Fasting may help some cancer drugs work better
Diet plus drugs may offer a powerful combination therapy.
Cancer cells are ravenous consumers of nutrients. For this reason, scientists are investigating whether fasting — essentially starving cancer (and the body) of nutrients — can impede malignant cells. Now, fresh findings in mice offer more evidence to back the hypothesis: Fasting combined with a drug treatment helped stall tumor growth in the animals. If it pans out in further studies in humans, fasting might become a weapon for treating these deadly diseases.
What’s New — In the new study, scientists at the Medical University of Graz in Austria found that fasting — combined with drug treatment — may delay tumor growth for a type of drug-resistant cancer. Specifically, the mice that fasted held off tumor growth for four weeks longer than mice on a regular diet. The study was published earlier this month in the journal Science Advances.
The study jibes with older research in animals and cells showing similar therapeutic effects. There have been some preliminary studies on humans, which have found that fasting can shrink tumors and help prevent cancer recurrence, too. But the evidence isn’t strong enough to make fasting a go-to treatment option in the clinic.
In this study, the researchers move the science forward by looking at the effects of fasting on tumor growth in two ways: in mouse models and in organoids, which are lab-created tissues that can mimic the traits of a cancerous tumor.
The researchers tested how a combination of fasting and a cancer drug called sorafenib altered the course of the illness in both models. The drug works by blocking a cancer cell’s ability to replicate, though it can become less effective as cancer cells develop resistance to it over time.
This research suggests that this drug resistance can potentially be delayed through fasting, Andreas Prokesch, one of the study authors, tells Inverse.
“[W]e could show that if we additionally fast — in either patient-derived organoids or mouse models — on top of the treatment with sorafenib, then we can alleviate this resistance towards the drug. So together the drug and fasting has a synergistic effect that slows down tumor growth.”
The study was specific to liver cancer, but the authors think it has implications for other types.
How They Did It — The researchers injected lab mice with hepatocellular carcinoma cells, a common type of liver cancer known to be drug-resistant.
The mice were separated into three groups, and each group was put on a different diet. One was fed a regular diet, another was made to fast for 24 hours twice a week, and the last group was fed a crushed-up, rodent-friendly mix of ProLon, a low-calorie food product that instigates a metabolic response that mirror’s the body’s reaction to fasting. Additionally, the researchers gave all the mice the cancer drug, sorafenib.
Prokesch notes that the two “fasting” diets were not designed to cause the mice to lose weight.
“In tumor patients, you don't want to cause [weight loss],” he says, “because very often, patients can be metabolically compromised.”
In a separate, but related experiment, the researchers generated cancerous cells (of the same type of liver cancer) and put them in a solution that was devoid of nutrients which would mimic starvation.
Organoids put in the starvation mix were unaffected; they continued to grow at an ordinary pace. But the organoids put in the starvation mix and treated with sorafenib had a reduced growth rate. This suggests the combination of the drug and fasting is critical. The study deems the p53 effect “necessary” and “crucial” to its results.
Why It Matters — Prokesch says there are many caveats to this study, and what it means for fasting’s role in cancer treatment. For example, the results may not apply to all types of cancers.
“If you look at it in another cancer type, it might not be the case that fasting has a big contribution,” he says.
But there is reason to think that further research might show fasting can be an extra weapon against cancer, with a range of uses, he says.
“With this energy demand of cancer cells, it is reasonable to believe that fasting can really be an additional therapeutic for many different cancer types because all of them need to grow, all of them need to double and multiply their biomass, and this is what fasting can restrict.”
What’s Next — It’s important to note that this research has a long way to go before being put to use regularly in cancer treatments for humans, even for this specific type of liver cancer. Next, Prokesch will need to complete clinical trials in humans, which could take a number of years. Then, if the results are still promising, fasting could potentially be used in humans.
Prokesch said that he is aware of as-yet-unpublished research that he says will show that fasting diets, like ProLon, are not harmful to cancer patients. That will allow his team to work on a clinical trial in humans that may validate some of the findings of the mouse study.
So all of this is to say fasting probably won’t be part of cancer treatments any time soon, but it shows that we still have much to uncover about how our bodies, including our cells, function in the absence of sustenance.
Abstract: Cancer cells voraciously consume nutrients to support their growth, exposing metabolic vulnerabilities that can be therapeutically exploited. Here, we show in hepatocellular carcinoma (HCC) cells, xenografts, and patientderived organoids that fasting improves sorafenib efficacy and acts synergistically to sensitize sorafenib-resistant HCC. Mechanistically, sorafenib acts noncanonically as an inhibitor of mitochondrial respiration, causing resistant cells to depend on glycolysis for survival. Fasting, through reduction in glucose and impeded AKT/mTOR signaling, prevents this Warburg shift. Regulating glucose transporter and proapoptotic protein expression, p53 is necessary and sufficient for the sorafenib-sensitizing effect of fasting. p53 is also crucial for fasting-mediated improvement of sorafenib efficacy in an orthotopic HCC mouse model. Together, our data suggest fasting and sorafenib as rational combination therapy for HCC with intact p53 signaling. As HCC therapy is currently severely limited by resistance, these results should instigate clinical studies aimed at improving therapy response in advanced-stage HCC.
