Platinum based cancer drugs
Despite nearly 50% of all anti-cancer treatments being platinum-based, there is an urgent need to develop novel therapeutics beyond those currently in use.1 The first platinum-based anti-cancer chemotherapeutic, cisplatin, was granted clinical approval in 1978. Only two further platinum drugs have gained full global approval namely carboplatin and oxaliplatin.2 Although hugely successful, the widespread application and efficacy of platinum drugs are hindered by their toxic side effects, their limited activity against many human cancers and their susceptibility to acquired drug resistance.3 As a consequence, many investigations have been conducted into trying to develop novel chemotherapeutics that would (i) have a mechanism of action different to classical platinum drugs and thus potentially overcome resistance issues by changing the metal centre and/or (ii) selectively target cancerous cells and thus have a more favourable toxicity profile as compared to platinum(II) drugs.
Keeping this in mind, our Group’s main research focus is the development of a new class of drugs - rationally designed to overcome the above mentioned shortcomings of classical platinum drugs. Herein, two such examples of our research are presented.
Next generation cancer therapies
Firstly, we took into consideration immunosuppressed patients undergoing chemotherapy. There are several bacterial strains that are clinically significant in the context of cancer and cause healthcare-associated infections in the immunocompromised including central venous or peripheral line infections, such as methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. Acknowledging this, we have successfully developed a dual-functioning anti-bacterial and anti-cancer ruthenium(II)-arene complex incorporating a derivative of the antibiotic ciprofloxacin.4 This novel ruthenium complex showed potent cytotoxicity towards a range of human cancer cells (both cisplatin and oxaliplatin resistant and p53 knockout) and is as potent as the clinically approved cisplatin. To get some further insight into its mechanism of action, cell cycle analysis and induction of apoptosis were carried out. These studies indicate that this cytotoxic agent begins to induce apoptosis after 24 h of drug exposure, but most importantly that this may not be the only cell death process occurring. To examine its toxicity in healthy cell lines, a simple in vivo Galleria mellonella larvae model was utilised. The complex was well tolerated across the concentration range tested. The anti-bacterial activity of the ligand - derivative of the antibiotic ciprofloxacin (a building block of this novel agent) and the cytotoxic agent was also evaluated in nine different bacterial strains. While the ligand alone showed excellent anti-bacterial activity across all nine strains, the complex only showed moderate activity on a selected strain of Escherichia coli and its clinical isolate and on a strain of Pseudomonas aeruginosa. Despite the novel ruthenium complex being highly cytotoxic, we concluded that the difference between the concentrations that show anti-cancer and anti-microbial activity was too great to warrant further investigations given the likelihood of a build up of resistance.
Following on this, we decided to change the metal centre from ruthenium to copper as there are numerous examples of copper complexes possessing anti-microbial activity.5 Copper complexes have also been developed as anti-cancer agents with two copper(II) complexes of the Casiopeínas® family in clinical trials. In addition, copper-phenantroline derivatives have received much attention due to their ability to intercalate DNA as well as their ability to act as chemical nuclease agents.6 We thus sought to combine into one drug molecule the anti-microbial and anti-cancer properties of the previously mentioned derivative if the antibiotic ciprofloxacin with the anti-cancer properties of the copper-phenantroline framework. We successfully developed a library of novel dual-targeting copper-N,N-CipA complexes in which N,N is 1,10-phenantroline or a designer ligand, DPQ or DPPZ.7All complexes possessed potent anti-cancer activity towards two human cancer cells (MCF-7 and DU145) and are as potent as the clinically approved doxorubicin. In a similar manner as for our previously reported ruthenium work, we also wanted to determine the toxicity of these chemotypes towards healthy cells. The same simple in vivo model was utilised. The least toxic complex was found to be the DPQ analogue. To understand the mechanism of action of these novel complexes, DNA binding properties and interactions with nucleic acids were explored. These studies suggested that all tested complexes could be considered as DNA intercalators. All complexes were also found to exhibit excellent nuclease activity. The mechanism of action of quinolones is not yet fully understood. It is envisaged that the quinolones bind to DNA, inhibiting bacterial topoisomerases thus preventing the bacteria from replicating.8 Keeping this in mind, inhibition of topoisomerase I was carried out and of the series the DPPZ analogue showed highest topoisomerase I inhibitory activity.
