As a condition that affects so many people, and so negatively impacts on treatment success and quality of life, the effective treatment of cachexia is increasingly acknowledged as imperative for improving patient care.
Unfortunately, there is no ‘Silver Bullet’ where cachexia is concerned. As a complex condition, involving many convoluted pathways, many potential treatments only treat one section of the syndrome, only work on a certain part of the cachectic population, or are simply ineffective. It’s like a game of Whack-A-Mole: you hit one thing on the head, and another pops up somewhere else.
For this reason, we need to look at what is called “multi-target therapy”, a treatment that hits the cachexia pathways in lots of places, rather than just one.
|Salmon & other oily fish are rich sources of EPA|
You know all those adverts on TV talking about fish oil, or krill oil, and how excellent for your health it is? There are two main reasons for that: EPA and DHA.
Not all omega-3s are created equal. While you can find some omega-3s in plant products, such as flax, soy and canola, our bodies have a hard time converting these to long-chain omega-3s, like EPA and DHA. EPA (Eicosapentaenoc acid) and DHA (docosahexanoic acid) are long-chain omega-3 fatty acids, oily substances found in fish, which are essential for the growth and health of our bodies. I am particularly interested in EPA, and how it may help us stop muscle loss in cachexia.
In my last post, I mentioned how oxidative stress, the imbalance of antioxidants and free radicals, is a key player in cachexia. There has been research suggesting that EPA added to your diet can encourage certain antioxidants to be more active, increasing the body’s capacity to deal with excess free radicals. We’re giving the body a few extra security guards to throw the rowdy footy-trippers back onto the bus.
Interestingly, when eaten in high levels, EPA also replaces Arachidonic Acid (AA). AA is an omega-6 fatty acid, which, for the purposes of this discussion, you could think of as an opposite of EPA. While EPA can be used by the body as an anti-inflammatory, mopping up after sometimes harmful chemicals released in response to the tumour, AA is used to create inflammation, which can lead to the release of factors that cause muscle wasting.
There have already been lots of trials looking at EPA in cachexia, with mixed results. Normally, it appears to work really well in animal models, slowing down muscle loss, and even slowing tumour growth. Unfortunately, when you give it to humans, it’s not terribly effective on its own. The most recent studies suggest that you need to combine EPA with exercise, good nutrition support, and some form of pharmaceutical agent. This is where oxypurinol comes in.
Oxypurinol is a strong inhibitor of the enzyme xanthine oxidase (XO), which produces free radicals as part of its normal processes. It blocks the ability for XO to convert hypoxanthine to xanthine to uric acid.
|It might look cool, but Xanthine Oxidase could be |
causing major problems for cachectic patients
Blocking this process could have several benefits in cachexia:
- Uric acid encourages the release of AA from cell membranes. AA is thought to be a key point in the pathway that leads to muscle wasting in cachexia. By making less of it available, we might slow down the muscle wasting
- Blocking XO will mean less free radicals being produced, meaning less oxidative stress, and the damage it causes.
Putting it all together
So, we have our two treatment strategies – a pharmaceutical (Oxypurinol), and a nutritional supplement (EPA). How do they work together to target cachexia?
|Figure 2. How EPA and Oxypurinol may act to interfere in the muscle wasting pathways of cancer cachexia. Adapted from Vaughan et al 2012, J Cachexia Sarcopenia Muscle|
As you can see in the diagram, EPA is stopping the release of tumour factors, and increasing antioxidant activity, while also replacing AA. Meanwhile, oxypurinol is blocking the production of free radicals by XO, and stopping the formation of uric acid, which stops the release of AA.
With this hypothesis in hand, we began the process of testing our treatments. In the next "See My Science" post, I’ll begin looking at the methods we use to study cancer cachexia in the lab, and how we can tell if the treatments are working.
“See My Science” aims to explain the science done by our group in a manner accessible to the public. The current series focuses on the following publication: Vaughan VC et al (2012) Eicosapentaenoic Acid and Oxypurinol in the Treatment of Muscle Wasting in a Mouse Model of Cancer Cachexia. PLoS ONE 7(9): e45900. doi:10.1371/journal.pone.0045900