Cancer Metabolism, Oxidative Stress and the Warburg Effect
One of the intriguing aspects of cancer metabolism is the significance of the Warburg effect and its role in driving the cancer phenotype – a subject with a long and contentious history. We shall try to link the Warburg effect to the deep evolutionary roots of cancer as part of the hypothesis that cancer is a default to an ancestral phenotype, and that oxygenic glycolysis represents an ancestral mode of metabolism. The goal of the workshop is not to merely review this field, but to try and settle its status. Has the time come for a radical shift in emphasis from genetics to metabolism and epigenetic control in cancer research and therapy?
Listen to Audio Interviews and Read Transcripts
Audio Interviews and Transcripts from the Workshop
- Eshel Ben-Jacob is a physicist at Tel Aviv University and also a research fellow at Rice University, in the Center of Theoretical Biological Physics. His specialty is bacteria. In this intriguing interview, he links the behavior of cancer cells to the behavior of bacteria, discusses why anti-malarial drugs have anti-tumor properties and speculates that prion-like proteins can help cancer cells spread. Interview Transcript
- Dominic D’Agostino is a Physiologist, Neuroscientist from the University of South Florida, College of Medicine in Tampa. He studies hyperbaric oxygen therapy as a potential therapy for cancer. He got into the field in a rather unusual way. interview Transcript
- Mark Vincent is an oncologist from the University of Western Ontario in Canada. Interview Transcript
- Georg Wondrak investigates why anti-malarial drugs can also be effective against cancer. Interview Transcript
- Anne Devin is a biochemist in Bordeaux, France. She is the director of Laboratoire métabolisme énergétique cellulaire, where she conducts research on the Warburg Effect. Interview Transcript
- Interview with Thomas Seyfried, a professor of biology at Boston College, Massachusetts. His book Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer (Wiley, 1st ed., 2012) discusses the ketogenic diet. This interview updates discussions with him in November 2012 and in March 2012, when he attended earlier workshops at ASU.Learn More about Thomas Seyfried Interview Transcript
Interview with Eshel Ben-Jacob
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Eshel Ben-Jacob: I have worked on bacteria for almost 25 years, on the collective behavior of bacteria or social behavior, and reading about cancer I started being interested in cancer about 3 or even 5 years ago. I started reading and I realized that there are many indications that cancer is also conducting a collective behavior, social behavior, and reading more into the literature I realized that there are any parallels between bacteria and cancer. So I started to look at what extent we can identify the parallels in a better way, and to what extent we can learn from what we know about bacteria to guide us to the collective behavior of cancer. That was the beginning. That helps us on different levels. We both conduct experiments on cancer, for example the migration, which is a very essential part of the metastasis process, and we also conduct theoretical studies of the cancer decision or cell-fate determination; for example, again in the context of metastasis, the transition between epithelial and mesenchymal. During these studies, I also extended my interest and what I presented today was something very new – we haven’t published it – and this is to try to understand the identity of cancer. This also had some link to what we did in bacteria. The science of bacteria that I developed – one strain – is marked by a very special ability to change or switch its identity. That led me to think about the identity of the cancer cells and looking at recent experiments, as were presented here in the lecture, that you can transfer the nucleus from of cancer cell into a normal cell and the cell will have normal cell characteristics, or take a normal cell nucleus into a cancer cell and the cell will remain cancer. And this raises the question, what is the identity? Is the identity in the nucleus, in the mitochondria? How is the information is transferred? And I think this is some puzzle, a very fundamental puzzle of the cancer identity paradox and I presented some ideas that I came across on how to resolve this paradox by linking into a problem of prion-like assembly.
Pauline Davies: Yes. That was particularly interesting and I think took everyone by surprise because we associate prion with disease, of course. But, you were saying that prions are part of our bodies – we need them anyhow, then for cancer, though you can use them in particular ways.
Eshel Ben-Jacob: That’s true. I felt that it’s very exciting because the most widely used drug for Diabetes II, which is called metformin is now being proposed to be used and has an anti-tumor effect. And that was really surprising for me and I couldn’t understand why. What is the connection? There is a trivial connection between cancer and diabetes because cancer metabolism uses more sugar – in a popular way, cancer loves candies, sweets.
Pauline Davies: Because naively you’d just think that this particular drug would lower the sugar and so cancer would away but you’re saying there is a different mechanism.
Eshel Ben-Jacob: Exactly. But then people did some more than that, and in particular it affects the cancer stem-like cells, And I tried to think, “What is the connection? Is there a deeper connection? And how can I get a clue?” So after I did a study on Google and I didn’t find any hints that could help me to understand what’s going on, I asked the question, “Let’s go back to the plant that secretes this compound, the French lilac”.
Pauline Davies: And it secrets the anti-diabetic drug.
