Death by metal: a hidden detonator inside cancer cells?

Our cells are wired to explode. Given the right signals they can burst open, scattering bits of crunched up DNA, shrivelled membrane and chemicals in all directions. Sometimes this is all part of the plan: controlled cell death it vital to defining the outline of our toes and fingers in the womb, and to the daily act of replacing old cells with new ones. Cell death is a part of life.

Could pools of iron inside cancer cells be exploited
to trigger their demise?
Iron in Lake Khövsgöl, Mongolia
(picture credit Josefontheroad) 

New research has uncovered a hidden route to cell death. Death by iron, or 'ferroptosis' may be a secret weapon against some forms of cancer.

In work published recently in Cell, Scott Dixon and colleagues triggered the death  of cells in a dish using chemicals which causes a build-up of Reactive Oxygen Species (ROS). ROS are volatile and highly damaging to cells, so death within a few hours came as no surprise. What did was another observation: erastin was only effective in cells with a healthy supply of iron.

Iron absorbed from the blood stream (but not other heavy metals such as copper, nickel or cobalt) appeared to sensitise certain cells to erastin and a quick death. 

Exactly what the link is between ROS-inducing chemicals such as erastin and iron has yet to be uncovered. But the team from Columbia University, New York, found evidence that ferroptosis has a "unique genetic network" that is entirely separate from other forms of cell death such as apoptosis (the 'culling' of cells, apoptosis helped to create the gaps between our toes) and necrosis (triggered when a cell is too injured to repair).


This distinct wiring presents an intriguing opportunity: to selectively activate ferroptosis to kill certain cancer cells.

Can death by iron, or 'ferroptosis' be aimed at cancer?
Or blocked in nerve cells to protect the nervous system?
(Iron Maiden. ' The Trooper' (1983))

"The RAS family [of genes] is mutated in 30% of cancers," Dr Dixon writes. These mutations lead to uncontrolled cell division, but also "for better or worse... elevated levels of iron... are observed in some cancer cells".

His team believes it is possible to activate ferroptosis in RAS-mutated cancers inside the human body, using the abnormal iron levels to sensitise the cells to chemicals like erastin.

But activating ferroptosis in cancer may not be its only health benefit. There may be a use for blocking the process too.

The team successfully rescued neurons in rodent brains from cell death by blocking ferroptosis with a chemical inhibitor called ferrostatin-1. They propose that blocking ferroptosis in human brain cells following a stroke or epileptic fit (when ROS and iron levels are high) might protect the central nervous system from long-term damage.

Although the wiring inside our cells is complex (and multitasking is common), ferroptosis is a rare example of independence. Its distinct wiring may allow selective activation or inhibition of cell death, and maybe even the treatment of cancer with fewer side effects. That this metal-based killer might be used to protect life is, in more ways than one, quite ironic.

What does this mean for me?

This study might lead to a whole new line of approach for the treatment of some cancers and diseases which damage the central nervous system. High levels of iron have been reported in cases of Alzheimer's and Parkinson's disease. Understanding exactly how our cells are wired to use ferroptosis will make it easier for scientists to manipulate its effects with drugs similar to erastin or ferrostatin-1.

What does this mean for science?

The discovery of a previously unknown route to cell death shows just how much about our cells we have yet to understand. Indeed, the authors of this work suggest there may be much more "hidden" wiring  used by the cell, waiting to be discovered.

Reference:

Dixon, S., Lemberg, K., Lamprecht, M., Skouta, R., Zaitsev, E., Gleason, C., Patel, D., Bauer, A., Cantley, A., Yang, W., Morrison, B., & Stockwell, B. (2012). Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death Cell, 149 (5), 1060-1072 DOI: 10.1016/j.cell.2012.03.042

Getting to the root of Type II diabetes... with liquorice?

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Metabolism is a balancing act that gets harder with age
(Picture of Philippe Petit on high wire, Notre-Dame
Cathedral, Paris, 1971. picture: Cordisere)

The liquorice root is full of surprises. Chewed as a breath freshener in Italy and a sweet in Sweden (and the north of England), this little brown stick has also been used as a remedy for mouth ulcers for thousands of years.

