Alternate-day fasting exacerbates cardiotoxicity of chemotherapy drug doxorubicin

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Alternate-day fasting exacerbates cardiotoxicity of chemotherapy drug doxorubicin

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Cell sub-journal: Alternate-day fasting exacerbates cardiotoxicity of chemotherapy drug doxorubicin.

Doxorubicin (Dox)is a commonly used broad-spectrum chemotherapy drug for acute leukemia, malignant lymphoma, breast cancer, etc., but its cardiotoxicity and possible heart failure severely limit its application.

It is generally believed that autophagy impairment caused by lysosome damageis one of the mechanistic features of doxorubicin cardiotoxicity.

Intermittent fasting (Intermittent Fasting, IF)is a popular diet restriction method, which alternates fasting and eating.

Many studies have found that intermittent fasting can not only effectively reduce weight, but also promote metabolism and improve physical health. It may even prolong life.

Intermittent fasting enhances autophagic flux, thereby aiding cancer therapy.

Previous studies in mice have shown that a type of intermittent fasting, alternate-day fasting (ADF, alternating between fasting and feeding days), stimulates transcription of master regulators of autophagy and lysosomal biogenesis. Nuclear translocation of factor EB (TFEB) to rescue advanced cardiomyopathy.

Fasting strategies, including alternate-day fasting , ameliorate glucose intolerance in diet-induced obesity and attenuate myocardial injury through mechanisms involving the autophagy-lysosome pathway.

And doxorubicin (Dox) can acutely reduce the expression and nuclear translocation of TFEB, and the overexpression of TFEB can improve the cardiotoxicity of doxorubicin.

So, can alternate-day fasting (ADF) combined with doxorubicin (Dox) reduce the cardiotoxic side effects of doxorubicin during treatment?

Recently, researchers from Washington University in St. Louis published a research paper entitled: Sustained alternate-day fasting potentiates doxorubicin cardiotoxicity in the Cell sub-journal Cell Metabolism .

This study found that alternate-day fasting (ADF) increased the expression of transcription factor EB (TFEB) during doxorubicin (Dox) treatment , thereby increasing the cardiotoxicity of doxorubicin (Dox) treatment.

This study reminds us that for cancer patients treated with doxorubicin (Dox) , prolonged, prolonged fasting may be detrimental to the efficacy of the treatment.

Given that doxorubicin (Dox) causes myocardial mass loss in mice and humans and skeletal muscle loss, TFEB regulates the E3 ubiquitin ligase muscle-specific ring finger protein 1 ( MuRF1 ) , which is associated with muscle atrophy and doxorubicin cardiotoxicity Therefore, the research team further explored the roles of alternate-day fasting (ADF) and TFEB in doxorubicin cardiotoxicity.

The research team found that in doxorubicin (Dox) -induced human end-stage heart failure, TFEB expression in cardiac tissue was increased, not decreased.

Moreover, in doxorubicin (Dox) -treated mice, increased TFEB expression induced by alternate-day fasting (ADF) , or adeno-associated virus (AAV) -mediated overexpression of TFEB, caused left ventricular atrophy and Heart failure, increased mortality in mice.

Cardiomyocyte-specific TFEB overexpression causes cardiac remodeling upon doxorubicin (Dox) treatment , whereas systemic TFEB overexpression increases growth differentiation factor 15 (GDF15) , leading to heart failure and death.

Deletion of TFEB in cardiomyocytes attenuated doxorubicin (Dox) cardiotoxicity, whereas increasing GDF15 was sufficient to cause cardiac atrophy.

These results suggest that both sustained alternate-day fasting (ADF) and the TFEB/GDF15 pathway exacerbate doxorubicin cardiotoxicity.

These data highlight the importance of pathways regulating left ventricular mass and cachexia during doxorubicin (Dox) chemotherapy and suggest increased clinical vigilance regarding the relationship between caloric intake and chemotherapy-related cachexia and cardiotoxicity .

Paper link :
https://doi.org/10.1016/j.cmet.2023.02.006

Alternate-day fasting exacerbates cardiotoxicity of chemotherapy drug doxorubicin

(source:internet, reference only)

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