Fasting-Mimicking Diet Inhibits Autophagy and Synergizes with Chemotherapy to Promote T-Cell-Dependent Leukemia-Free Survival

Roberta Buono; Jonathan Tucci; Raffaello Cutri; Novella Guidi; Serghei Mangul; Franca Raucci; Matteo Pellegrini; Steven D Mittelman; Valter D Longo

doi:10.3390/cancers15245870

Fasting-Mimicking Diet Inhibits Autophagy and Synergizes with Chemotherapy to Promote T-Cell-Dependent Leukemia-Free Survival

Cancers (Basel). 2023 Dec 16;15(24):5870. doi: 10.3390/cancers15245870.

Authors

Roberta Buono^{1

2}, Jonathan Tucci³, Raffaello Cutri¹, Novella Guidi¹, Serghei Mangul^{4

5}, Franca Raucci⁶, Matteo Pellegrini^{5

7}, Steven D Mittelman^{3

8}, Valter D Longo^{1

6

9}

Affiliations

¹ Department of Biological Sciences, Longevity Institute, School of Gerontology, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089, USA.
² Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, USA.
³ Center for Endocrinology, Diabetes & Metabolism, Children's Hospital Los Angeles, 4650 Sunset Blvd, Los Angeles, CA 90027, USA.
⁴ Department of Computer Science, University of California Los Angeles, 580 Portola Plaza, Los Angeles, CA 90095, USA.
⁵ Institute for Quantitative and Computational Biosciences, Boyer Hall, 611 Charles Young Drive, University of California Los Angeles, Los Angeles, CA 90095, USA.
⁶ IFOM AIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy.
⁷ Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, 801 Hilgard Avenue, Los Angeles, CA 90095, USA.
⁸ Division of Pediatric Endocrinology, UCLA Mattel Children's Hospital, 10833 Le Conte Avenue, MDCC 22-315, Los Angeles, CA 90095, USA.
⁹ Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.

Abstract

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.

Keywords: Leukemia; autophagy; cancer treatment; fasting-mimicking diet; pre-B-ALL.

Abstract

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