Platinum-based compounds, such as cisplatin and carboplatin, are among the most powerful and widely used chemotherapeutic drugs. Their platinum centers bind to the DNA of cancer cells, ultimately triggering apoptosis. Unfortunately, resistance to these drugs is fairly common across a variety of cancer types. Inorganic chemist and F1000 member Jon Zubieta discusses the efforts of a fellow Syracuse University chemist in synthesizing new metal-based compounds with anti-cancer activity (J Inorg Biochem, 103:1254–64, 2009).
TS: Why should chemists turn to transition metals—the more than three dozen elements that populate the middle of the periodic table—for developing cancer treatments?
JZ: It would be rather silly to ignore the chemistry of the vast majority of the periodic table and simply concentrate on carbon-based compounds. It’s well known that metals have profound influences on the activity of a variety of biological agents. So it certainly makes sense to look at metal-containing alternatives for drugs and therapies. In terms of the platinum compounds, there are of course large numbers of cancers and cell lines that are resistant to platinum drugs. So of course one of the things we’d like to do then is to find some alternatives to the platinum therapy by potentially using other metal-type reagents.
TS: In this paper, Robert Doyle and colleagues from Syracuse University synthesized three different complexes using cobalt, copper, and nickel as the metal centers and found they were toxic to an adriamycin-resistant ovarian cancer cell line in concentrations as low as in the pico-molar range. Moreover, not only did the complexes interact with DNA, they also inhibited topoisomerase I—an enzyme involved in DNA replication, transcription, and recombination—and induced oxidative stress in cells.
JZ: It’s really a trifecta in this case. In fact, originally these compounds were being looked at for their magnetic properties. So this is a very interesting example of following some fundamental chemistry and then finding some applications that could really be quite remarkable.
TS: A crucial part of synthesizing these metal complexes is choosing the atoms that are bonded to the metal. Known as ligands, these surrounding structures influence how the metal reacts. The researchers selected pyrophosphate as a ligand. Pyrophosphates are ubiquitous in living organisms and are at the heart of energy production in cells, for example, through phosphorylation and production of ATP. Why use them to make metal complexes?
JZ: Pyrophosphate is quite an effective bridging ligand, so it tends to bridge between metal sites. So if you go back and look at the paper, most of these are binuclear complexes. You have two metal[s] that are bridged by the pyrophosphate. The pyrophosphate itself is quite susceptible to hydrolysis, so if it sees water it breaks up and forms phosphate. The pyrophosphate is not just an innocent scaffold that’s holding the two metals together, but it may actually undergo some reactivity that is activating the complex. It may be that somewhere along the line the binuclear complex breaks down because of the hydrolysis of the pyrophosphate, and this then might expose some site on the metal for further reactivity.
TS: What exactly is making them so toxic to these cancer cells? The study suggests that these compounds can break down to form various chemical species, which may have different mechanisms of cytotoxicity.
JZ: The compounds don’t simply behave as an inert material throughout their functioning. Either through hydrolysis or through other processes, they are undergoing some chemical change so that these molecules are being transformed into something that’s more reactive with respect to the target molecule. So you have very simple molecules, but because of their inherent properties—for example, the tendency of the pyrophosphate to undergo hydrolysis—you have some relatively complicated chemistry going on either within the cell, during the diffusion process into the cell, or possibly even before that.
TS: What are some other next steps?
JZ: Of course, there are the usual things that chemists do, which are modifications of the molecules. What modifications can be introduced to make them more effective? To make them less toxic for healthy cells? Modifications that allow the drug to flush through the system more effectively and minimize side effects? Whether or not these things turn out to be effective therapeutics, I think we’re going to learn something about how these molecules behave and maybe gain some useful leads for future development of some metal-based therapeutics.
Zubieta’s lab works on the development of metal oxides. You can access his review of the paper at: http://bit.ly/bR4BT8