Part 2 of 3
The first generation of novel therapies to treat CML – the TKIs (for tyrosine kinase inhibitors) – is now a decade old and they’ve proven to be highly effective in targeting BCR-ABL, the acquired cancer gene that is generally the underlying cause of the disease. Suppressing BCR-ABL can cause leukemic cells to die off, and a proportion of people can achieve what amounts to a cure – no evidence of leukemia even when they stop taking a medication.
But CML can re-emerge even if it has been successfully suppressed because TKIs may not kill off the leukemic stem cells that are harbouring the disease. Leukemic stem cells are now a major focus of CML research as scientists explore ways to destroy them. In Part 1 of this article, we looked at signalling pathways called JAK-STAT and WRT-catenin and how treatments that target these disease mechanisms may lead to better outcomes for people with CML.
Now let’s turn our attention to red wine.
The skins of grapes used to make red wine contain a naturally-occurring chemical called resveratrol, which has attracted a great deal of attention in recent years. Resveratrol has the potential for benefit and harm (not unlike red wine itself). In some situations it can be harmful, such as to a developing fetus. But in other circumstances it has the potential to have anti-inflammatory and anti-cancer effects.
Resveratrol is an interesting chemical because it inhibits an enzyme called sirtuin-1 (SIRT1, for Silent mating type Information Regulation 2 homolog [S. cerevisiae]; S. cerevisiae is a species of yeast in which SIRT1 was originally found). Understanding why this is important requires a bit of background.
You may be familiar with the structure of DNA, which is usually depicted as a spiral ladder. But inside a cell, DNA appears more like a badly rolled ball of wool. What this means is that individual genes buried in the ball of wool may not get expressed. They are hidden, or silenced. So even though you have a gene coding for a certain trait or function, it may not be evident (genetics are not necessarily destiny) because the bit of code isn’t expressed. But sometimes these silenced genes need to get expressed, such as when the cell is under stress. So cells have mechanisms to expose silenced genes should the occasion arise. In effect, these mechanisms have a higher authority than the genes themselves, so they are called epigenetic mechanisms (“epi” means “over”). Epigenetics allow a cell to adapt to new situations without requiring a change to the actual genetic structure (such as through a mutation).
How tightly the ball of DNA is wound is regulated by enzymes called deacetylases. Inhibiting these enzymes can unlock silenced genes and allow genes to express themselves. An early example of a deacetylase inhibitor is valproic acid (Depakote), a medication used to treat epilepsy. More recently, vorinostat (Zolinza) has already been approved to treat a form of blood cancer, and panobinostat (LBH589; Faridak) is currently in development for a number of cancers, including CML. Thus far, a laboratory study has reported that the combination of Tasigna and panobinostat appeared to be effective at killing TKI-resistant leukemia cells, including those carrying the T315I mutation (Fiskus and colleagues. Blood 2006;108:645-652).
Another type of deacetylase is SIRT1, and blocking it may be very helpful in CML. SIRT1 has been shown to be activated by BCR-ABL, and this activation promotes the development of CML (Yuan and colleagues. Blood 2012;119:1904-1914). All of which brings us back to red wine. A laboratory study found that inhibiting SIRT1 with resveratrol promoted the destruction of leukemic stem cells obtained from people with chronic-phase or blast-crisis CML (Li and colleagues. Cancer Cell 2012;21:266-281). This effect was even better when resveratrol was combined with Gleevec (Puissant and colleagues. FASEB J 2008;22:1894-1904). Other substances that inhibit SIRT1, such as compounds related to niacin (vitamin B3), have also been shown to target leukemic stem cells (Ogata and colleagues. Biosci Biotechnol Biochem 2000;64:1142-1146).
But the story doesn’t end there. Resveratrol may also target a mechanism called autophagy (meaning “self eating”). When a cell is under stress (e.g. if there’s not enough food or oxygen), it can tough it out by reducing/reusing/recycling. If resources are scarce, the cell will essentially break up the furniture and put the raw materials to more productive use. Autophagy allows a cell to survive hard times, but it also means that cancer cells can hunker down when exposed to anti-cancer therapies. Autophagy has become enough of a hot topic that it now has its own eponymous medical journal.
Some preliminary studies have shown that resveratrol can inhibit autophagy in CML cells so that the leukemic cells run out of resources and die off (Puissant and colleagues. Autophagy 2010;6:655-657; Tan and colleagues. Tumour Biol 2014;35:5381-5388). Other compounds have also been shown to inhibit autophagy, such as chloroquine, a malaria drug that has been studied in the CHOICES study of CML; and clarithromycin (Biaxin), an antibiotic that has been tested in treatment-resistant CML (Carella and colleagues. Leuk Lymphoma 2012;53:1409-1411).
These studies are still in the preliminary stage and so it’s too early to say if red wine, vitamin B3, malaria drugs or antibiotics can help CML. But targeting SIRT1 and other cancer pathways may be a step along the road to a cure.
In Part 3, we’ll look at other avenues of research, including how fish oils may play a role in treating CML.