Switch to low-fat diet improves outcome of acute lymphoblastic leukemia in obese mice

Abstract

BackgroundIt is becoming increasingly recognized that weight and nutritional status can impact cancer survival. We have previously shown that obese mice with syngeneic acute lymphoblastic leukemia (ALL) have poorer response to chemotherapy treatment than control mice. We therefore investigated whether dietary intervention could improve outcome from the most common pediatric cancer, ALL.MethodsDiet-induced obese (DIO) mice raised on a 60% calories from fat diet and control mice were implanted with syngeneic ALL cells. Some DIO mice were switched to the low-fat control diet. Survival from ALL was assessed without or with chemotherapy treatment starting at the time of the diet switch. Cells from DIO mice before and after diet switch were assessed by FACS for BrdU incorporation and phosphorylation status of AKT, S6K, and EIF2a. Similar experiments were done with human ALL xenografts. Mouse and human ALL cells were cultured in media with 10% or 5% fetal bovine serum, and sensitivity to chemotherapies assessed.ResultsDIO mice had poorer survival (17%) after vincristine monotherapy than control mice on a 10% low fat diet (42%; n = 12/group; p = 0.09, log rank). However, switching obese mice to the low-fat diet prior to initiation of vincristine led to dramatically improved survival (92%, p < 0.01 vs both other groups). In vitro, FBS restriction made murine and human ALL cells more sensitive to vincristine. Interestingly, while serum restriction enhanced ALL sensitivity to dexamethasone and l-asparaginase, dietary switch did not improve survival of DIO mice treated with either drug in monotherapy. Thus, it appears that dietary intervention has a unique effect to improve ALL cell sensitivity to vincristine in vivo.ConclusionsWe report herein that a dietary intervention can improve ALL outcome in a preclinical model. Further work is needed to identify the mechanisms of this effect and investigate potential impact on human leukemia in patients.Electronic supplementary materialThe online version of this article (10.1186/s40170-018-0189-0) contains supplementary material, which is available to authorized users.

Exposure to maternal high-fat diet induces extensive changes in the brain of adult offspring

“…Offspring exposed to maternal high-fat diet during the in utero and perinatal periods showed some recovery in metabolic measures after transitioning to the low-fat diet at weaning – similar to results in literature 61 – 63 . This metabolic recovery minimises the confounding effect of aberrant metabolism during adulthood on brain structure.…”

Impacts of Environmental Factors on Head and Neck Cancer Pathogenesis and Progression

“…While likely not as effective, caloric restriction may also provide benefits to those undergoing anticancer therapies. In mice, greater treatment efficacy of vincristine, for example, was seen when a high-fat diet was switched to a low-fat one [ 104 ]. Aside, ketogenic diets have sparked great interest and shown to enhance survival and the effectiveness of antitumor drugs, such as carboplatin, in mice [ 105 ].…”

Metabolic reprogramming in childhood acute lymphoblastic leukemia

“…Inhibition of FAO, which is another NADH source for the mitochondria and is critical for cALL cell survival, can enhance the cytotoxic effect of L‐asparginase via the simultaneous inhibition of glycolysis, pyrimidine synthesis, and FAO 63 . Supporting the role of FAO, low‐fat diet can improve the outcome of chemotherapy treatment (vincristine, dexamethasone, and L‐asparginase) in obese mice with ALL 101 . Targeting several aspects of cell metabolism simultaneously through deprivation of fatty acyl residues and glucose starvation, presents a potential metabolic vulnerability in daunorubicin‐resistant cells in vitro 77…”

“…63 Supporting the role of FAO, low-fat diet can improve the outcome of chemotherapy treatment (vincristine, dexamethasone, and L-asparginase) in obese mice with ALL. 101 Targeting several aspects of cell metabolism simultaneously through deprivation of fatty acyl residues and glucose starvation, presents a potential metabolic vulnerability in daunorubicin-resistant cells in vitro. 77…”