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.
EPA
 |
| 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
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.
Neysa
“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
