This 2012 mouse trial tested the effects of fasting on the growth of various cancers and considered potential mechanisms for these effects. Fasting’s clinical significance lies in its ability to induce differential stress sensitization — that is, to simultaneously increase the susceptibility of cancer cells to chemotherapy while protecting healthy cells.
First, breast cancer cells were incubated (in vitro) in medium supplemented with serum from either fasted mice or mice fed ad libitum (i.e., able to eat as they wished). The cancer cells in serum from fasting mice proliferated more slowly and showed increased cell death when the cells were exposed to a chemotherapeutic agent. When the same test was repeated in vivo (in mice bearing subcutaneous murine breast cancer), two cycles of fasting alone were as effective as two cycles of chemo, while the combination of fasting and chemo reduced mean tumor size by 50%. Similar effects were shown when mice were instead given human breast cancer or ovarian cancer xenografts.
When mice were given metastatic tumors, mice treated with both fasting and chemotherapy were half as likely to show evidence of metastasis as those treated with chemo alone. When treated with neuroblastomas, 100% of mice on chemo alone died within 180 days, while 42% of those treated with chemo + fasting survived for this period. When the cells were injected rather than implanted and allowed to grow for nine days before treatment, 100% of mice on chemo alone died within 75 days, while 25% of mice on chemo + fasting survived this period. All surviving mice remained cancer-free at 300 days and regained healthy weight.
Mechanistically, the authors argue the beneficial impact of fasting is related to its effects on glucose and IGF-1 levels. During fasting, normal cells downregulate growth, an adaptation that reduces the level of chemotherapy-induced oxidative stress they experience. Cancer cells, conversely, show the opposite effect, increasing growth signaling and so exacerbating the impact of chemotherapy on oxidative stress and DNA damage. This was supported by in vitro tests, which showed serum low in glucose and IGF-1 reduced cancer cell growth and increased sensitivity to chemotherapy, while adding IGF-1 to fasted mouse serum protected tumor cells from chemotherapy’s effects.
In summary, this trial showed that in mice, fasting increases the sensitivity of tumors to chemotherapy and so may increase the effectiveness of chemotherapeutic agents. These effects are likely related to the impact of fasting on blood glucose levels and/or IGF-1.
The authors noted multiple clinical trials testing this hypothesis in humans. One that has since been published showed fasting is well tolerated and appears to improve quality of life during chemotherapy. One is ongoing. A third was completed in late 2018, but results have not been published.
Fasting, the authors note, differs markedly from broad caloric restriction with regard to the observed effects. The beneficial effects of fasting seem to be related to its impact on glucose and IGF-1 levels (or mechanisms closely related to these biomarkers). Fasting leads to substantial reductions in both blood glucose and IGF-1 within two to four days, without weight loss; conversely, 20 to 40% caloric restriction requires weeks to months to have a similar effect (and even then, only when protein is restricted as well) and necessarily induces weight loss in the process.
Comments on Fasting Cycles Retard Growth of Tumors and Sensitize a Range of Cancer Cell Types to Chemotherapy
Great way to apply the Metabolic Theory of Cancer to new ways to fight Cancer.
Dr. Valter Longo and his group have been evaluating the influence of therapeutic fasting on tumor growth and patient response to chemotherapy for some time. His findings in mice support our original results showing that calorie restriction (CR) of either a standard high carbohydrate diet or a ketogenic diet can lower glucose and IGF-1 levels (DOI:10.1038/sj.bjc.6600298; DOI:10.1038/sj.bjc.6601269; DOI:10.1158/1078-0432.CCR-04-0308). We showed that a 40% calorie restriction in the mouse is comparable to water-only fasting in humans due to differences in basal metabolic rate, which is about 7x faster in mice than in man (DOI:10.1186/1476-511X-5-13). It is therefore important to distinguish the differences in calorie restriction in mice and in humans. Nevertheless, water-only fasting in humans or a 40% CR in mice will produce similar effects in reducing tumor growth in “natural hosts”. These therapeutic effects observed in natural syngeneic hosts, however, might not be seen when human tumors are grown as xenografts especially in immunocompromised Non-Obese-Diabetic mice (NOD/SCID) that have characteristics of Type1 and Type 2 diabetes, as was recently described (http://dx.doi.org/10.1101/659474). Caution is therefore necessary when interpreting data obtained from human tumors grown in unnatural hosts.
In addition to reducing glucose and IGF-1 levels, we showed that CR and restricted ketogenic diets also reduces AKT-linked angiogenesis and NFk-b mediated inflammation in the tumor microenvironment (doi: 10.1158/1078-0432.CCR-08-0213; doi: 10.1371/journal.pone.0018085). Unrestricted consumption of ketogenic diets in mice, however, can provoke tumor growth by creating insulin insensitivity leading to elevated glucose and IGF-1 levels (DOI:10.1186/1743-7075-4-5; doi: 10.1186/1743-7075-11-23). Hence, restricted consumption of KD is necessary for therapeutic effect.
It is important to mentioned that in addition to glucose, glutamine also fuels tumor growth through a fermentation mechanism in the mitochondria. Our new studies highlight the synergistic action of glucose and glutamine targeting for the metabolic management of malignant cancers (doi: 10.1038/s42003-019-0455-x; doi: 10.1007/s11064-019-02795-4; doi: 10.1177/1759091418818261). Cancer cells cannot survive in the absence of glucose and glutamine after the body is first transitioned to therapeutic ketosis.
Sorry if I missed it but I don't see a link to the original paper or title, authors etc that would let me look it up. Can you share?
Thank you for the catch, Charlie. The link and citation are in the post now.
Would a keto diet have similar results to fasting? Especially if limiting protein intake?
Depends on how you interpret this data, and what you believe the ketogenic diet specifically does.
The authors here certainly try to argue the effects on IGF-1 are particularly important...in another paper Valter Longo authored (https://www.crossfit.com/essentials/fasting-molecular-mechanisms-and-clinical-applications), he doubles down on this argument, pointing out that fasting leads to more rapid and more significant IGF-1 suppression than either general caloric restriction or a ketogenic diet. I don't recall ketogenic diets leading to significant IGF-1 suppression, but I'm not aware of research specifically on protein-limited KDs, which could capture this effect.
Of course, the glucose suppression likely has an impact as well, but the researchers didn't test the impact of glucose as specifically as they did IGF-1. (Namely, they didn't test whether adding glucose alone to a serum that remained low in IGF-1 reduced the effectiveness of chemo - a state that would roughly mimic the effects of a KD).
If there's data showing a KD can suppress both glucose and IGF-1 levels the same way fasting does, then I would expect - based on this trial and a couple others by many of the same group - for the KD to have similar benefits. I don't THINK it does, but I can't say for sure, nor can I say that specific forms of the KD wouldn't have those benefits.
The effects would be expected to be similar or related to effects of KD. The strange thing about this paper is the absence of the EIR (elephants in the room): ketone bodies and the effects of insulin. The animals are presumably in ketosis and insulin and IFG-1 interact with each other. I think that generally insulin is more important in that it directly regulates IGF-1 binding. The direct effect of ketone bodies on the metabolic pathways, however, is of clear importance.
Because of many precedents, one has to be suspicious that this may be another attack on ketogenic diets, however much passive aggressive.
Fasting Cycles Retard Growth of Tumors and Sensitize a Range of Cancer Cell Types to Chemotherapy
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