Cranberries, Anyone?

Author: canscinalism

We have all heard about the health benefits of antioxidants, be they in tea, blueberries or whatever else you can think of; most things containing antioxidants are commonly heralded as ‘super-foods’. However, a study published in Nature during October 2014 – which has identified a potential therapy for a leukaemia for which there are currently slim to no effective treatments – may offer evidence contrary to our current beliefs about antioxidants.

The paper, which began by investigating the unknown mechanism by which the gene “MLL4” provides protection from some cancers soon yielded unexpected yet interesting results.  As is usually the case with experiments assessing the function of certain parts of the genetic code, the study was performed by comparing observations between standard, healthy, mice with variant ‘mutant’ mice missing the a target gene (in this case “MLL4”) . “MLL4” is responsible for the regulation of the body’s ability to prevent the formation of reactive oxygen species, highly reactive, harmful molecules which can form naturally in (and cause damage to) cells over time and are usually associated with the presence of cancer.  Initially it was observed that the mutant, ‘knock-out’ mice experienced several phenomena: low Blast cell counts (with higher blast cell counts being associated with the presence of leukaemias) and the inability to efficiently create new cells.

Further observation showed that the mutant “MLL4” knock-out mice suffered increased cellular damage caused by ‘reactive oxygen species’, which is hardly surprising, since some of their mechanisms to prevent this were experimentally prevented. Interestingly, though the presence of these molecules and the concurrent cellular damage is associated with causing cancer, the presence of these reactive oxygen species was shown to provide resistance to one type of leukaemia (specifically MLL-AF9 leukaemia) in the mutant “MLL4” knock-out mice.  In addition to this, experimental interference with the “MLL4” gene in healthy “wild type” mice (meaning that, temporarily, the gene does not work, like in the mutant knock-out mice) also resulted in the build-up of reactive oxygen species, providing MLL-AF4 leukaemia resistance. To demonstrate this protective phenomenon: when healthy “wild type” mice were exposed to the leukaemia, 70% of them died within 80 days, whereas none of the “mutant” mice did.

The leukaemia preventing role of reactive oxygen species was demonstrated by subjecting cells to total oxidative damage using hydrogen peroxide.  Whilst this did prevent MLL-AF9 leukaemia prevalence, it hardly seemed to provide a useful therapeutic option due to the highly lethal nature of hydrogen peroxide. Intuitively, it was theorised that the reactive oxygen species caused DNA damage – which may lead to MLL-AF9 leukaemia resistance.  Using endonucleases, chemicals which directly damage the DNA, it was discovered that DNA damage of the MLL4 gene led to the leukaemia resistance. Following this discovery, it was experimentally proven that such DNA damage, if provided in a controlled way, could provide patients with an effective therapy for MLL-AF9 leukaemia – a condition which is currently considerably lacking in effective therapeutic strategies. Needless to say, this will likely be the subject of subsequent publications.

“But what’s all this about cranberries?” I hear you roar!  Well, if reactive oxygen species cause resistance to MLL-AF9 leukaemia, and antioxidants naturally mop these up, then it stands to reason that in this particular case, antioxidants will do more harm than good!  This was also explored by the paper, showing that previously resistant MLL4 knock-out cells were 3-5 times more likely to form blast cells – meaning they became 3 – 5 times more susceptible to the MLL-AF9 leukaemia when treated with antioxidants. This resulted in only a 60% survival rate with antioxidant treated mutant mice, compared with the 100% survival rate of the antioxidant free mutant mice. To demonstrate this point, I have constructed the following graphic from the paper’s experimental data:

image

Still fancy that cranberry juice?

Link to the original study

Link to a related news story in ‘Nature’

Author: canscinalism