Eshel Ben-Jacob: Yeah. The metformin. And I try to think what is. Clearly, the plant didn’t develop this for our benefit to fight diabetes or to fight cancer. So I try to think of the reason. And because by comparing it with another drug – a compound I happened to know that is produced by bacteria, I assumed that it is used by the plants to fight parasites. But again, I couldn’t find any confirmation for this assumption. So I decided to do a search and try to see if by some good luck someone tried to study if metformin has an effect against malaria. And, to my delight I discovered that it was studied and they showed that it does have an effect against malaria. Then I studied, and discovered that about 20 compounds that people studied that act against malaria – and they did check the anti-tumor capabilities – showed anti-tumor capabilities.
Pauline Davies: That’s amazing! So drugs like artimesinin
Eshel Ben-Jacob: Yeah. By the way, this plant goes all the way back to the bible, it’s mentioned that it’s good for you. It it is very popular in Israel for different things. And quinine is also anti-cancer. So then I tried to think more about the parallels between malaria and cancer and I realized that it has to do with the metabolism because the parasite, when it invades a cell, has to change the way that the mitochondria of the host cell functions, so they will produce more energy for the parasite to replicate and develop more parasites, and that it also has to change the function of its own mitochondria because it doesn’t depend on the energy production. Then I tried to look what the parallels are between malaria; I knew that malaria is associated with higher level of iron. So I did a search and I found that it’s known, but somehow it’s not a main part of the discussion, that one of the hallmarks of cancer is a much significantly higher level of iron and it (cancer cell) has a special mechanism to maintain the iron level.
Pauline Davies: Is that so it can just carry more oxygen?
Eshel Ben-Jacob: The reason for the iron is, and this brings us back to the topic of the Warburg effect and the mitochondria and the cancer metabolism, because people focus on the fact that cancer depends less on production of energy from the mitochondria. The Warburg effect is that even in even presence of oxygen, it (the cancer cell) can do fermentation, so that’s why it needs the sugar, the glucose. But the iron level is associated with the fact that at the same time, there is other part of the Warburg effect, the complementary part that is equally important, that it also makes the respiration or oxidation energy production by the aerobic process of the mitochondria more effective. So it elevates the iron level, it also elevates the reactive oxygen species, the ROS. It’s true that the ROS are toxic to the cell but part of the strategy of cancer is to replicate very fast and if some cells die, that’s fine. So cancer in the tumor cells replicate of the time and some of them or many of them die also. Ok so, once I realized these things that these parallels and there are some other parallels, I also discovered that the malaria – people did a study and it has much more, or higher function of proteins that have prion-like properties and they can change their assembly. Then I looked closer into what is known about prions in normal cells and in particular what you find is that prions are used in normal cells in order to go through phenotypic changes when they have exposure to size. It’s not normal cells in the body so much, but if you go to older atavistic cells, eukaryotic but more primitive cells, it’s used even more frequently. And if you take the Paul and Charlie idea of going back in the method, that brings to mind that that is something which is very essential. Now in particular did people a study, and there is a very nice paper in Cell from 2012 that changes on the functions of the mitochondria – if you change the assembly of the proteins which are prion-like, because it can change the way that the fraction on the surface of the mitochondria, it can change the protein – protein interaction in the bulk. And the most important thing is that the prion-like protein can be infectious. You can transfer it to other cells. And then I discovered that malaria causes the host to produce exosomes with prion-like protein that are then released and infect other cells and then they change the other cells in a way that paved the way for the parasite to invade these other cells and are prepared for the parasite to come in and benefit from the changes. We know that cancer cells also send prions. They also have gap junctions. So I thought about the idea that maybe cancer uses the same thing. And then once we accept the idea of the prion-like protein it can help to resolve the paradox of the identity because some of the characteristics and special properties can be transferred or infected by the protein-like. So when you transfer the nucleus from another cell into cancer cell, it’s not only the mitochondria that are different but also you have there the prion-like, which are very essential for changing the regulatory pathways and then they cause or maybe induce some genome plasticity and mutation in a specific direction that feeds the selection which is imposed by this prion-like structure. So we have the information that can help the mutation to occur in a specific way, so it’s not a random mutation, not random.
Pauline Davies: Are you saying that prions can actually help cancer cells spread around the body?
Eshel Ben-Jacob: Ok. So, I say that the prion helps the cancer cells to spread. but it can also help the cancer cell to maintain some identity, which is very important. And it might be used by the cancer cells to infect nearby stromal cells so they will change the way they function. We know that in some cases stromal cells change their identity and start to produce energy in a way that helps the cancer cells. It’s called the reversed Warburg effect and maybe this is the way it does it. So, if you have an exosome that’s prion-like, it can also be something like cancer ability or the ability to develop specific cancers, increases their level. There is some indirect evidence that support this very alarming possibility.
Pauline Davies: Because then of course cancer would be spreadable between individuals.
