Fasting-Mimicking Diet Inhibits Autophagy and Synergizes with Chemotherapy to Promote T-Cell-Dependent Leukemia-Free Survival.
Roberta BuonoJonathan TucciRaffaello CutriNovella GuidiSerghei MangulFranca RaucciMatteo PellegriniSteven D MittelmanValter D LongoPublished in: Cancers (2023)
Fasting mimicking diets (FMDs) are effective in the treatment of many solid tumors in mouse models, but their effect on hematologic malignancies is poorly understood, particularly in combination with standard therapies. Here we show that cycles of a 3-day FMD given to high-fat-diet-fed mice once a week increased the efficacy of vincristine to improve survival from BCR-ABL B acute lymphoblastic leukemia (ALL). In mice fed a standard diet, FMD cycles in combination with vincristine promoted cancer-free survival. RNA seq and protein assays revealed a vincristine-dependent decrease in the expression of multiple autophagy markers, which was exacerbated by the fasting/FMD conditions. The autophagy inhibitor chloroquine could substitute for fasting/FMD to promote cancer-free survival in combination with vincristine. In vitro, targeted inhibition of autophagy genes ULK1 and ATG9a strongly potentiated vincristine's toxicity. Moreover, anti-CD8 antibodies reversed the effects of vincristine plus fasting/FMD in promoting leukemia-free survival in mice, indicating a central role of the immune system in this response. Thus, the inhibition of autophagy and enhancement of immune responses appear to be mediators of the fasting/FMD-dependent cancer-free survival in ALL mice.
Keyphrases
- free survival
- insulin resistance
- high fat diet induced
- high fat diet
- blood glucose
- cell death
- endoplasmic reticulum stress
- acute lymphoblastic leukemia
- papillary thyroid
- rna seq
- oxidative stress
- signaling pathway
- single cell
- squamous cell
- immune response
- adipose tissue
- metabolic syndrome
- bone marrow
- physical activity
- skeletal muscle
- tyrosine kinase
- acute myeloid leukemia
- poor prognosis
- type diabetes
- glycemic control
- childhood cancer
- gene expression
- binding protein
- cancer therapy
- high throughput
- wild type
- lymph node metastasis
- combination therapy
- drug delivery
- toll like receptor
- allogeneic hematopoietic stem cell transplantation
- clinical trial
- long non coding rna
- transcription factor
- young adults
- dendritic cells