Therapies
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"Everyone has a doctor in him; we just have to help him in his work. The natural healing force within each one of us is the greatest force in getting well...to eat when you are sick, is to feed your sickness."
- Hippocrates.
In the previous article, we introduced a metabolic theory of cancer.
Such a theory provides a proximate (the how) and an ultimate (the why) explanation for cancer (the what). Proximately, prolonged exposure to a cell environment containing toxins, radiation, or some other mitochondria-damaging factor is followed by mitochondrial dysfunction, forcing the cell to decrease oxygen-based respiration and compensate by increasing non-oxidative glucose fermentation and glutamine pseudo-respiration. Ultimately, any additional prolonged exposure to an oxygen-deprived, nutrient-rich cell environment is followed by ancient gene reactivation which instructs the cell to revert even further to non-oxidative metabolism as well as non-stop growth and replication. The end result is a cell that has been both forced by its dysfunctional mitochondria and instructed by its reawakened ancient genes to endlessly ferment, pseudo-respire, grow, and replicate. A cancer cell.
In this metabolic theory of cancer, it is the cell environment that dictates whether mitochondria become dysfunctional and whether ancient genes are reawakened. There is little doubt that prolonged exposure to myriad environmental factors is associated with increased cancer development and progression (1,2). Yet the "why" of cancer - an oxygen-deprived, nutrient-rich cell environment - dates much further back into evolutionary history, so it is arguably the more important driver of cancer. Let us examine the evidence for this statement - do cancer cells actually survive, grow, and replicate in an oxygen-deprived, nutrient-rich cell environment?
Regarding the former, it is a well-known fact that oxygen deprivation, or hypoxia, is a hallmark of cancer (3,4). Due to their chaotic, leaky blood supply, most advanced solid tumours contain hypoxic "pockets" distributed throughout the tumour mass (4). With hypoxia, normal cells reduce their growth and replication, but cancer cell simply shift to non-oxygen dependent metabolic pathways and carry on growing and replicating (5). In fact, a number of studies have shown that hypoxia selects for even more aggressive, malignant cancers (3,6).
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Solid tumours have a chaotic blood supply, with hypoxic pockets distributed throughout the tumour mass.
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Thus, the evidence suggests that the answer is yes - an oxygen-deprived, nutrient-rich environment encourages the survival, growth, and replication of cancer cells. Moreover, it is important to note that hypoxia and obesity are not mere "side-effects" of cancer (5), but key factors that tumours rely upon to promote their expansion.
The implications that environmental conditions trigger cancer formation on an ultimate, "why" level are enormous, for it means that the creation of an oxygen-rich, nutrient-deprived cell environment should:
(1) Provide a major survival advantage to normal cells - Normal cells rely heavily on oxygen for respiration (oxygen-based ATP production) and in times of nutrient scarcity can enter a protective state of catabolism (focus on repair and survival).
(2) Provide a major survival disadvantage to cancer cells - Cancer cells rely heavily on the nutrients glucose and glutamine for fermentation and pseudo-respiration (non-oxygen based ATP production) and remain stuck in non-stop anabolism (focus on growth and replication).
If such an oxygen-rich, nutrient-deprived cell environment enhances respiration and catabolism, then perhaps we can "turn" cells that are half-way down the road to cancer, and make conditions incompatible with survival for cells that are already highly cancerous.
Let's examine the evidence for this proposition.
Enhancing Cell Respiration
If the metabolic theory is correct, an increase in oxygen levels in the cell environment ought to favour normal cells that rely largely on oxygen-dependent respiration while disadvantaging cancer cells that rely on oxygen-independent means of energy production, such as fermentation and pseudo-respiration. Let's see if this is really true.
(1) Hyperbaric oxygen therapy (HBOT).
The most direct way to increase oxygen levels in the cell environment is to flood the body with oxygen using HBOT, which involves breathing 100% oxygen at high pressures. HBOT substantially raises oxygen levels within tumours (2), dissipating the hypoxic pockets and relieving the pressure on cells to resort to pseudo-respiration and fermentation. Moreover, it increases intracellular levels of reactive oxygen species (free radicals) - normal cells can tolerate this, but cancer cells, with their damaged mitochondria, are prone to oxidative damage and cell death with even modest increases in reactive oxygen species (11).
