bims-medica 2024-05-05 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2024–05–05
24 papers selected by
Brett Chrest, East Carolina University

The ketone body β-Hydroxybutyrate as a fuel source of chondrosarcoma cells.
Investigating the thermal sensitivity of key enzymes involved in the energetic metabolism of three insect species.
Cycling back to folate metabolism in cancer.
Inhibition of mammalian mtDNA transcription acts paradoxically to reverse diet-induced hepatosteatosis and obesity.
Mitochondria and Cancer.
Dual targeting of glutamine and serine metabolism in acute myeloid leukemia.
Mitochondrial redox state, bioenergetics, and calcium transport in caloric restriction: A metabolic nexus.
The ketogenic diet does not improve cardiac function and blunts glucose oxidation in ischemic heart failure.
A systematic review of second-generation FLT3 inhibitors for treatment of patients with relapsed/refractory acute myeloid leukemia.
A novel inhibitor of the mitochondrial respiratory complex I with uncoupling properties exerts potent antitumor activity.
The mitochondrial multi-omic response to exercise training across rat tissues.
A shift to a standard diet after exposure to a high-fat, high-sucrose diet from gestation to weaning restores brain metabolism and behavioral flexibility in adult rats.
Characterizing OXPHOS inhibitor-mediated alleviation of hypoxia using high-throughput live cell-imaging.
Venetoclax, a new player in the treatment of children with high-risk myeloid malignancies?
Switching diets after 6-months does not result in renewed weight loss: a secondary analysis of a 12-month crossover randomized trial.
Patient-Derived Xenograft Models for Leukemias.
Dietary dicarboxylic acids provide a non-storable alternative fat source that protects mice against obesity.
Spatially resolved analysis of microenvironmental gradient impact on cancer cell phenotypes.
Statin treatment reduces leucine turnover, but does not affect endogenous production of beta-hydroxy-beta-methylbutyrate (HMB).
Efficacy and safety of venetoclax plus hypomethylating agents in relapsed/refractory acute myeloid leukemia: a multicenter real-life experience.
Post-diagnosis dietary factors, supplement use and colorectal cancer prognosis: A Global Cancer Update Programme (CUP Global) systematic literature review and meta-analysis.
Post-diagnosis adiposity, physical activity, sedentary behaviour, dietary factors, supplement use and colorectal cancer prognosis: Global Cancer Update Programme (CUP Global) summary of evidence grading.
Glutamate-reduced diet and ketogenic diet for pediatric drug-resistant epilepsy: a novel approach to treatment.
High-fat diet enhances cell proliferation and compromises intestinal permeability in a translational canine intestinal organoid model.

Heliyon. 2024 May 15. 10(9): e30212

The ketone body β-Hydroxybutyrate as a fuel source of chondrosarcoma cells.

Misael Vargas-López, Carlos A Quiroz-Vicente, Nury Pérez-Hernández, Fernando Gómez-Chávez, Angel E Bañuelos-Hernández, Elizabeth Pérez-Hernández.

  Chondrosarcoma (CS) is a malignant bone tumor arising from cartilage-producing cells. The conventional subtype of CS typically develops within a dense cartilaginous matrix, creating an environment deficient in oxygen and nutrients, necessitating metabolic adaptation to ensure proliferation under stress conditions. Although ketone bodies (KBs) are oxidized by extrahepatic tissue cells such as the heart and brain, specific cancer cells, including CS cells, can undergo ketolysis. In this study, we found that KBs catabolism is activated in CS cells under nutrition-deprivation conditions. Interestingly, cytosolic β-hydroxybutyrate dehydrogenase 2 (BDH2), rather than mitochondrial BDH1, is expressed in these cells, indicating a specific metabolic adaptation for ketolysis in this bone tumor. The addition of the KB, β-Hydroxybutyrate (β-HB) in serum-starved CS cells re-induced the expression of BDH2, along with the key ketolytic enzyme 3-oxoacid CoA-transferase 1 (OXCT1) and monocarboxylate transporter-1 (MCT1). Additionally, internal β-HB production was quantified in supplied and starved cells, suggesting that CS cells are also capable of ketogenesis alongside ketolysis. These findings unveil a novel metabolic adaptation wherein nutrition-deprived CS cells utilize KBs for energy supply and proliferation.