Eshel Ben-Jacob: Yeah. Not the cancer would spread but the cancerability, the ability to develop cancer. So it’s less alarming than if cancer itself would spread. Still alarming. In normal cells we know that the prion assembly, the prion-like of protein can be reversed so we might want to look and learn how they’re reversed back to normal and that can be another way that we could fight cancer. This is an obvious conclusion. I also didn’t mention another thing that now that we talk, in a relaxed way under the trees, I remember, I didn’t mention that there is evidence that p53 forms ac prion-like assembly.
Pauline Davies: And just to be absolutely clear, the prions that you’re talking about, you’re saying that we have normal prions-like structures that help our normal cells in the body and the ones that are supporting cancer cells have changed; they’re a little bit different.
Eshel Ben-Jacob: Yeah. They change their confirmation. It’s a little bit, but this is a singular perturbation. The little bit can cause them to aggregate together and it can cause other proteins to change their confirmation, so it’s a little bit that can have very, very strong consequences, far reaching consequences, and that’s why it’s called in mathematics ‘singular perturbation’.
Interview with Dominic D’Agostino
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Dominic D’Agostino: Well, I started studying the negative effects of hyperbaric oxygen as it relates to diving and the consequences it produces in NAVY Seal divers, which is seizures.
Pauline Davies: And are you a diver yourself?
Dominic D’Agostino: Yes. I am a diver and that’s kind of what led me into this direction of research and throughout my diving experiences I became familiar with the consequences of the undersea environment. So, I really wanted to study the effects of high levels of oxygen on the brain and our physiology. And in the process of studying hyperbaric oxygen, I stumbled across the observation that cancer cells are selectively vulnerable to high levels of oxygen.
Pauline Davies: So how did you make that connection?
Dominic D’Agostino: Well, studying the various responses of cells to high levels of oxygen, we looked at a variety of cell types so we could firmly understand the cellular response to hypo-oxygenation. We looked at muscle cells, brain cells, fibroblasts, and a few cancer cell lines. We saw that the cancer cells would fail to grow, and high levels of oxygen caused them to over-produce oxygen free radicals, which ultimately led to membrane lipid peroxidation and cellular damage. This was above and beyond what was observed with healthy cells.
Pauline Davies: So what’s going on there? You have more damage from the free radicals within the cancer cells. Why would that be?
Dominic D’Agostino: Well we know that cancer cells thrive in a low oxygen environment. When they are hypo-oxygenated they can over produce oxygen free radicals that they are not adapted to cope with. By being adapted to a low oxygen environment, it makes them kind of vulnerable to levels of oxygen that are well above, up to 100 times higher than they are used to seeing. It works through a variety of mechanisms. One is oxygen free radicals, another is that it can reverse HIF-1-alpha. It can reduce the persistent activation of HIF-1-alpha that is usually found in tumor cells that are growing in a low oxygen environment. HIF-1-alpha causes an aggressive growth, and helps the cancer cells evade normal things that would kill them. By decreasing HIF-1-alpha, it can make the cancer cells more vulnerable to the oxygen environment.
Pauline Davies: In particular, I think you were looking at brain cancer cells?
Dominic D’Agostino: Yes, that’s correct. We were looking at a glioblastoma cell line, and a number of cancer cells we are now looking at. We started looking at brain cancer cell lines originally because they were easy to grow and we just wanted to understand some fundamental mechanisms of how cells respond to hyperbaric oxygen. We didn’t intentionally study cancer cells from the beginning, but in studying a variety of cells, our observation that cancer cells were vulnerable to high oxygen, we had to study this. It wasn’t something that we originally sought out to do, but it was very clear that these cancer cells were vulnerable to high levels of oxygen.
Pauline Davies: Actually, that reminds me of an article written by Jim Watson who said that “To protect yourself against cancer you should take anti-oxidants but if you have cancer, you should take anti-anti-oxidants.
Dominic D’Agostino: That is an important observation there. Anti-oxidants can protect our normal cells from oxidative damage. In particular, it prevents the mitochondria from insults that would normally cause them to be dysfunctional. In a way, I think of anti-oxidants as playing more of a preventative role. Some people are looking at anti-oxidants though as a cancer therapy. I think, once you have cancer, anti-oxidants can be used to protect healthy cells. If you are going in for, for example, radiation treatment or chemotherapy, it can help prevent damage to the healthy cells. Hyperbaric oxygen produces damage to healthy cells at a high enough level. But at a level of oxygen that does not cause damage to healthy cells, is actually damaging to cancer cells. We say that cancer cells are selectively vulnerable. A level of oxygen that is damaging to the cancer cells is relatively non-toxic to the healthy cells. So we want to exploit that advantage with non-toxic cancer therapy. And we find that a nutritional intervention, such as a calorie restricted ketogenic diet, combined with hyperbaric oxygen – the two together can have a synergistic combination, an anti-cancer effect. We want to move this from our lab into therapy, into the clinics, so we are making efforts to do that now.
