Biology

Fasting Mimicking Diet Improves Chemotherapy Effectiveness and Reduces Side Effects


The fasting mimicking diet emerged from efforts to better define the dose-response curve for beneficial effects resulting from a reduced calorie intake. Fasting is beneficial, calorie restriction is beneficial, but where are the dividing lines? How much food can one eat and still obtain near all of the benefits of fasting? As a result of this work, the fasting mimicking diet has undergone clinical testing in cancer patients. Numerous benefits have been demonstrated, and the paper here is an example of the type. In this human trial, fasting mimicking reduced the negative short term impact of chemotherapy on health, and, further, three to four times as many patients experienced a strongly beneficial response to the chemotherapeutic treatment.

Extensive preclinical evidence suggests that short-term fasting and fasting mimicking diets (FMDs) can protect healthy cells against the perils of a wide variety of stressors, including chemotherapy, simultaneously rendering cancer cells more vulnerable to chemotherapy and other therapies. Essentially, fasting causes a switch in healthy cells from a proliferative state towards a maintenance and repair state. Malignant cells, in contrast, seem to be unable to enter this protective state because of oncoprotein activity, and therefore fail to adapt to nutrient scarce conditions. Instead, fasting deprives proliferating cancer cells of nutrients and growth factors, which renders them more sensitive to cancer therapy and increases cell death. The phenomenon by which normal but not cancer cells become protected to toxins is termed differential stress resistance (DSR) whereas the specific sensitization of cancer cells to stress is called Differential Stress Sensitization (DSS).

Declines of plasma levels of insulin like growth factor-1 (IGF-1), insulin, and glucose are among the mediators of the effects of fasting on cancer cells, as these factors can promote growth and prevent apoptosis. Fasting periods of at least 48 hours are required to induce a robust decrease in circulating glucose, IGF-1, and insulin levels. A very low calorie, low protein FMD was developed for its ability to cause metabolic effects on various starvation response markers similar to those caused by water-only fasting, while reducing the burden associated with a water only fast.

In the DIRECT trial, we randomized 131 patients with HER2-negative stage II/III breast cancer, without diabetes and a BMI over 18 kg/m2, to receive either FMD or their regular diet for 3 days prior to and during neoadjuvant chemotherapy. Here we show that there was no difference in toxicity between both groups, despite the fact that dexamethasone was omitted in the FMD group. A radiologically complete or partial response occurs more often in patients using the FMD (odds ratio 3.168). Moreover, per-protocol analysis reveals that the 90-100% tumor-cell loss is more likely to occur in patients using the FMD (odds ratio 4.109). Also, the FMD significantly curtails chemotherapy-induced DNA damage in T-lymphocytes. These positive findings encourage further exploration of the benefits of fasting and FMD in cancer therapy.

Link: https://doi.org/10.1038/s41467-020-16138-3

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