Interview between Daleen Totten and Professor Dan Burke
Curcumin: ‘The emperor of anticancer phyto-chemicals’
Prof Burke: I know you’re interested in curcumin. It’s not my main topic but I’ve developed great respect for curcumin. And I’ve looked into its pharmacology for several years now. There’s a very good book, for anyone who is not a scientist and wants to understand cancer, and especially chemotherapy, called Cancer, Emperor of Maladies. One can see why it is called that and it was written by a doctor in America. The more I learnt about the pharmacology of curcumin, and its anticancer mechanisms, the more and more I came to regard it, the higher I came to regard it, and might even use that terminology and call curcumin the ‘emperor of anticancer phyto-chemicals’.
Daleen: Oh my goodness! Would you put curcumin above cannabinoids? Would you put it above salvestrols?
Prof Burke: Oh yes! In one particular respect. I don’t personally think it’s productive, really, to enter into these comparisons. Each of these you’ve mentioned – cannabinoids, salvestrols of course, the active chemicals in green tea, garlic and in broccoli – all of these are very powerful pharmacologically in their own right. So, it is not that one is superior to the other. But the state of knowledge of each is that curcumin alone has been identified as having so many different important molecular targets in cancer cells that it’s like an arsenal all of its own.
I remind you that the likely problem that we’re going to face once we have all of the new targeted anticancer drugs is the resistance. (Please see Daleen’s interview with Professor Burke in this same issue.) Of all the natural anticancer phyto-chemicals that have been identified and researched curcumin alone has the mass of different targets. It can block all those alternative bypass roads that you can take. There are at least 100 different molecular targets to do with cancer that curcumin can adjust. And the amazing thing is, all the identified targets of curcumin seem only to be therapeutic to us and maybe that’s happened by trial and error. I used to have to teach toxicology to medical students and I enjoyed teaching it. I’d ask them, ‘What’s the longest clinical trial in human existence?’ – the answer is probably our diet. We eat what’s good for us and we avoid what’s probably going to kill us and be harmful, and that’s trial and error. We’ve ended up sticking with curcumin in the form of turmeric because it turns out to be good in its chronic-inflammatory process which we now know is underlying in so many different diseases.
Daleen: I would love to just understand more about exactly the role and mechanism of action of the bio-curcumin extract in not the treatment of, but rather the opening of, the blockages that develop during the resistance process of the chemotherapy drug treatment.
Prof Burke: What I’ve been trying to explain to medical doctors treating cancer (oncologists) is that maybe if you give curcumin alongside your clever new targeted anticancer drugs, just maybe the curcumin, by blocking many of the alternative resistance pathways in the cancer cell, might lessen the chance – slow down the development – of resistance.
Daleen: That’s where the hope is.
Prof Burke: That’s what I’m thinking. Now I am not being spectacularly effective in convincing oncologists of this, especially in the UK where they really don’t like alternative complementary therapies. But there are two doctors in Munich that I talk to who have reached this conclusion on their own. So, there are doctors out there.
Daleen: So would they look at doing trials?
Prof Burke: They will and it won’t just be curcumin, but curcumin is the best of them, right now.
Daleen: Tell me a little bit about salvestrols, as you are the man to interview about salvestrols!
Prof Burke: Our cancer research carried on of course as a theme (Again refer to our other interview) with my interest in the CYP enzymes. Then in the early 1990s I was trying to map out CYP enzymes in various human tissues. I was working with a pathologist at the University of Aberdeen because I thought that maybe this will help us understand tissue-specific side effects of drugs.
Daleen: So you’re talking apoptosis, so you’re talking about the chemotherapy killing off cells and die-off of the cells?
Prof Burke: I wasn’t even really looking at cancer to start with. The reason so many drugs cause side effects is because often it is their derivative that’s made by CYP enzymes; it is their metabolite, it’s toxic. So, I thought if we know more about how they map out into different tissues then we’ll understand why sometimes the side effects are tissue specific. And so I teamed up with the pathologists (they taught me a great deal) and we started using their techniques and were able to start mapping CYP enzymes. Because of the methodology we developed, we made a chance discovery.
In science, the things come across (at a speed), and you have a fleeting chance at recognising them, and if you don’t, that discovery is gone. And we realise that there was something wrong with our results. We were seeing something that can only be described as a type of CYP enzyme (a certain family) that seemed to be present only in cancer cells. We couldn’t detect it in the normal cells. And the characteristics of it meant that it couldn’t be any of the then known CYP enzymes. And we know that because of our methodology, and our antibody methodology, that it was of a certain group.
Daleen: So this is now you and Prof Gerry Potter, in the early 1990s.
Prof Burke: With Gerry, yes, but he is the second important stage. As he is now, Professor Graham Murray (he started as my PhD student), eventually professor of pathology at the University of Aberdeen. We wrote grand applications to the main granting bodies for cancer research, describing what we had discovered and of course they had turned us down – we were heretics! I wish I kept some of the letters, I remember one particular response which said that, ‘It’s well known that there are only two members of this particular sub-family of CYP enzymes, and the applicants are claiming that there must be a third.’
Well now we know it is the third. Fortunately, at that time Professor Bill Greenly in the States, he and his team, discovered the existence of CYP1B1 using a new type of DNA-related methodology. We were protein people – I am a protein person (that’s old-fashioned now). Just at the right time – luck comes into discovery – he announced his discovery. He then graciously consented to collaborating with us, provided us with the tools that he had and we needed so that we could ‘nail’ this to the CYP1B1.