Pauline Davies: And you’re suggesting that if you use the hyperbaric oxygen and the ketogenic diet before chemotherapy, you might have a better effect?
Dominic D’Agostino: Yes. The thinking is that the restricted ketogenic diet causes a lot of metabolic stress to cancer cells. So it compromises the cancer cell metabolism by limiting glucose availability to cancer cells, lowering insulin, and also by elevating ketone bodies in the blood. Ketone bodies are an alternative form of energy that your normal cells can readily adapt to and use as a great source of energy, but cancer cells can’t use ketone bodies for fuel. By putting yourself into a state of nutritional ketosis, you’re compromising the cancer cell function. If you do that, in combination with hyperbaric oxygen, which puts a lot of oxidative stress on cancer cells, you have two overlapping, non-toxic therapies that can specifically target the cancer cells.
Pauline Davies: Have you tried this in animals or in humans?
Dominic D’Agostino: Yes, we recently published an article in PLOS ONE journal. I think the article name is, “The Ketogenic Diet and Hyperbaric Oxygen Prolong Life in a Mouse Model of Metastatic Cancer.” We have a number of articles now that have been written, and some are in review. So what we have been doing is using a combination of nutritional therapies, which would be the ketogenic diet. But we have also developed ketone supplements which can artificially raise ketone levels in the blood and we know that this has an anti-cancer effect. We are looking to combine the ketogenic diet, with ketone supplementation and also looking into what would be the optimal hyperbaric oxygen protocol. We just tested one protocol and it worked remarkably well. So what we need to do now is a dose response study to see what would be optimal for cancer managing.
Pauline Davies: And do divers have fewer cancers?
Dominic D’Agostino: That’s a really interesting question and no one has looked into it. More and more people are diving with a closed circuit re-breather and that re-breather is 100% oxygen. So that would be very similar to if someone did multiple dives during the week. That would be similar to someone getting hyperbaric oxygen therapy and this could potentially have a, prophylactic effect at preventing cancer in the long term. But no one has looked at that. Although, I do know a lot of divers that have robust health and continue to dive into their 80’s and 90’s, so I think there might be something to it too. I mean, look at Jacque Cousteau and a number of these military divers in particular that live to a very old age, above and beyond the mean age for men, you know. So definitely something to look into!
Pauline Davies: Well, good luck!
Dominic D’Agostino: Thank you very much!
Interview with Mark Vincent
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Mark Vincent: I am Mark Vincent. I am a physician, I treat cancer patients most of the time. I think about the nature of cancer occasionally, and I try to develop novel drugs based upon these insights, if they are indeed insights.
Pauline Davies: Now I was struck by how deep of a thinker you are. You said that you’re seeing all these patients in the clinic, and you’re thinking; “Well really, cancer fundamentally is the same disease, which might surprise as lot of people”.
Mark Vincent: Yes. We’re always told that it is one hundred different diseases and it’s different in every patient and treatment should be individualized, but of course there are certain things that makes all cancers a common group, or we wouldn’t be able to use the word cancer to group them together. So I try to think about what they have in common and treatments that could be applicable across a broad range of cancers, just because I think it is potentially simpler and easier to have one treatment that works for everybody – though I don’t think we’ll get there – rather than have a million different treatments and a million different drugs for every patient, which I think is impossible. It’s better to think of large groups of people rather than individualizing it too fine, which I think is not a feasible achievement actually.
Pauline Davies: How does that go down with your patients when you say that?
Mark Vincent: Well, they don’t really mind. They are just desperate for any kind of help. I think people are truly desperate. This is an awful disease, they know they are in deep trouble and they will take any kind of help that I think is going to work. They place a lot of faith in me, I feel a great deal of responsibility for them and a lot of the time we end up failing them and that is just the way it is. I think I’m just provoked all the time to think of new and better ways to do it.
Pauline Davies: You’ve come up with a particular set of ideas. Can you tell me about them?