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In HBOT, the body is flooded with oxygen by breathing 100% oxygen at high pressures. HBOT is already used for many medical conditions, such as wound healing - could it be useful in cancer? |
The evidence that HBOT can treat cancer is preliminary, but it is suggestive. In studies using animal models, HBOT has generally been shown to induce cancer cell death, and can lead to a less aggressive tumour type (12,13). Multiple studies involving animals and humans also show that HBOT enhances tumour destruction when used alongside conventional surgery, chemotherapy, and radiotherapy (14). To date, the main problem with the studies on HBOT and cancer is that there simply aren't enough of them.
(2) Exercise.
A more indirect method for increasing oxygen levels in the cell environment is exercise. Surprisingly, exercise training in rodents with tumours results in a substantial 100% increase in oxygen partial pressure in the tumour circulation, an effect that is maintained for at least 48 hours after exercise cessation (15). Moreover, tumours in exercise-trained rodents at rest are only 4% hypoxic by area, whereas tumours in sedentary rodents are 39% hypoxic by area (15), an appreciable difference.
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If wheel-based exercise training in rodents with tumours increases tumour oxygen levels by 100%, what could the effect be in humans undergoing high-intensity training? |
The evidence that exercise can treat cancer is preliminary, but intriguing. In rodents, "jump" exercise training induces a significantly lower tumour weight compared to sedentary rodents (16). In humans, a 2016 meta-analysis involving 1.44 million participants that encompassed 26 different types of cancer showed that people who took part in leisure time physical activity acquired less cancer compared to people who did not (17). Unfortunately, at this time human studies on exercise and cancer are mostly observational in nature.
In summary, the evidence for HBOT and exercise in reducing cancer development and progression is preliminary, but it is tantalizing. The main problem is the relative lack of research into the effects of HBOT and exercise on cancer in humans.
Enhancing Cell Catabolism
The metabolic theory also predicts that a decrease in nutrient levels in the cell environment ought to favour normal cells capable of switching into a protective state of catabolism while disadvantaging cancer cells that remain stuck in non-stop growth and replication mode. Once again, let's see if this is true.
(1) Calorie restriction.
It has long been known that calorie restriction, defined as a 20-40% reduction in calorie intake, results in myriad effects that promote catabolism. Calorie restriction modestly reduces the anabolic nutrient sensors insulin, insulin-like growth factor 1 (IGF-1), and mTOR, all of which play significant roles in the development and progression of many cancer types (7,8). Moreover, calorie restriction mildly stimulates the catabolic nutrient sensor AMPK, which promotes cell catabolism and autophagy (recycling of damaged or unnecessary cell components so they may be used for energy) (7,8).
There is compelling but impractical evidence that calorie restriction can treat cancer. In animals, a review of 21 studies involving multiple cancer types showed that calorie restriction reduced tumour incidence by 75.5% (18). Moreover, a 20-year randomized controlled trial involving rhesus monkeys showed that calorie restriction reduced cancer incidence by 50% in the calorie-restricted group compared to the controls (19). In humans, many studies show that calorie restriction correlates with less cancer - for example, residents of Okinawa, Japan, who traditionally consumed fewer calories compared to residents of the main Japanese islands, have always had comparatively lower death rates from cancer (20), and patients with anorexia nervosa, a condition associated with periods of calorie restriction, have a reduced risk of breast cancer (21). The main problem with calorie restriction is that it is too difficult for most people to maintain it for long time periods, so its practical feasibility in humans is limited.
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In a 20-year randomized controlled trial involving rhesus monkeys (19), calorie restriction reduced cancer incidence by 50% in calorie-restricted monkeys (the monkey on the right, boxes C and D) compared to controls (left, boxes A and B). Although the control monkeys look much older, both monkeys are 27.6 years old. |
(2) Ketogenic diets.
A ketogenic diet typically consists of high fat, moderate to low protein, and very low carbohydrate content with a 2:1, 3:1, or even 4:1 ratio of fat to protein + carbohydrate by weight (22). The carbohydrate shortage forces the body to burn fat instead of glucose for energy; much of the fat is oxidized by the liver to produce ketones, which in turn are transported to cells throughout the body and used to make ATP energy. Ketones are converted into acetyl-CoA, which bypasses glycolysis and is instead respired in the Krebs cycle and electron transport chain, producing ATP energy in the process. One powerful aspect of ketogenic diets is that they enhance both cell respiration and catabolism. Regarding respiration, such a diet provides low amounts of glucose and glutamine but plenty of ketones, thus depriving cancer cells of their primary fuels while providing an alternative fuel that they cannot use and may even harm them (22) - in contrast, normal cells have no problem respiring ketones for ATP energy. Regarding catabolism, ketogenic diets reduce the anabolic nutrient sensors insulin and IGF-1 (22), and to an extent mTOR if the protein content is low enough (23). It is well-known that high-fat diets can result in considerable weight loss, thus counteracting obesity.
