Postdoctoral researcher, University of Sheffield
Investigating the mechanism and ability of new anticancer drugs to overcome existing drug resistance
The inherent or acquired resistance of cancerous tumours to a leading chemotherapeutic drug, cisplatin, reduces or inhibits the effectiveness of this therapy and leads to a bleak prognosis for survival. My research investigates alternative treatments using new molecules - ruthenium based metal complexes (RBMCs) - through both chemical and biological studies. These studies span from the synthesis of new drug molecules to the exploration of DNA binding ability (the key characteristic for anti-cancer activity) and biological testing to determine how effective the drugs are and what is happening inside the cancer cells when they are successfully killed.
In the presented work the cisplatin sensitive and resistant human ovarian cancer cells are being treated with RBMCs targeted to DNA. The aim of this work is to improve therapeutic properties relative to cisplatin, and elucidate the mode of cell death and the cellular mechanism behind potential leads so that methods to combat cisplatin resistance can be developed.
In this project five RBMC's have been synthesized, and their contrasting ability to kill cancerous cells has been determined as a clear series relative to cisplatin. Using techniques based on labelled protein molecules inside the cells (SILAC proteomic analysis) data has been obtained on the response to the drug treatment. In addition, all of these complexes display a phenomenon called the “DNA light switch effect” where upon interaction between the drug and DNA, fluorescence can be observed by microscopy techniques. Due to these properties the RBMCs have the potential to image cellular and tissue localisation, as well as provide therapeutic effects, and microscopy studies have acquired videos of cell death to categorise the mode of action and relate to the proteomic data gathered.
This study is currently being submitted as a high impact publication, and should be in press by the time of the conference. I will also be able to report on two recent publications involving new molecules with favourable light induced anti-cancer activity (phototoxicity) with potential clinical applications for photodynamic therapy (PDT).
Abstract: With the long-term aim of enhancing the binding properties of dinuclear RuII-based DNA light-switch complexes, a series of eight structurally related mono- and dinuclear systems are reported in which the linker of the bridging ligand has been modulated. These tethered systems have been designed to explore issues of steric demand at the binding site and the thermodynamic cost of entropy loss upon binding. An analysis of detailed spectroscopic and isothermal titration calorimetry (ITC) studies on the new complexes reveal that one of the linkers produces a dinuclear systems that binds to duplex DNA with an affinity (Kb > 107 M-1) that is higher than its corresponding monometallic complex and is the highest affinity for a non-threading bis-intercalating metal complex. These studies confirm that the tether has a major effect on the binding properties of dinuclear complexes containing nintercalating units and establishes key design rules for the construction of dinuclear complexes with enhanced.
Pub.: 11 Jan '17, Pinned: 18 Sep '17
Abstract: Although metal‐ion‐directed self‐assembly has been widely used to construct a vast number of macrocycles and cages, it is only recently that the biological properties of these systems have begun to be explored. However, up until now, none of these studies have involved intrinsically photoexcitable self‐assembled structures. Herein we report the first metallomacrocycle that functions as an intracellular singlet oxygen sensitizer. Not only does this Ru2Re2 system possess potent photocytotoxicity at light fluences below those used for current medically employed systems, it offers an entirely new paradigm for the construction of sensitizers for photodynamic therapy.
Pub.: 22 Mar '16, Pinned: 18 Sep '17
Abstract: Cytostatic agents that interfere with specific cellular components to prevent cancer cell growth offer an attractive alternative, or complement, to traditional cytotoxic chemotherapy. Here, we describe the synthesis and characterization of a new binuclear Ru(II) -Pt(II) complex [Ru(tpy)(tpypma)Pt(Cl)(DMSO)](3+) (tpy=2,2':6',2''-terpyridine and tpypma=4-([2,2':6',2''-terpyridine]-4'-yl)-N-(pyridin-2-ylmethyl)aniline), VR54, which employs the extended terpyridine tpypma ligand to link the two metal centres. In cell-free conditions, VR54 binds DNA by non-intercalative reversible mechanisms (Kb =1.3×10(5) M(-1) ) and does not irreversibly bind guanosine. Cellular studies reveal that VR54 suppresses proliferation of A2780 ovarian cancer cells with no cross-resistance in the A2780CIS cisplatin-resistant cell line. Through the preparation of mononuclear Ru(II) and Pt(II) structural derivatives it was determined that both metal centres are required for this anti-proliferative activity. In stark contrast to cisplatin, VR54 neither activates the DNA-damage response network nor induces significant levels of cell death. Instead, VR54 is cytostatic and inhibits cell proliferation by up-regulating the cyclin-dependent kinase inhibitor p27(KIP1) and inhibiting retinoblastoma protein phosphorylation, which blocks entry into S phase and results in G1 cell cycle arrest. Thus, VR54 inhibits cancer cell growth by a gain of function at the G1 restriction point. This is the first metal-coordination compound to demonstrate such activity.
Pub.: 08 May '15, Pinned: 18 Sep '17
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