Intermittent Fasting Exacerbates Toxicity of Anti-Cancer Drug

The term "intermittent fasting" can potentially be used to describe many different types of dieting but in the clinical setting this type of dieting generally refers to three main forms. These three forms are alternate day fasting (ADF), time-restricted eating (TRE), and the 5:2 diet.

Alternate day fasting, as the name implies, involves eating one day and fasting the next, repeating over and over. In some examples of ADF diets the fasting day involves only the consumption of water, referred to as a zero calorie alternate day. There are some versions of ADF that involve consuming calories on the fast day but only up to 25% of caloric need.

Several clinical studies, as well as studies carried out in laboratory animals, have shown that the ADF diet results in rescue of glucose responses in cases where there is intolerance resulting from diet-induced obesity. In addition, ADF has been shown to mitigate myocardial injury through a pathway that is referred to as autophagy. For a detailed explanation of autophagy go to the Protein, Organelle, and Cell Turnover page of my website.

Simply put, autophagy represents a normal cellular process by which cells can degrade damaged cellular components and reuse their constituent parts.

Intermittent fasting diets have clearly been shown to be beneficial for weight loss, at least in the short term. However, as I recently discussed, clinical data indicates that despite the benefits of intermittent fasting diets with respect to weight loss, the clinical data seems to indicate that these diets may not result in significant health benefits at the level of blood pressure, blood lipid profiles, and regulation of blood glucose. In addition, these diets do not maintain their benefits of weight loss beyond around 12 weeks:

INTERMITTENT FASTING FOR WEIGHT LOSS BUT OVERALL HEALTH BENEFITS MAY BE LIMITED

Now, a newly published study in the prestigious journal, Cell Metabolism, demonstrates that intermittent fasting, by cancer patients being treated with the drug doxorubicin (Adriamycin), is likely to further exacerbate the already known cardiotoxicity of doxorubicin:

Sustained alternate-day fasting potentiates doxorubicin cardiotoxicity

Along with other anti-cancer drugs, doxorubicin is used in the treatment of breast, lung, gastric, ovarian, and thyroid cancers, non-Hodgkin’s and Hodgkin’s lymphoma, multiple myeloma, and sarcomas.

The primary impetus for this study was the fact that alternate day fasting (ADF) had been shown to rescue advanced forms of cardiomyopathy. The molecular mechanism behind the effect of this type of diet is the stimulation of the activity of a transcription factor identified as transcription factor EB (TFEB). TFEB is identified as a master regulator of autophagy and lysosomal biogenesis.

During normal cellular function TFEB is localized to the cytosol due to its state of phosphorylation. During periods of nutrient deprivation, oxidative stress, or with DNA damage, TFEB is dephosphorylated and migrates to the nucleus where it can activate expression of target genes that then promotes the processes of autophagy.

Part of the mechanism by which doxorubicin therapy leads to cardiotoxicity is by acute inhibition of TFEB migration to the nucleus. Since intermittent fasting has been shown to stimulate TFEB translocation to the nucleus, thereby stimulating autophagy, the authors of this study set out to determine if intermittent fasting could be used by cancer patients in conjunction with doxorubicin therapy to reduce the chance for heart pathology.

It is important to point out that studies that demonstrated doxorubicin acutely suppressed TFEB migration to the nucleus were performed in cell culture models and not in whole animals (nor humans).

The current study examined the effects of doxorubicin, at the level of TFEB activity and autophagy, in laboratory animals. The results are, nonetheless, directly applicable to humans given that the effects of doxorubicin in mice and humans, at the level of the loss of cardiac muscle, are identical.

The critical finding from this study was that intermittent fasting (specifically ADF) resulted in increased systemic mobilization of TFEB to the nucleus, increased myocardial fibrosis, and cell death in the animals who were treated with doxorubicin.

Additionally, ADF was found to stimulate weight loss and mortality after doxorubicin administration. However, when targeted overexpression of TFEB in the heart was carried out, there was no weight loss nor increased mortality when doxorubicin was administered. This indicated that TFEB is likely exerting cardiac effects that are not directly due to TFEB activity in the heart. Results from this study indicated that this systemic effect is likely to be via the stimulation of a protein called GDF15 (growth differentiation factor 15). Doxorubicin is known to induce GDF15 and that this associated with the cardiotoxicity of doxorubicin. In the normal situation GDF15 plays a role in regulation of appetite and body weight as well as participating in the pathogenesis of a number of disease processes. Indeed, overexpression of GDF15 in patients with prostate cancer is associated with significant loss of body mass proportional to the level of circulating GDF15.

Intermittent fasting on its own, in the absence of any other stimulus, results in suppression of GDF15. However, this study showed that when mice were administered doxorubicin in conjunction with ADF there was no suppression of GDF15. The authors suggest that the failure to suppress GDF15, in the context of ADF and doxorubicin administration, is a significant contributor to the exacerbation of cardiotoxicity exerted by doxorubicin.

TAKE HOME: Clearly, attempting to starve cancer in conjunction with the use of a drug like doxorubicin is contraindicated. It is important to stay informed and be aware of facts that are relevant to ones particular therapies.