There is compelling but convoluted evidence that ketogenic diets can treat cancer. In animals, ketogenic diets in rodents have been shown to significantly reduce tumour volumes and increase survival time compared to those fed a standard "Western diet" (24), and other animal studies show similar results (25). In humans, approximately 75 patients with advanced cancer have attempted to treat their tumours with a ketogenic diet (26-33). In general, the ketogenic diet slowed or halted - but rarely reversed - the advanced cancers in these people. However, these human studies are difficult to interpret as (1) most of the diets contained too much protein, which would have supplied plenty of glutamine to fuel tumour growth, (2) in virtually all patients, the ketogenic diet was used as an adjunct therapy to conventional surgery, chemotherapy, or radiotherapy, muddying interpretation of the results, and (3) most conventional regimes included corticosteroids, anabolic drugs that elevate blood glucose and insulin levels, which would have supplied plenty of glucose to fuel tumour growth while also counteracting the catabolic effects that ketogenic diets seek to enhance.
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A ketogenic diet is low in carbohydrates and moderately low in protein. The Atkins diet is also ketogenic, but the moderately high protein content makes it unsuitable for treating cancer. The standard US diet is high in (refined) carbohydrates - perfect for cancer growth.
Corticosteroids are frequently prescribed for people on chemotherapy, but given that they elevate blood glucose and insulin levels, these drugs are counterproductive for treating cancer from a metabolic standpoint. |
(3) Periodic fasting.
Beyond calorie restriction and ketogenic diets, there is periodic fasting, defined as a willing abstinence from all or nearly all food and drink for 24 hours or more (typically, two to seven days) (34). Such fasting can be done several ways - the usual ways are a water-only fast, or a fast that also allows drinks with virtually no calorie content such as black coffee or tea, or a fast that allows meals with minimal calorie content such as bone broth. With periodic fasting, the carbohydrate shortage is severe - like a ketogenic diet, the body is forced to burn fat for energy, but unlike a ketogenic diet, all of that fat comes from the body's own fat reserves. Like ketogenic diets, periodic fasting enhances both cell respiration and catabolism, but the effect is much more powerful. Regarding respiration, compared to ketogenic diets the glucose and glutamine levels are pushed even lower and the ketone levels even higher - thus, rather than merely depriving cancer cells of their primary fuels, periodic fasting virtually starves them while also immersing them with an alternative fuel that they cannot use and may even harm them (22) - in contrast, normal cells easily survive such an environment. Regarding catabolism, compared to calorie restriction and ketogenic diets the anabolic nutrient sensors insulin and IGF-1 are pushed even lower, and since there is no protein entering the body, periodic fasting profoundly reduces the cancer-promoting nutrient sensor mTOR (34,35). Moreover, the often-forgotten but extremely powerful catabolic nutrient sensor AMPK rises sharply with multiday fasts (34). Periodic fasting is probably the most effective method for inducing weight loss and counteracting obesity.
There is compelling but insufficient evidence that periodic fasting can treat cancer. It is known that fasting promotes longevity in a broad range of organisms, from bacteria to mammals (34). In humans, two studies have investigated periodic fasting in patients with advanced cancers. The first study involved ten patients with various advanced cancers who fasted for 48-140 hours before and 5-56 hours after chemotherapy (35). It showed that periodic fasting was feasible, reduced chemotherapy toxicity, and the advanced cancers remained stable. The second study was a randomized controlled trial involving 13 women with breast cancer, with seven patients randomized to a 24-hour water, coffee, and tea fast before and after chemotherapy (36). Periodic fasting was well-tolerated, reduced chemotherapy toxicity, and induced faster recovery from chemotherapy-related DNA damage in normal cells. Unfortunately, there are serious problems with these studies including (1) in most patients, the fasting regimes were too short to awaken the more powerful aspects of fasting, with most lasting 24-48 hours, (2) periodic fasting was used as an adjunct therapy to chemotherapy, with an emphasis placed on fasting feasibility rather than effects on tumour growth, and (3) most conventional regimes included corticosteroids, thus supplying plenty of glucose to fuel tumour growth as well as counteracting the catabolic effects of fasting.
