of research include the characterisation of plasma nontransferrin bound iron, a major source of toxicity in iron overload disorders.