Dietary modifications for enhanced cancer therapy

Kanarek, Naama; Petrova, Boryana; Sabatini, David M.

doi:10.1038/s41586-020-2124-0

Cited by 283 publications

(209 citation statements)

References 145 publications

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“…The eventual progression of tumors in all DDDAtreated mice, despite impressive initial responses (Fig. 2B-D) was in keeping with numerous other studies involving dietary interventions administered either singly or in combination with chemotherapeutic agents (4,36,40,42,62,63). Resistant HBs that failed to re-express Ehhadh and Cyp4a10 (Fig.…”

Section: Discussionsupporting

confidence: 88%

“…The optimization of tumor growth and survival in response to metabolic re-programming is welldocumented and theoretically affords unique therapeutic opportunities, including those based on dietary manipulation (1,2,4,6,7,37-39).The latter include caloric restriction or glucose deprivation, which reduce Warburg-type respiration and temper insulin and/or insulin-like growth factor signaling (4,(40)(41)(42)(43). The ensuing changes in the micro-environmental nutrient supply can impact tumor cell signaling pathways, growth and chemotherapeutic sensitivity (9,(44)(45)(46).…”

Section: Discussionmentioning

confidence: 99%

“…Cancer cells undergo numerous metabolic adjustments to acquire and maintain proliferative and survival advantages and these represent essential features of the transformed state (1)(2)(3)(4)(5)(6)(7). The classic example of metabolic reprogramming is the Warburg effect, whereby the anaerobic process of glycolysis continues or is even accelerated under aerobic conditions (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

“…Indeed the up-regulation of pathways that provide anaplerotic sources of these TCA cycle substrates is another important metabolic feature of many cancers (1,2,5,14,15). Many studies have attempted, with variable success, to leverage some of the more prominent metabolic differences between normal and transformed cells for therapeutic benefit (1,4,9,14,16,17).…”

Section: Introductionmentioning

confidence: 99%

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Acquired deficiency of the peroxisomal enzyme enoyl-CoA hydratase/3-hydroxyacyl CoA dehydrogenase is a metabolic vulnerability in hepatoblastoma

Wang

Chen

Schwalbe

et al. 2020

Preprint

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Metabolic reprogramming provides transformed cells with proliferative and/or survival advantages. However, capitalizing on this therapeutically has been only moderately successful due to the relatively small magnitude of these differences and because cancers may re-program their metabolism to evade metabolic pathway inhibition. Mice lacking the peroxisomal bi-functional enzyme enoyl-CoA hydratase/3-hydroxyacyl CoA dehydrogenase (Ehhadh) and supplemented with the 12-carbon fatty acid lauric acid (C12) accumulate dodecanedioic acid (DDDA), a toxic C12 metabolite that causes hepatocyte necrosis and acute liver failure. In a murine model of pediatric hepatoblastoma (HB), down-regulation of Ehhadh also occurs in combination with a more general suppression of mitochondrial β- and peroxisomal ω-fatty acid oxidation (FAO) pathways. HB-bearing mice provided with C12 and/or DDDA-supplemented diets survived significantly longer than those on standard diets. The tumors also developed massive necrosis in response to short-term DDDA supplementation. Reduced Ehhadh was noted in murine hepatocellular carcinomas (HCCs) and in substantial subsets of human cancers, including HCCs. Acquired DDDA resistance was not associated with Ehhadh re-expression but was associated with 129 transcript differences ~90% of which were down-regulated in DDDA-resistant tumors and ~two-thirds of which correlated with survival in several human cancers. These transcripts often encoded components of the extracellular matrix suggesting that DDDA resistance arises from its reduced intracellular transport. Our results demonstrate the feasibility of a metabolic intervention that is non-toxic, inexpensive and likely compatible with traditional therapies. C12 and/or DDDA-containing diets could potentially be used to supplement other treatments or as alternative therapeutic choices.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Acquired deficiency of the peroxisomal enzyme enoyl-CoA hydratase/3-hydroxyacyl CoA dehydrogenase is a metabolic vulnerability in hepatoblastoma

Wang

Chen

Schwalbe

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…These personalized metabolic predictions also demonstrate the significant amount of heterogeneity in redox metabolism between patient tumors. While the majority of initiatives for precision medicine for cancer treatment has focused on mutations and expression differences in signaling pathway proteins, there is currently a greater focus on exploiting metabolic differences between patient tumors (DeBerardinis and Chandel, 2016; Kanarek et al, 2018;Kanarek et al, 2020). For example, heterogeneity in glycolytic metabolism is being used to identify diagnostic biomarkers and treatment strategies for both pancreatic cancer and acute myeloid leukemia patients (Follia et al, 2019;Stuani et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Personalized Genome-Scale Metabolic Models Identify Targets of Redox Metabolism in Radiation-Resistant Tumors

Lewis

Forshaw

Boothman

et al. 2020

Preprint

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Redox cofactor production is integral towards antioxidant generation, clearance of reactive oxygen species, and overall tumor response to ionizing radiation treatment.To identify systems-level alterations in redox metabolism which confer resistance to radiation therapy, we developed a bioinformatics pipeline for integrating multi-omics data into personalized genome-scale flux balance analysis models of 716 radiationsensitive and 199 radiation-resistant tumors. These models collectively predicted that radiation-resistant tumors reroute metabolic flux to increase mitochondrial NADPH stores and ROS scavenging. Simulated genome-wide knockout screens agreed with experimental siRNA gene knockdowns in matched radiation-sensitive and -resistant

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Cysteine is a limiting factor for glioma proliferation and survival

et al. 2022

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Nutritional intervention is becoming more prevalent as adjuvant therapy for many cancers in view of the tumor dependence on external sources for some nutrients. However, little is known about the mechanisms that make cancer cells require certain nutrients from the microenvironment. Herein, we report the dependence of glioma cells on exogenous cysteine/cystine, despite this amino acid being nonessential. Using several 13C‐tracers and analysis of cystathionine synthase and cystathioninase levels, we revealed that glioma cells were not able to support glutathione synthesis through the transsulfuration pathway, which allows methionine to be converted to cysteine in cysteine/cystine‐deprived conditions. Therefore, we explored the nutritional deprivation in a mouse model of glioma. Animals subjected to a cysteine/cystine‐free diet survived longer, although this increase did not attain statistical significance, with concomitant reductions in plasma glutathione and cysteine levels. At the end point, however, tumors displayed the ability to synthesize glutathione, even though higher levels of oxidative stress were detected. We observed a compensation from the nutritional intervention revealed as the recovery of cysteine‐related metabolite levels in plasma. Our study highlights a time window where cysteine deprivation can be exploited for additional therapeutic strategies.

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Dietary modifications for enhanced cancer therapy

Cited by 283 publications

References 145 publications

Acquired deficiency of the peroxisomal enzyme enoyl-CoA hydratase/3-hydroxyacyl CoA dehydrogenase is a metabolic vulnerability in hepatoblastoma

Acquired deficiency of the peroxisomal enzyme enoyl-CoA hydratase/3-hydroxyacyl CoA dehydrogenase is a metabolic vulnerability in hepatoblastoma

Personalized Genome-Scale Metabolic Models Identify Targets of Redox Metabolism in Radiation-Resistant Tumors

Cysteine is a limiting factor for glioma proliferation and survival

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