Abstract
Taking the cancer stem cell gamble with cytotoxic metal complexes
Department of Chemistry, King’s College London
Cancer stem cells (CSCs) are a distinct population of tumour cells that have the ability to self-renew, differentiate, and form metastatic tumours.1 CSCs effectively evade conventional chemotherapy and radiotherapy as these treatments specifically target fast growing cancer cells, and CSCs, due to their stem cell-like properties, divide more slowly.2 After surviving treatment, CSCs are able to regenerate the original tumour and/or produce invasive cancer cells that are able to colonise distant organs. For these reasons, CSCs are widely thought to be responsible for cancer relapse. Therefore, to provide a durable response and prevent tumour recurrence, chemotherapeutics must have the ability to remove the entire population of cancer cells, including CSCs. Therapeutic strategies capable of selectively killing CSCs and disrupting the microenvironments (niches) supporting these cells are the focus of several research programmes. Potential CSC therapeutic targets such as cell surface markers and various deregulated signalling pathways have been identified, but there is still no clinically approved drug that specifically kills CSCs.2 Most of the compounds undergoing pre-clinical or clinical investigation as CSC-specific agents are completely organic in nature. Recent work by our group has shown that metal complexes (copper, cobalt, and nickel) are capable of potently and selectivity killing CSCs (over bulk cancer cells).3a-e Here we present a series of novel copper(II)-phenanthroline complexes bearing nonsteroidal anti-inflammatory drugs or organelle-targeting peptides that can specifically kill CSCs in vitro, and provide insight into their mechanism of action.4a,b Encapsulation of the former into polymeric nanoparticles with CSC-targeting antibodies and their delivery into CSCs will also be discussed.5
References
1. L. V. Nguyen, R. Vanner, P. Dirks and C. J. Eaves, Nat. Rev. Cancer, 2012, 12,133-143.
2. J. Kaiser, Science, 2015, 347, 226-229.
3. (a) P.B. Cressey, A. Eskandari, P.M. Bruno, C. Lu, M.T. Hemann, K. Suntharalingam, ChemBioChem, 2016, 17 (18), 1713-1718. (b) P.B. Cressey, A. Eskandari, K. Suntharalingam, Inorganics, 2017, 5(1), 12. (c) M. Flamme, P.B. Cressey, C. Lu, P.M. Bruno, A. Eskandari, M.T. Hemann, G. Hogarth, K. Suntharalingam, Chem. Eur. J, 2017, 23, 9674-9682. (d) C. Lu, A. Eskandari, P.B. Cressey, K. Suntharalingam, Chem. Eur. J, 2017, 23(47), 11366-11374. (e) C. Lu, K. Laws, A. Eskandari, K. Suntharalingam Dalton Trans., 2017, 46, 12785-12789
4. (a) J. N. Boodram, I. J. McGregor, P. M. Bruno, P. B. Cressey, M. T. Hemann and K. Suntharalingam, Angew. Chem. Int. Ed., 2016, 55, 2845-2850. (b) K. Laws, G. Bineva-Todd, A. Eskandari, C. Lu, N. O’Reilly, K. Suntharalingam, Angew. Chem. Int. Ed., accepted DOI: 10.1002/anie.201710910.
5. A. Eskandari, J.N. Boodram, P.B. Cressey, C. Lu, P.M. Bruno, M. Hemann, K. Suntharalingam, Dalton Trans., 2016, 45 (44), 17867-17873
Brief Bio
Rama received a MSci degree in Chemistry from Imperial College London (UK) in 2008. Rama completed a PhD in Chemistry from Imperial College London (UK) in 2012 under the supervision of Prof. Ramon Vilar. Upon completion of his PhD, Rama joined Prof. Stephen J. Lippard’s research group at Massachusetts Institute of Technology (MA, USA) were he was a Misrock Postdoctoral Fellow (Dept. of Chemistry and Koch Institute of Integrative Cancer Research). Rama began his independent research group at King’s College London in 2014 after the award of a Leverhulme Early Career Fellowship. He was appointed Lecturer in Bioinorganic Chemistry at King’s College London in 2017.