Current Research
| My current research looks into the mechanism of action of metal-based anticancer agents. |
Background |
| Cancer, defined by the WHO as ‘the uncontrolled growth and spread of cells’, is responsible for at least 13% of world-wide deaths. Current statistics indicate that 1 in every 3 people will develop some form of cancer during their life time. It is estimated that by 2030 there will be 21.4 million new cases diagnosed every year.
The most well-known metal-based anticancer drug cisplatin (CDDP) arose from serendipity and is now used in more than 50% of chemotherapeutic regimes. Since its approval, several attempts have been made to improve the pharmacological properties of CDDP. Two important derivatives have gained FDA approval, carboplatin in 1989 and oxaliplatin (OXA) in 2002. It is widely accepted that the antineoplastic properties of CDDP rely on its interaction with DNA, which in turn activates apoptosis. However, this is a reductionist view of a process in which several important events are involved from drug administration to cellular death. One of the major challenges in the use of platinum complexes as chemotherapeutic agents for cancer treatment is to combat the high incidence of resistance and the severe adversise side effects. New generations of metal chemotherapeutics offer the prospect of combating Pt-resistance and expanding the range of treatable cancers. |
What has been done so far |
| The Sadler group, based in the Chemistry department, has developed a novel range of organometallic osmium, ruthenium and iridium (Os, Ru, Ir), piano-stool complexes as potent anticancer agents to overcome the limitations posed by the platinum metallodrugs.
Our 'piano-stool' complexes have already shown potential clinical advantages over the currently used platinum metallodrugs. Exhibiting antiproliferative activities in the low micromolar range, these complexes are capable to overcome CDDP resistance in ovarian cancer cells (A2780cis) and dual CDDP/OXA resistance in colorectal cancer cells (HCT116Ox). A further clinical advantage for these 'piano-stool' complexes is the possibility of equipotent activity in p53-deficient cell lines. p53 is a common mutation, thought to occur in approximately 50% of all cancers. We have demonstrated that in selected complexes the antineoplastic activity is independent of the p53 status. Preliminary in vivo work carried out in colon xenographs indicates that FY26, one of the selected Os complexes, is capable of tumour reduction with minimum weight loss. |
Where I come in |
| Little is known on novel pathways followed by non-platinum transition metal complexes. This impairs rational design and further improvement of drugs, especially of metal-based chemotherapeutics. Os/Ru/Ir-based drugs as the ones synthesised by the Sadler Group are most likely multi-targeted, which makes more difficult the study of the activation of cellular pathways that can lead to cell death.
The immediate need is to establish the mechanism of action of these novel metal-based complexes and identify their target sites. A large number of these chemotherapeutics have a potential redox arm to their mechanism of action; therefore, exploiting their ability to target the redox balance in cancer cells may be a highly effective strategy for cancer treatment, especially since it is a multiple site approach and offers selectivity over normal cells. I am developing cell-based experiments in order to determine the mechanism of cell death, activated by the complexes, narrowing down possible molecular targets. To this effect I explore three main mechanisms of cell death: apoptosis, necrosis and autophagy. It has been demonstrated that metal complexes can affect the redox imbalance of rapidly proliferating cells. I also investigate, the origin and mechanism of such activity. |