Mark Vincent: The idea about the biological nature of cancer is that a speciation event has occurred to give rise to the cancer. It is no longer the same thing that you and I were, or the patient used to be. It has become a different organism. Basically, there are a couple of opportunities that come from this. The first is to see what kind of organism it is. I think it is a very primitive sort of organism, similar to what used to be in the oceans about one and a half billion years ago when eukaryotic life first evolved and multicellular animals first evolved in a situation of rising oxygen and under stress and so on. I think cancer goes on to the sort of decision of an individual cell; should it be part of the multicellular organism, or should it strike out on its own? When it strikes out on its own, I think it scrambles its genome looking for a better fit with the environment, it multiplies itself, it gets biomass and it escapes out of whatever animal it is in, like a sponge or something. Cancers do that. They all do those three things. They have biomass accumulation, which is growth, they scramble the genome, which is called genomic instability or heterogeneity, but I think there is a purpose behind it, which is, I think an aspect of my thinking which may be unique to what I think about. It also breeches the anatomy, so that it eats its way out of the host into what the cancer thinks is water, as a way to escape from this host. There is a purpose here, it’s a lifeboat and it is trying to survive because it may have sensed that something is wrong with the host, and that the host may die, so it’s trying to check out of the hotel before the hotel burns down, so to speak. All of these cancers have these three things in common. They grow and proliferate, they scramble the genome, and they eat their way out of the host or eat their way through the host tissues. That is common to all of them. I think once you realize it’s a type of life that does that, then I think there are at least four therapeutic opportunities. One is, if it is a foreign organism, it’s going to be antigenic and we know all of this genomic, heterogeneity and so on, displays antigens that are on the cell that the body recognizes as foreign. So there are immense opportunities in immunomodulation that are now being realized. There are drugs now approved to treat melanoma, and very soon lung cancer, that are as effective, or more effective than the chemotherapies that we have. Also, the immune system is sensing the tumor every day and can modulate itself every day for whichever way the tumor tries to find a way around it, the immune system can find a way to beat it. I’m enormously optimistic about that. That is one implication. The second implication is the energy metabolism that cancers use, called the Warburg effect, is fairly different from what normal cells do most of the time. I think there are immense opportunities for selective toxicity between tumor cells and normal cells. Thirdly, I think there is a DNA instability within tumors that everyone recognizes and instead of trying to fix it up and stop it, I think you can block the DNA repair and make the DNA instability worse. We’ve done that in our lab, and the tumors start to go over the edge. There is so much DNA instability, and they live on the edge; if you block the repair that they do have they go right over the edge and I think that is an unusual way of treating cancer. Finally, in order to grow, cancers have to eat otherwise they violate the laws of physics. Basically, there are enormously, we say hyperphagic, they consume enormous amounts of sugar and amino acids and so on. I think that they may even eat the normal cells that they are next too, so I think you can poison the cockroaches by feeding them food particles that are either laced with poison or radioactivity in some way; these cancer cells will digest them greedily and selectively poison themselves, while the host cells get a very low dose, but they can probably survive it. Thinking about cancer as a different kind of organism, whether or not it is strictly true, has certainly led me to think of novel and useful ways to treat cancer, which hopefully independent of whatever theoretical basis they may or may not have, may prove to be useful and we are pursuing at least two of these in our laboratories right now, and hopefully we can get financing to take them into human beings.
Pauline Davies: Which ones are you doing, if you are allowed to say?
Mark Vincent: The one thing that we do, is knock down the gene called BRCA2, which is a gene that is common in breast cancer patients. Women who inherits the BRCA 2 deficiency, the other copy of the gene goes down, in a breast or ovary and they get cancer. But they (the tumors) are very sensitive to platinum chemotherapy or other chemotherapeutics because they cannot repair the DNA damage that is aggravated by the chemotherapy, so I thought, why don’t we make everyone BRCA deficient, and in fact it certainly potentiates platinum and alkylating agents and radiation and other things that cut the DNA with a double stranded break and need repair, but amazingly, what we noticed is that when you do that, the cancer cells themselves are so genomically unstable that you don’t even need chemotherapy or radiation; they start to die. If you block DNA repair, they start to die on their own, that’s a selective difference with normal cells. Normal cells regulate the genome very strictly and cancer cells are so unstable that they, as Shakespeare said, “They are near the edge of doom.” If you simply block the repair, they go over the edge. You sensitize them to platinum, and radiation and alkylating agents, so we are quite hopeful where that’s concerned. Secondly, the other thing we are doing in our laboratory, is looking at tagging amino acids with radiation, radioisotopes. Amino acids like phenytanine and glutamine which cancer cells ingest in very high quantities. They will take in these amino acids thinking that they are simple kinds of food, but if you lace it with poison or radioactive isotopes that’s therapeutic, like a beta emitter or iodine 131, or even an alpha particle emitter, you will kill the tumor fairly selectively with an acceptable radiation dose to the normal tissues is what we think and what we calculate. So we are pursuing both of these opportunities, quite aggressively.
Pauline Davies: Have you had any other ideas for treatment based on what you heard today?
Mark Vincent: I think the other wide range of speakers have talked about other vulnerabilities of the cancer cell related to the metabolism such as the reactive oxygen stress that cancers on, and the proteotoxic. Other people are developing these avenues and including a ketogenic diet or low blood sugars and replacing it with ketones and the cancer cells may not be able to tolerate that. I think other people are trying to develop that and I think they are struggling because the pharmaceutical industry is not involved and you can’t find an easy way to exploit this. I think they are going to have difficulties and I think this may be an example of market failure, where the government might need to step in and provide at least proof of principle to see whether or not these treatments will work because it is not so obvious how the pharmaceutical industry and the private sector might take them forward. I think America is a very inventive country and I’m hoping they can find a way forward, at least in animals, dogs, for example, with hyperbaric oxygen. This is very doable; you just need a bit of government money to achieve proof of principle so, I’m going to let other people take these other avenues forward. We have our hands full just trying to do these two projects and I don’t want to take on more than I can deal with. That’s kind of what we are doing, and over the next couple of years that is what we hope to achieve.
