Cardiac drug gets to heart of cancer killing
Mon, 30th Jul 2012
A commonly-prescribed heart drug also has powerful anti-cancer actions, scientists have discovered.
Cancer chemotherapy agents work in a range of ways but they all aim to kill malignant cells. Some are more effective than others and partly what sets them apart is the ability of certain drugs to trigger dying tumour cells to behave like a vaccine, priming the immune response against the surviving cancer cells. This can help to combat recurrence. Identifying drugs that can do this, though, is a hit and miss affair.
Now, writing in Science Translational Medicine, Universite Paris Descartes researcher Guido Kroemer and his colleagues have developed a screening system to spot drugs capable of doing this and made a surprising discovery at the same time: the heart drug, digoxin, prescribed to regulate heart rate, also has these sought-after anti-cancer properties.
The screening system employed by the team, which enabled them to examine over 1000 currently-licensed drugs, involved administering the agents to cultured cancer cells and looking for 4 features known to correspond to changes induced by drugs with the properties they were looking for. These were expression on the surface of the cells of a marker called CRT, the release of the energy chemical ATP, self-destruction of the treated cells (known as apoptosis) and the release of a substance called HMGB1.
At the top of the list of hits generated by the screening system were the anti-cancer drugs already known to behave this way, validating the model, but when digoxin also turned up in the top ten the team were intrigued and tested it further. It seems, they found, to stress cancer cells more than healthy cells, triggering them to die catastrophically, stimulating an immune response to the cancer.
To prove this, they injected into mice dead or dying cancer cells that had been pre-treated either with digoxin or with a control solution. A week later the animals were then challenged with living, viable cancer cells. Those that had received cells pre-treated with digoxin mounted a strong immune response the second time and most of the animals remained tumour-free. The animals that were exposed to the control-solution treated tumour cells all succumbed to cancers.
Intriguingly, the same trick also appears to work in humans. Because when the team examined the medical records of cancer patients treated between 1981 and 2009 at a certain institution, they found that the 5 year survival rate amongst patients who were being treated with digoxin for other reasons at the time of their cancer therapy was 65% compared with 52% for patients not on digoxin.
It's early days, but, as the team emphasise in their paper, they have so far examined only a handful of the hits their model has pulled out, so there may well be more surprises lurking in the medicine cupboard yet...
Cardiac Glycosides Exert Anticancer Effects by Inducing Immunogenic Cell Death; Laurie Menger, Erika Vacchelli, Sandy Adjemian, Isabelle Martins, Yuting Ma, Shensi Shen, Takahiro Yamazaki, Abdul Qader Sukkurwala, Mickaël Michaud, Grégoire Mignot, Frederic Schlemmer, Eric Sulpice, Clara Locher, Xavier Gidrol, François Ghiringhelli, Nazanine Modjtahedi, Lorenzo Galluzzi, Fabrice André, Laurence Zitvogel, Oliver Kepp and Guido Kroemer; Sci Transl Med 18 July 2012 4:143ra99. DOI:10.1126/scitranslmed.3003807