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Review
. 2015 Mar 13;373(2037):20140185.
doi: 10.1098/rsta.2014.0185.

Third row transition metals for the treatment of cancer

Timothy C Johnstone  1 , Kogularamanan Suntharalingam  1 , Stephen J Lippard  2
Affiliations
Review

Third row transition metals for the treatment of cancer

Timothy C Johnstone et al. Philos Trans A Math Phys Eng Sci. .

Abstract

Platinum compounds are a mainstay of cancer chemotherapy, with over 50% of patients receiving platinum. But there is a great need for improvement. Major features of the cisplatin mechanism of action involve cancer cell entry, formation mainly of intrastrand cross-links that bend and unwind nuclear DNA, transcription inhibition and induction of cell-death programmes while evading repair. Recently, we discovered that platinum cross-link formation is not essential for activity. Monofunctional Pt compounds such as phenanthriplatin, which make only a single bond to DNA nucleobases, can be far more active and effective against a range of tumour types. Without a cross-link-induced bend, monofunctional complexes can be accommodated in the major groove of DNA. Their biological mechanism of action is similar to that of cisplatin. These discoveries opened the door to a large family of heavy metal-based drug candidates, including those of Os and Re, as will be described.

Keywords: anti-cancer; monofunctional; osmium; platinum; transition metal.

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Figures

Figure 1.
Figure 1.
Compounds discussed in this review.
Figure 2.
Figure 2.
Mechanism of action of cisplatin comprising (i) cellular uptake, (ii) aquation/activation, (iii) DNA platination, and (iv) cellular processing leading to apoptosis. (Online version in colour.)
Figure 3.
Figure 3.
The crystal structures of duplex DNA oligonucleotides platinated with either (a) cisplatin, PDB: 1AIO or (b) pyriplatin, PDB: 3CO3. (Online version in colour.)
Figure 4.
Figure 4.
(a) Space-filling representation of the structure of the phenanthriplatin complex cation demonstrating the steric hindrance provided by phenanthridine ligand. (b) Light micrographs of E. coli that were (right) or were not (left) treated with 15 μM phenanthriplatin for 2 h. (c) The preferred diastereomer of cis-[Pt(NH3)2(phenanthridine)(9-alkylguanine)]2+ observed in the solid state and solution when R is methyl or ethyl. (Online version in colour.)
Figure 5.
Figure 5.
Top: surface representations of the cisplatin (a) and pyriplatin (b) adducts on duplex DNA with the atoms of the platinum lesion shown as spheres. The structures are oriented such that the platinum coordination plane lies in the plane of the page. Bottom: magnification of the platinum lesion illustrating the occlusion of the space above the platinum atom in the cisplatin lesion. (Online version in colour.)
Figure 6.
Figure 6.
Mechanism of action of the osmium-based anti-cancer agents Os-1 and Os-2. (Adapted with permission from Suntharalingam et al. [43]. Copyright XXXX 2013 American Chemical Society.) (Online version in colour.)
Figure 7.
Figure 7.
Efficacy of a variety of chemical agents, including Os-1, in preventing mammosphere formation by CSC-enhanced HMLER breast cancer cells. Scale bar, 0.3 mm. (Online version in colour.)
See this image and copyright information in PMC

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