Pauline Davies: What about the artemisinin idea, that they were using that to push cells over the edge? That was another person who spoke at the conference.
Mark Vincent: I have a paper together called the 8 vulnerabilities of cancer cells, but actually I think there are more than 8, but this is certainly one of them – that they are under reactive oxygen stress and that instead of trying to fix this, (the idea is that if there is something wrong with a cancer cell you should try and fix it,) but instead of trying to fix it, you should give it the rope to kind of hang itself. This is a kind of paradoxical approach that has great intellectual appeal to me because it is indirect and cunning; that you can aggravate the abnormalities in cancer cells, rather than trying to fix them. This way of increasing reactive oxygen stress in cancer is enormously attractive because they are near the red line, much nearer than normal cells are. I think you can increase the amount of reactive oxygen species in cancer, you can push them over the edge whereas normal cells can deal with it. I will briefly describe one experience I had with a company that I helped advise: There is a drug call tesmilifene that was actually put into clinical trials, thought to be inactive, but later showed to have a large survival advantage in breast cancer with doxorubicin, (both with and without doxorubicin ). Turns out the way that that drug kills cancer cells is by revving up the P-glycoprotein (Pgp)pump which extrudes something like doxorubicin out of the cancer cell as a way of drug resistance. Instead of blocking that pump, which is what a lot of people think these things should do, it just makes the pump work much harder and by working much harder it depletes the gasoline, which is the ATP. When the ATP drops below a certain level, the mitochondria kick in. The mitochondria are probably abnormal and you get this enormous burst of reactive oxygen species and you selectively kill these cells. This is how I know this drug works because we looked at it with taxol, with vinblastine and a whole variety of tumor cells, Pgp positive/ Pgp negative cells. It only kills the Pgp positive, drug resistant cells and it is almost certainly through this ATP depletion mechanism because these pumps are using up so much ATP you have to aggravate that; instead of trying to stop it, you actually make it worse and they die.
Pauline Davies: Thank you very much!
Mark Vincent: You’re welcome, thank you.
Interview with Georg Wondrak
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Georg Wondrak: My name is Georg Wondrak. I’m working at the University of Arizona, at the College of Pharmacy at the Arizona Cancer Center and I’m an associate professor of pharmacology and toxicology.
Pauline Davies: And in fact your talk just now spent a lot of time discussing possible new drugs that you could use to treat cancer. These are drugs that are being used for other things and haven’t been considered before for cancer.
Georg Wondrak: Yeah right, because it’s repurposing. So you have a drug that has shown efficacy for an indication that is not cancer directed; it could be a blood pressure medication, it could be anti-microbial, anti-malarial and some of these drugs that are, have been well characterized with regard to toxicity, adverse effects, etc., that are known to work in humans. If they can do other tricks, we’ve sort of tried to repurpose them and teach old dogs new tricks.
Pauline Davies: And have you been getting any good results?
Georg Wondrak: Well we work with anti-malarials that are working through induction of oxidative stress. So, these are called artemisinins and it turns out that cancer cells are sensitive to the same mechanisms as malarial parasites being killed by these anti-malarial drugs. So, it’s about these drugs being able to induce oxidative stress. These are peroxides that can decay with the formation of free radicals and they find the targets, because the target is iron rich. Targets with a lot of free iron, such as malaria parasites or cancer cells that mishandle iron, they’re more sensitive to theses drugs. So it is sort of a common denominator that malaria parasites and cancer cells share.
Pauline Davies: That surprises me enormously. I mean I heard about it for the first time today but I believe there is a literature going back a few years.
Georg Wondrak: Yes. So, the fun of repurposing is that you stand on the shoulders of others that have done extensive investigations but have not considered certain new applications, and so you do not have to reinvent the wheel. You can just take the wheel and drive somewhere else, and we drive towards fighting cancer using drugs that can induce oxidative stress or can increase the unfolded protein burden in cancer cells. And cancer cells happen to be very vulnerable to oxidative stress or what’s called a proteotoxic stress. So if you have an agent that can induce oxidative or proteotoxic stress it might preferentially target cancer cells and leave normal cells alone.
Pauline Davies: And I saw that you had some beautiful examples with melanoma.
Georg Wondrak: Yeah so melanoma, you know, it ultimately always depends on which tumor are we talking about, which stage of the tumor, is it a tumor inside you or a metastatic disease, but turns out that melanoma cells, malignant metastatic melanoma cells, are actually under a lot of stress, under a lot of oxidative stress. And so if you stress them further, you can red line the cancer engine and kill them through these drugs.