Drugs targeting novel molecular targets
Secondly, in recent years, many investigations into new molecular targets which may present unique opportunities for therapeutic exploitation have been carried out. Histone deacetylase (HDAC) enzymes have been identified as novel cancer targets, the inhibition of which suppresses tumour cell proliferation.9 One such example is the clinically approved HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA), which not only possesses potent anti-cancer activity but also demonstrates selectivity towards tumour cells over normal cells.10 SAHA is well tolerated by patients at doses which induce a potent anti-cancer effect. We have successfully derivatised SAHA to facilitate it’s binding to platinum core and we managed to develop a library of platinum(IV)–HDAC inhibitor prodrugs, which feature a cisplatin core and two modified SAHA ligands. We are currently working on increasing the solubility of these novel complexes and examining their mechanism of action.
In conclusion, we have developed a series of novel metal complexes as potential anti-cancer agents. This is just a small portion of the work we are trying to carry out in our Group to overcome the drawbacks associated with the current anti-cancer drugs in clinical use. Of all the complexes developed, we have already selected our lead candidates that have great potential to enter clinical trials at a later stage in the drug process development and currently warrant further investigations.
1 Galanski, M., Jakupec, M. A. and Keppler, B. K. (2005) ‘Update of the Preclinical Situation of Anticancer Platinum Complexes: Novel Design Strategies and Innovative Analytical Approaches’, Current Medicinal Chemistry, 12(18), pp. 2075-2094.
2 Kelland, L. (2007) ‘The resurgence of platinum-based cancer chemotherapy’, Nature Reviews Cancer, 7, pp. 573-584.
3 Wheate, N. J., Walker, S., Craig, G. E. and Oun, R. (2010) ‘The status of platinum anticancer drugs in the clinic and in clinical trials’, Dalton Transactions, 39, pp. 8113-8127.
4 Ude, Z., Romero-Canelón, I., Twamley, B., Fitzgerald Hughes, D., Sadler, P. J. andMarmion, C. J. (2016) ‘A novel dual-functioning ruthenium(II)–arene complex of an anti-microbial ciprofloxacin derivative — Anti-proliferative and anti-microbial activity’, Journal of Inorganic Biochemistry, 160, pp. 210-217.
5 Hanahan, D. and Weinberg, R. A. (2000) ‘The Hallmarks of Cancer’, Cell, 100(1), pp. 57-70.
6 Rivero-Muller, A., De Vizcaya-Ruiz, A., Plant, N. Ruiz, L., and Dobrota, M. (2007), ‘Mixed chelate copper complex, Casiopeina IIgly®, binds and degrades nucleic acids: A mechanism of cytotoxicity’, Chemico-Biological Interactions,165(3), pp. 189-199.
7 Ude, Z., Kavanagh, K., Twamley, B., Pour, M., Gathergood, N., Kellett, A. and Marmion, C. J. (2019) ‘A new class of prophylactic metallo-antibiotic possessing potent anti-cancer and anti-microbial properties’, Dalton Transactions, 48, pp. 8578-8593.
8 Boulikas, T. (2009) ‘Clinical overview on Lipoplatin: a successful liposomal formulation of cisplatin’,Expert Opinion on Investigational Drugs,18(8), pp. 1197-1218.
9 Mottet, D. and Castronovo, V. (2008) ‘[Histone deacetylases: a new class of efficient anti-tumor drugs]’, Medical Sciences, 24, pp. 742-746.
10 Griffith, D., Morgan, M. P. and Marmion, C. J. (2009) ‘A novel anti-cancer bifunctional platinum drug candidate with dual DNA binding and histone deacetylase inhibitory activity’, Chemical Communications, pp. 6735-6737.