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Greek philosopher and "Father of Medicine" Hippocrates knew about the potential power of periodic fasting when he stated, "Everyone has a doctor in him; we just have to help him in his work. The natural healing force within each one of us is the greatest force in getting well...to eat when you are sick, is to feed your sickness." This quote may be particularly applicable to cancer.
Corticosteroids also hijack the fasting studies on treating cancer in humans. |
In summary, the human evidence for calorie restriction, ketogenic diets, and periodic fasting in reducing cancer development and progression is supportive, but suffers from crucial limitations. In most people, calorie restriction is not practically feasible. Regarding ketogenic diets, the high protein content and emphasis on conventional treatments, including counter-productive corticosteroids, makes the results of the ketogenic diet studies difficult to interpret. In theory, periodic fasting is the most powerful anti-cancer treatment of them all, but the insufficient lengths of the fasting regimes and emphasis on chemotherapy, and again the presence of corticosteroids, severely hinders the interpretation of the true effects of periodic fasting on cancer.
A Metabolic Therapy For Cancer
The metabolic theory of cancer incriminates mitochondrial dysfunction and ancient gene reactivation as the proximate and ultimate forces driving cancer cell behaviour. If true, then cancer is fostered by prolonged exposure to toxins, radiation, and other mitochondria-damaging factors in the cell environment, but more importantly it is fostered by prolonged exposure to an oxygen-deprived, nutrient-rich cell environment. The latter is critical, for it implies that in order to cure cancer, the most imperative therapeutical aspect is to correct the "why" of cancer. So long as an oxygen-deprived, nutrient-rich cell environment continues to encourage normal cells to become cancerous, cancer will thrive no matter how many cancer cells we destroy with conventional methods.
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The what - cancer.
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Make no mistake, the weakness of cancer cells is that they are actually damaged, metabolically inflexible cells - impaired in their ability to respire oxygen, susceptible to energy failure when nutrients are scarce outside the cell. Normal cells, in contrast, get stronger under the very conditions that weaken cancer cells - they actually prefer to respire oxygen, and they enter a self-reparative catabolic state in times of nutrient scarcity. The Achilles' heel of cancer cells is their preference - no, their reliance - on an oxygen-deprived, nutrient-rich cell environment. Rather than use conventional surgery, chemotherapy, and radiotherapy, perhaps it would be more successful if we changed the rules of the game - the cell environment - to tilt the odds in favour of normal cell behaviour over cancer cell behaviour.
Although we have discussed several therapies that can alter the cell environment, we are not restricted to one therapy at a time. Therapies can be combined, and some studies have explored this possibility. One 2013 randomized controlled trial separated rodents with metastatic cancer into three groups - HBOT alone, ketogenic diet alone, and a third group, HBOT combined with a ketogenic diet (14). The HBOT group had no increase in mean survival time whereas the ketogenic diet group increased mean survival time by 57%. However, the HBOT plus ketogenic diet group had a 78% increase in mean survival time, suggesting synergy in combination. Another 2012 study examined the effects of a 35% calorie restriction combined with a ketogenic diet in humans with incurable cancers for 28 days (29). Unfortunately, the ketogenic diet was weak and had a protein content that was far too high - even higher than the fat content! - thus the cancer cells would have been deprived of glucose but immersed in plenty of glutamine, and the anabolic nutrient sensor mTOR could not have been appreciably suppressed. Still, the six patients with the highest ketone levels demonstrated either partial remission or stable disease.
At the end of the day, I suspect the best way to prove or disprove the metabolic theory of cancer is to combine the only two therapies that enhance both cell respiration and catabolism - ketogenic diets and periodic fasting. In theory, an advanced cancer could be held in check by a ketogenic diet low in carbohydrates, limiting glucose fermentation, insulin, and IGF-1, as well as moderately low in protein, limiting glutamine pseudo-respiration and mTOR. Then, periodic fasts of at least four to seven days duration could be incorporated at regular intervals; these fasts would severely restrict glucose, glutamine, insulin, IGF-1, and mTOR, and critically they would elevate AMPK. Theoretically, the ketogenic diet would weaken the most cancerous cells, and the periodic fasts would kill them. Normal cells would survive, and crucially, given the nutrient-deprived cell environment, they would not be encouraged to alter their metabolism, reactivate their ancient genes, and become cancerous in the first place.
Can such a study be done, and more importantly, could it actually work?
Given time, perhaps - let's wait a while, see what happens.
Solace.
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