Pauline Davies: Well that’s amazing! Is that started to be used now, for patients? Are patients starting to use it now?
Georg Wondrak: Yeah well, the nature of the repurposed drugs is if they are approved for clinical use. then the translational aspect is very favorable in that you can switch them quickly. You need still, you know, clinical studies, but they will not run into unanticipated toxicity issues. And so there is anti-malarial called chloroquine that is approved and it is being studied now, clinically in cancer patients for anti-cancer intervention. And so, we’ve sort of build up a pipeline of approved drugs that then can easily be switched.
Pauline Davies: Have you done any research, for instance with the artemisinins in China? Because the people in China were using these drugs as anti-malarials well, since time immemorial. Were they also using them against cancer?
Georg Wondrak: I’m not aware of this, but you’re right the artemisinins are a sort of a prime example of the success of Chinese herbal medicine, you know. The potential anti-cancer activity of artemisinins has been recognized, I would say, not longer than 10 years ago that people started thinking about it. However, the redox directed activity of this agent is very recently only appreciated and so we’re sort of at the forefront of this.
Pauline Davies: And you’ve got some terrific examples.
Georg Wondrak: Well, once you’ve sort of have pharmacological ways that enable you to modulate cell stress responses, whether it’s a heat stress response, proteotoxic stress response, oxidative stress, then you can also use this to protect good cells. You can think about protecting skin cells from environmental damage, for skin photo protection, for protection against environmental carcinogens because if you can up-regulate these kinds of cell stress responses in tissue that you want to protect, then you have a great way of blocking environmental damage.
Pauline Davies: So that’s really the counterview of using these products.
Georg Wondrak: Right. So they could be chemo preventive and they could be chemotherapeutic and that cancer cells cannot deal with increased oxidative, proteotoxic stress, whereas normal cells will adapt to this type of stress and up-regulate endogenous responses. So we’re working on a transcription factor called enerve2, that is an oxidative stress response transcription factor, and if you have ways to mildly stress cells they will become very strong through enerve2 up-regulation and then will be very resistant to environmental stress. So if you find compounds again that impose mild oxidative stress, then you can actually tell good cells to protect themselves and thereby have chemo preventive agents.
Pauline Davies: So ultimately, what are you doing?
Georg Wondrak: Well, we basically harness the cells endogenous ability to adapt to stress. That’s what we are doing. We impose stress in the hope of tweaking the cell stress responses in a way that good cells adapt and become more resilient and cancer cells, which are already under high stress levels, just fall apart because it’s getting too much. That’s what we do.
Pauline Davies: Thank you very much.
Georg Wondrak: You’re welcome!
Interview with Anne Devin
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Anne Devin: My name is Ann Devin. I’m French and I’m a biochemist research director in France and I study the biochemistry of the Warburg effect.
Pauline Davies: You just gave a talk this morning and it generated a lot of conversation, didn’t it?
Anne Devin: It did. It did. Absolutely. Well, I wanted to introduce new concepts, and I think, I think I made my point.
Pauline Davies: Ok, well before we get into that controversial stuff. I was really struck by a particular number you put on the white board. You had, the fact that I think that ATP turns over at a very fast rate and I think it’s 70 kilograms a day, that’s made out of ATP and then destroyed. Is that correct?
Anne Devin: That’s correct. Absolutely. That’s for a regular individual of course, of regular build, but that’s 70 kilos a day, yeah.
Pauline Davies: I just find that totally stunning.
Anne Devin: It is. And that’s why we can’t have any defect in ATP production in the cell. Otherwise, it shuts down immediately.
Pauline Davies: Which brings us straight away to the mitochondria, that are so important to making the ATP.
Anne Devin: Exactly. It’s very efficient in making ATP. A lot more than the other pathway that makes ATP, which is glycolysis, and if you shut down mitochondria than you have troubles.
Pauline Davies: Now, a speaker before you, Thomas Seyfried, was talking about mitochondria being defective and maybe vanishing entirely from cells but you say that’s not the case.
Anne Devin: Yeah, that’s what I said. There’s a big difference in being defective and having less mitochondria that are functional. So that was my first point, I’m not sure they’re defective, but you have less so you make less ATP from the mitochondria. And the second part of your questions was?
Pauline Davies: That the mitochondria never completely disappear. They always have to be there in some form but just less in some tumors, is that correct?
Anne Devin: Yeah. that’s correct. So what I was saying is that there’s a difference in the mitochondrial oxidative phosphorylation that makes ATP, that we look at most of the time and the mitochondrial compartment, which does a lot of other things. And you can have mitochondria, which do not make ATP but you have to have mitochondria to make all the other things that are necessary for cells to survive.
Pauline Davies: So in your opinion, what importance do mitochondria have in tumor formation?
