How Scientists Are Using Metals to Kill Cancer

Curing cancer isn't easy. This isn't just because it's a nasty disease, it's because there are more than 100 types of cancer and all of them behave in different ways and respond to different treatments. This means research funding has to be split on a range of potential remedies. But there is one highly promising cancer treatment that remains mostly unknown to the general public—and that's the use of metal.

Since ancient times, metals have been used to treat a variety of medical conditions. The Romans, for example, used copper to rid the body of intestinal worms, and silver filings were to treat maladies ranging from bad breath to heart palpitations. It is even believed Cleopatra slept in a mask of gold in order to keep her skin looking young and beautiful.

While many of these ancient treatments have been superseded (I'm certainly pleased we don't use mercury to treat syphilis anymore), metals are still widely used in medicine. We have iron supplements for anaemia and gold anti-arthritic compounds, to name but a few. Arguably the most successful use of metals in modern medicine has been platinum-based anticancer drugs, namely cisplatin.

Since its approval by the United States Food and Drug Administration in 1978, cisplatin has been used to treat a variety of solid tumor types, such as ovarian, bladder, and cervical cancer. It's also responsible for curing more than 90 percent of testicular cancer cases, and was the drug used to treat disgraced cyclist Lance Armstrong.

Armstrong's autobiography It's Not About The Bike: My Journey Back To Life sheds some light on the drawbacks of cisplatin and its related drugs (second-generation carboplatin and third-generation oxaliplatin). He describes how platinum chemotherapy "attacked my bone marrow, my muscle, my teeth, and the linings of my throat and stomach." At times he felt like his "veins were being scoured out."

Cisplatin treatment can cause nausea, vomiting, and in the most severe cases, damage to the kidneys, inner ear, and nervous system. The majority of these side effects stem from the drug's non-specific binding. Not only will cisplatin react with its target molecule (the DNA of tumor cells), but also with the DNA of healthy cells as well as other molecules such as phospholipids, RNA, and peptides. Other disadvantages include the possibility of the cancers becoming cisplatin-resistant, and the fact that it can only be administered intravenously because the drug is not water-soluble.

These drawbacks have provided the impetus for the development of better metal-based drugs, with the field becoming the principal area of interest for many research groups worldwide. Much of this research has focused on developing more effective ways to harness platinum's cancer killing capabilities.

At the University of Warwick in the UK, Professor Peter Sadler's research group has developed a highly potent platinum drug that is activated when exposed to certain wavelengths of light. Light-activation means that more of the drug can reach the cancer tissue without becoming deactivated along the way, and also means that by selectively irradiating only the cancerous area, damage to non-cancer cells can be minimized.

Not content with just focusing on platinum however, several other groups from around the world are studying the anticancer properties of different metals: copper in Italy and Brazil, gold in the Netherlands, rhodium in the USA, and ruthenium in Russia (to name but a few). Sadler's team at Warwick have also strayed into non-platinum territories, including anticancer drugs made from ruthenium and osmium.

Where I live in Australia, discoveries and research into both platinum and non-platinum metal-based anticancer drugs have been taking place for years. At the University of Western Australia, Professor Sue Berners-Price's team (in collaboration with chemists from Virginia Commonwealth University) studied the action of several polynuclear platinum complexes.

Where cisplatin has only one platinum atom, these anticancer compounds have two or three. This means they bind to DNA in a more severe and less reparable way than cisplatin, making them more harmful to cancer cells. Additionally, because of this different response to cancer cell DNA, these compounds (including the celebrated BBR3464 that reached phase II clinical trials) have also been shown to be effective against cisplatin-resistant cancer cells.

The team at UWA also synthesized, characterized, and studied the anticancer properties of gold-based drugs. Unlike cisplatin, these drugs target the tumor cell's power source, the mitochondria. Most notably, the team described a new use for two common imaging techniques—nanoscale ion mass spectrometry and energy filtered transmission electron microscopy. They found both could be used pinpoint the exact location of the gold complexes inside cells in a non-destructive way. Understanding how these drugs work and their eventual location inside cells is an important step to getting them into the clinic.

An area that will be addressed more in the future is metalloglycomics (the relationships between metals-based drugs and carbohydrates made from simple sugars).

Now based at Griffith University, Berners-Price is heading up an Institute for Glycomics that aims to, among other things, clarify the role of carbohydrates in cancer and determine whether carbohydrates could be the next anticancer drug target. While only in its early stages, the institute has already been awarded a competitive ARC Discovery grant and recently publishing a proof-of-concept on the strong binding of polynuclear platinum complexes to oligosaccharides means this is a group to watch.

Despite their obvious promise, metal-based anticancer drugs have traditionally been difficult to get into the clinic. Not only must all drugs undergo very stringent testing but the idea of drugs containing metals, like platinum, often freaks out the general public. However, with the aging population leading to increasing rates of multiple cancers in the future (in 2015 it was estimated that the risk of being diagnosed with cancer by the age of 85 is one in two for men and one in three for women), hopefully metal-based anticancer drugs will be given the funding and recognition they deserve.

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