CBDD’s discoveries under Prof. Richardson are summarized below and are divided into 3 sections:

1.       Development of “Frontier” Anti-Cancer Drugs that Overcome the Triad-of-Death: Entrance into Multi-Centre, Clinical Trials

Richardson’s pioneering, interdisciplinary work on the design/development of metal-binding agents provided a paradigm-shifting approach to cancer treatment. Indeed, he elucidated crucial structure-activity relationships of novel ligands (chelators) through 30-years of analysis, which led to novel, patented therapeutics at the pharmacological frontier that have entered Phase-I clinical trials. In fact, these agents not only demonstrate potent and safe anti-tumour activity, but also overcome drug-resistance and metastasis, the major killers in cancer: the “triad of death” (Pharmacol.Res.2015;100:255-60).

In fact, his research and new drugs stimulated a burgeoning field that now realises the potential of targeting essential metals, which like folate, are critical nutrients for DNA synthesis. Unlike folate, which received tremendous attention as a target for anti-cancer therapy and for which a Nobel Prize was awarded, iron had been largely ignored. This was due to the lack of specifically designed ligands that demonstrated potent and selective activity and prevented whole body iron- or copper-depletion. As such, the examination of metal-binding chelators for cancer therapy was initially considered sheer folly.

However, Richardson felt differently. Despite marked resistance to such ideas, he initiated a highly integrated, interdisciplinary approach embracing: chemistry/medicinal chemistry/pharmacology/biochemistry/cell-molecular biology/animal biology/clinical trials. (Read more…)

2.       Nitric Oxide is Not Freely Diffusible in Cells, But Bound and Transported by GSTP1 and MRP1 as a Dinitrosyl-Dithiol Iron Complex

A second paradigm-shifting area is Richardson research (again elucidated over a period of 20 years) on a novel storage and transport system for nitric oxide (NO).  Nitric oxide was thought generally as a freely diffusible molecule in cells, as it is a small molecular weight diatomic gas actively involved in a wide variety of biological signaling functions including blood pressure control and the cytotoxic activity of macrophages against tumour cells.

However, in a series of innovative studies, Richardson demonstrated that the ability of NO to induce iron release from cells was coupled to glucose metabolism and the generation of glutathione (GSH) and ATP (Fig. 3). These studies led to the demonstration that NO acted somewhat like a chelator in cells to bind cellular iron to form a  dinitrosyl dithiol iron complex (DNIC) which was then actively transported out of cells.

In fact, in this case, the DNIC was then actively transported out of cells by the glutathione transporter, MRP1. These studies then led to the demonstration that the DNIC was bound to glutathione-S-transferase P1 (GSTP1) and could store DNICs to prevent their release by MRP1.  This transport and storage of NO as a DNIC “currency” was proven in tumour cells, but also NO-generating macrophages, where the cooperation between GSTP1 and MRP1 prevents NO-induced cytotoxicity.

This storage and transport system provides the cell with a mechanism to regulate NO and use its key signalling and effector roles, e.g., blood pressure regulation and the cytotoxic activity of macrophages. (Read more…)

3.       A Novel Pathological Iron Crystallite within Mitochondria that is Formed Through Dysregulation of Iron Metabolism Due to the Genetic Loss of Frataxin

Richardson’s third paradigm-shifting research centered on understanding mitochondrial iron metabolism and the concept of how the mitochondrion was damaged by iron in the cardio-and neuro-degenerative disease, Friedreich’s ataxia, where there is a decrease in frataxin expression. While frataxin was known to facilitate iron sulphur cluster and heme synthesis, and that its loss markedly decreased these processes, the reason why loss of frataxin induced mitochondrial iron-loading was paradoxical and totally unknown.

Through the dissection of cellular and mitochondrial iron metabolism, Richardson demonstrated that the dysregulation of iron metabolism in the mitochondrion due to the loss of frataxin, leads to a full reprogramming of cytoplasmic iron metabolism that results in iron being sent to the mitochondrion to try and rescue the defect in mitochondrial iron sulphur cluster and heme synthesis.

This includes marked up-regulation of the transferrin receptor 1 (Tfr1) to increase cellular iron uptake and iron trafficking away from cytoplasmic iron pools (e.g., ferritin) to be directed to the mitochondrion in an effort to rescue the metabolic defect, i.e., the critical decrease in iron containing haem and iron sulphur clusters (Fig. 4).

Unfortunately, while this rescue is effective, it leads to cytoplasmic iron depletion and a massive excess of toxic iron being transported to the mitochondrion. This newly delivered iron then cannot be utilized due to the defective synthesis of iron sulphur clusters and haem (due to the loss of frataxin in this disease), resulting in mitochondrial iron overload. (Read more…)