Anne Devin: Uh, that’s a good question. Well you have to repress mitochondrial ATP synthesis to be able to over-activate glycolysis, the Warburg effect, so that’s the first thing. And the second thing is that mitochondria is going to provide precursors to biomass so you cannot shut it down completely. You can shut down the ATP synthesis part, but not the matrix part, which provides precursors.
Pauline Davies: So, are you finding also that when you have few mitochondria, cancer is more likely to come about?
Anne Devin: It’s more likely to proliferate faster.
Pauline Davies: Right. So you want to normalize the number of mitochondria in a cell. Is that correct?
Anne Devin: That’s correct right now we’re more looking into how not to get the mitochondrial repression as a way to limit tumor proliferation, exactly.
Pauline Davies: What else did you talk about?
Anne Devin: Oh I talked about the other thing that I think is very important in cell proliferation, which is NADH that’s co-enzyme reoxidation. I talked about it just because it tends to be forgotten, but during proliferation cells are going to produce NADH. And in order to sustain proliferation, you need to reoxidize it and glycolysis or fermentation is not the way to do it. So you need to find a way and that’s why you can’t completely repress mitochondria, because mitochondria is able to reoxidize NADH very efficiently.
Pauline Davies: And for tumor cells, what is the implication of having a lot of NADH.
Anne Devin: If they have too much NADH they won’t be able to proliferate any more because they need the oxidized form that’s NAD, to be able to proliferate.
Pauline Davies: And finally, how would you write the importance of mitochondria in causing cancer as opposed to changes in nuclear DNA.
Anne Devin: I think mitochondrial metabolism is primary in causing tumor progression. Definitely.
Pauline Davies: Thank you.
Interview with Tom Seyfried
Thomas Seyfried: It’s the ketogenic diet that is restricted in the amount of consumption. The purpose is to lower the fuel for cancer cells, which is glucose, and elevate an alternative fuel, which is ketones, that the cancer cells cannot use but the normal cells can use. So the normal cells transition away from their traditional fuel, which is glucose, to an alternative fuel, a ketone body, and the cancer cells cannot use the ketone body effectively because of their mitochondrial dysfunction.
Pauline Davies: And very basically, this diet avoids starch, doesn’t it? It avoids starch and sugars.
Thomas Seyfried: Yes. It avoids most starches and most sugars. There are some complex carbs that are ok. The idea is getting the blood sugars, blood glucose down into the ranges that would put stress on cancer cells. That’s the key.
Pauline Davies: Ok, so when we were last speaking, I think it was of an extremely restrictive diet for several days or weeks but you feel that now people don’t have to be so extreme for so long to have a really good effect on cancer?
Thomas Seyfried: It’s quite variable from one person to the next. Some people don’t require as much restriction or such an extreme form, whereas others, to get their management under control, will require a little bit more restriction and careful management. So we’re learning as more and more people do this what seems to be a range of variability among people with cancer from one person to the next. So it has to be an individual preparation for that person.
Pauline Davies: And who can advice on that?
Thomas Seyfried: Usually nutritionists will get the feedback from the patients’ blood glucose and ketones and then will know what they’re reading and how it effects their overall metabolic homeostasis with respect to those molecules. And then based on that information we can add or subtract components from the diet to keep the person in a metabolic state.
Pauline Davies: Now this is a completely different way of thinking about nutrition when it comes to cancer patients, isn’t it?
Thomas Seyfried: Yeah, the design of this therapy, metabolic therapy is to kill the cancer cells while enhancing the health and vitality of the normal cells. So this is a metabolic therapy. It’s an alternative to chemo and radiation.
Pauline Davies: And to get more information, how can people find out more about this?
Thomas Seyfried: Well, there are certain organizations. I would suggest that they look to the Single Cause, Single Cure Foundation from Travis Christofferson. It’s on the web. http://www.singlecausesinglecure.org/author/travisc/ They’re collecting a lot of information from different scientists, books, and other organizations that are starting to focus their attention on metabolic therapy as an alternative or complimentary approach to managing cancer. There is a nice website. There is a lot of information on this website.
Pauline Davies: And do you think that using this sort of therapy is a good way of actually avoiding cancer in the first place?
Thomas Seyfried: Well, that’s a different story. I mean, most people deal with the disease once they have it. Most people live their life not worrying everyday about whether they’re going to get cancer or not. Certainly, there are paleolithic groups and calorie restrictive groups. These people are already doing this kind of a diet. There are small groups of people out there that are doing this. Although the people who follow these Paleolithic diets, which are basically low carbs diets, they are similar in some ways – not as restrictive. They’re doing it to become overall in better health but of course the secondary effect would be the risk for cancer would go down significantly.
Pauline Davies: Ok. Well I’ll let you go off to dinner now. What are you going to eat?
Thomas Seyfried: A nice glass of water.