I was then appointed head of Lester School of Pharmacy in England, and took with me this idea that what we now knew about CYP1B1: It’s an enzyme of a type that specialises in changing the chemical structures of drug-like molecules. It’s the precise chemical structure of a drug that determines what targets it hits; if you change that structure you can change its effects. You only need a small change, it has to be very specific.
In theory then, CYP1B1 should be able to change an inactive compound to an active anticancer compound and in the case of CYP1B1, because it’s almost exclusive to cancer cells, that would happen almost exclusively in cancer cells – no side effects! Whatever happened in the cancer cell, stayed in the cancer cell. And that type of compound is called a pro-drug, it’s designed to be activated by a specific process, in a specific place in the proximity of its target. CYP1B1 would do that.
My next bit of luck was when we were able to attract Dr (at the time) Gerry Potter to the team. And he had already had the successful track of developing and designing some anticancer drugs that were very important clinically – especially a new anti-prostate cancer drug.
I needed a new pharmaceutical chemist on the staff and he came along. We appointed him and I explained the idea of the pro-drug and he had had some similar ideas of his own. He took it on board, and we combined forces, and he designed and made these compounds (because that is the skill of a medicinal chemist). My team and I tested them. And indeed, we did come up with a prototype – a new type of anticancer pharmaceutical pro-drug that was activated by CYP1B1 and we showed this inside the cancer cells. And Gerry went from being doctor to professor in record time. But more importantly that led us to the salvestrols. Because then we theorised: Maybe equivalent anticancer pro-drug molecules might occur naturally in some of our food plants. So, we went looking and in 2002 we found the first of them; and then subsequently we called them salvestrols. They are indeed nature’s natural anticancer prodrugs – at least in the laboratory.
Daleen: I’ve followed your research around the discovery of these compounds in food and it was discovered only in organic food, is that correct?
Prof Burke: It’s much higher in organic food. After we’d found them, we decided that we might find a way of helping people benefit from them by extracting the individual salvestrols and concentrating them in a supplement-type product. We spent the best part of a year also chemically analysing (with modern sophisticated pharmaceutical style analytical procedures) all the different types of fruits, vegetables and herbs that we could get our hands on, and indeed we found that salvestrols, as a type, are widespread but that some fruits and vegetables were better sources than others. But the big shock was that they weren’t present in anything like the abundance that we expected like we knew from the other types of phytonutrients. The Victorian diet, the old Victorian era diet, more and more nutritionists regard as a healthy diet; the advantage also is that science has a pretty good idea of which plants and in what amount were in that diet. We’ve analysed modern plants for the spectrum and quantity of salvestrols. We were able then to extrapolate and estimate what range of salvestrols and in what quantity they were available in the Victorian diet, and we estimated that our modern, Western- European diet has less than a fifth of the salvestrol spectrum and content of the Victorian diet. And then the question arises, why?
Daleen: What did we do to our food since then?
Prof Burke: And what we did to our food; this is where the organic comes in. The main reason for this, clearly is, to know why the plants make the salvestrols in the first place. Plants have a very sophisticated chemical defence system against pathogens, against insects, against microbes, but in this case against fungi – fungal infection, against mould. It turns out the salvestrol compounds are a very important part of a plant’s chemical defence against fungal infection. And a key characteristic of the salvestrols turns out to be that they are made by the plant primarily and in direct response to the fungal attack. So, there’s a little there normally, fungus hits the plant, biochemistry happens, genes are turned on in the plant and more salvestrols are made. That puts them squarely into a type of natural chemical called phyto-elixens which are made primarily to the response of the problem. You have to be careful because there are lots and lots of phyto-elixens but not all of them are salvestrols. All the salvestrols that we know are phyto-elixens but not all phyto-elixens are salvestrols. All dogs are animals but not all animals are dogs! So, you see something labelled phyto-elixen in a herbal store, it’s probably not a salvestrol – not unless we say it is.
So, the problem then becomes clear: When you spray a food crop with these nasty modern synthetics, agro-chemical fungicides, specifically fungicides, by removing the fungi you remove the stimulus for the plant to produce salvestrols.
Daleen: So then they don’t need to make anymore, so they don’t manufacture it anymore. But an organic crop doesn’t get sprayed, they keep manufacturing salvestrols.
Prof Burke: And we found that they can have up to 30 times higher salvestrols and that also goes for many other important phytonutrients as well. There are some other reasons, like the manufacturing of foods and how we cook them.
Daleen: Retaining those compounds once you’ve picked them: obviously storage, whether you freeze them, how you consume them . . .
Prof Burke: How industry de-bitters its fruit juices, developing sweeter apples and other fruits. And also the well-known concept of empty calories. Too many calories, not enough phytonutrition. I am often asked; can we get enough salvestrols for our health purposes from our diet alone.
We think salvestrols have three roles: prevention (and I wish we had more time to talk about the role of prevention – maybe another time), rescue and maintenance. We think that if you really worked at it, that you could probably get enough salvestrols from your diet for protection. You’d have to have organically grown your food and you’d have to make sure it was picked at the right time, etc. But for rescue and for maintenance, for all sorts of reasons not least the fact that salvestrols turn up primarily on the outside part of the plant (no problem eating apples, but oranges and avos). So, for all sorts of reasons and including pharmacological dose.
Daleen: And then you’re talking about orthomolecular medicine actually, when you’re looking at a high concentration of supplements that you use to activate a cure, a treatment, not just the maintenance.
Prof Burke: We don’t use the term cure. You remember, salvestrols have a proven scientific anticancer mechanism of action; we’ve established that beyond all doubt, but they’re not a licenced medicine. They must never be described as a cure for cancer. They are part of phytonutrition, and help to optimise our diet.