New research has identified a natural chemical extracted from the liquorice root that could be used to treat Type II diabetes.

Our metabolism is a delicate balance. Insulin, a hormone secreted by the pancreas, regulates levels of glucose and fatty acids in the blood by storing them out of the way in fat and muscle tissue. Some stored compounds can be converted back into glucose when the body needs energy.

Wear and tear on this balance,  as our cells age or through diet or stress, can overload our tissues with fatty acids. Fat and muscle cells become unable to soak up excess glucose and in some cases build a resistance to insulin, a hallmark of Type II diabetes.

Recent drug-based therapies aimed to restore the metabolic balance by targeting the wiring of PPAR-gamma, a receptor protein in the nuclei of many fat cells.  PPAR-gamma responds to fatty acids in digested food by activating genes to boost metabolism. The hope was to manipulate PPAR-gamma to lower the level of fatty acids and improve the cells' sensitivity to insulin.

But there was a problem. The synthetic drug rosiglitazone triggers PPAR-gamma very strongly, successfully lowering blood glucose levels but also firing many other genes at the same time. Out of context, some of these genes were linked to unforeseen side-effects such as weight gain, fluid retention and heart disease.

The liquorice root.
Amorfruitins found at low levels inside
might be extracted to treat Type II diabetes.
(Picture: Ryan Opaz)

In a recent study in PNAS, Christopher Weidner and colleagues investigated a natural alternative. Amorfruitins, extracted from the edible roots of Amorpha fruticosa (the indigo bush) and  Glycyrrhiza foetida (a species of liquorice) are natural activators of PPAR-gamma. Amorfruitins were shown to influence glucose and fatty acid metabolism similarly to rosiglitazone but with more selective targeting of PPAR-gamma,  respectful of its powerful role in controlling different sets of genes.

The team, led by Sascha Sauer from Max Planck Institute for Molecular Genetics in Berlin  showed that amorfruitins decreased insulin resistance in the fat cells of diabetic mice without any observed weight gain. Amorfruitins also reversed some of the genetic changes brought about by a high-fat diet.

Dr Sauer said. “In view of the rapid spread of metabolic diseases like diabetes, it is intended to develop these substances further so that they can be used on humans in the future.”

Sauer's team have begun to investigate how amorfruitins steer the wiring of PPAR-gamma so effectively. They found differences between the genes expressed by PPAR-gamma in response to rosiglitazone or amorfruitins. This is something of a smoking gun: a first step towards understanding what it is about liquorice, a legume, that gives amorfruitins their remarkable ability to correct wiring inside mammalian cells.

What does this mean for me?

It’s estimated that 190 million people are affected by Type II diabetes worldwide and that this figure will double over the next 20 years. This study shows not only a direct health benefit of a natural plant extract on metabolic diseases, but also suggests the mechanisms for how it might work inside mammalian cells. Sauer's team hope the edible nature of the liquorice root, will make it easier to obtain approval for the use of amorfruitins in humans.

What does this mean for science?

This study highlights the importance of "basic" cell biology research to support medicine: only after investigating how a drug works can we confidently predict what (side) effects it may have on the wiring inside our cells. The differences in gene expression patterns between natural and synthtic PPAR-gamma activators suggest clear differences in how they act inside the cell. This raises questions for future drug design approaches - what makes amorfruitins so subtle and selective? Can their mechanism be copied synthetically, maybe to target other important transcription factors?


Reference:

Weidner, C., de Groot, J., Prasad, A., Freiwald, A., Quedenau, C., Kliem, M., Witzke, A., Kodelja, V., Han, C., Giegold, S., Baumann, M., Klebl, B., Siems, K., Muller-Kuhrt, L., Schurmann, A., Schuler, R., Pfeiffer, A., Schroeder, F., Bussow, K., & Sauer, S. (2012). From the Cover: Amorfrutins are potent antidiabetic dietary natural products Proceedings of the National Academy of Sciences, 109 (19), 7257-7262 DOI: 10.1073/pnas.1116971109