Keywords:  Chondrosarcoma; Ketolysis; Starvation; β-hydroxybutyrate dehydrogenase 2 (BDH2)

DOI:  https://doi.org/10.1016/j.heliyon.2024.e30212
J Exp Biol. 2024 Apr 29. pii: jeb.247221. [Epub ahead of print]

Investigating the thermal sensitivity of key enzymes involved in the energetic metabolism of three insect species.

Adèle Léger, Simon B Cormier, Arianne Blanchard, Hichem A Menail, Nicolas Pichaud.

  The metabolic responses of insects to high temperatures have been linked to their mitochondrial substrate oxidation capacity. However, the mechanism behind this mitochondrial flexibility is not well understood. Here, we used three insect species with different thermal tolerances (the honey bee, Apis mellifera; the fruit fly, Drosophila melanogaster; and the potato beetle, Leptinotarsa decemlineata) to characterise the thermal sensitivity of different metabolic enzymes. Specifically, we measured activities of enzymes involved in glycolysis (hexokinase, HK; pyruvate kinase, PK; and lactate dehydrogenase, LDH), pyruvate oxidation and the tricarboxylic acid cycle (pyruvate dehydrogenase, PDH; citrate synthase, CS; malate dehydrogenase, MDH; and aspartate aminotransferase, AAT), the electron transport system (Complex I, CI; Complex II, CII; mitochondrial glycerol-3-phosphate dehydrogenase, mG3PDH; Proline dehydrogenase, ProDH; and Complex IV, CIV) as well as ATP synthase (CV) at 18, 24, 30, 36, 42 and 45˚C. Our results show that at high temperature, all three species have important increased activity of enzymes linked to FADH2 oxidation, specifically CII and mG3PDH. In Drosophila and honey bees, this coincides with an important decrease of PDH and CS activity, respectively, that would limit NADH production. This is in line with the switch from NADH-linked substrates to FADH2-linked substrates previously observed with mitochondrial oxygen consumption. Thus, we demonstrate that even though the three insect species have a different metabolic regulation, a similar response to high temperature involving CII and mG3PDH is observed, denoting the importance of these proteins for thermal tolerance in insects.

Keywords:  Drosophila; Glycolysis; Honey bee; Metabolic pathways; Mitochondria; Potato beetle; Temperature; Tricarboxylic acid cycle

DOI:  https://doi.org/10.1242/jeb.247221
Nat Cancer. 2024 May 02.

Cycling back to folate metabolism in cancer.

Younghwan Lee, Karen H Vousden, Marc Hennequart.

Metabolic changes contribute to cancer initiation and progression through effects on cancer cells, the tumor microenvironment and whole-body metabolism. Alterations in serine metabolism and the control of one-carbon cycles have emerged as critical for the development of many tumor types. In this Review, we focus on the mitochondrial folate cycle. We discuss recent evidence that, in addition to supporting nucleotide synthesis, mitochondrial folate metabolism also contributes to metastasis through support of antioxidant defense, mitochondrial protein synthesis and the overflow of excess formate. These observations offer potential therapeutic opportunities, including the modulation of formate metabolism through dietary interventions and the use of circulating folate cycle metabolites as biomarkers for cancer detection.

DOI: https://doi.org/10.1038/s43018-024-00739-8
Nat Metab. 2024 Apr 30.

Inhibition of mammalian mtDNA transcription acts paradoxically to reverse diet-induced hepatosteatosis and obesity.

Shan Jiang, Taolin Yuan, Florian A Rosenberger, Arnaud Mourier, Nathalia R V Dragano, Laura S Kremer, Diana Rubalcava-Gracia, Fynn M Hansen, Melissa Borg, Mara Mennuni, Roberta Filograna, David Alsina, Jelena Misic, Camilla Koolmeister, Polyxeni Papadea, Martin Hrabe de Angelis, Lipeng Ren, Olov Andersson, Anke Unger, Tim Bergbrede, Raffaella Di Lucrezia, Rolf Wibom, Juleen R Zierath, Anna Krook, Patrick Giavalisco, Matthias Mann, Nils-Göran Larsson.

The oxidative phosphorylation system1 in mammalian mitochondria plays a key role in transducing energy from ingested nutrients2. Mitochondrial metabolism is dynamic and can be reprogrammed to support both catabolic and anabolic reactions, depending on physiological demands or disease states. Rewiring of mitochondrial metabolism is intricately linked to metabolic diseases and promotes tumour growth3-5. Here, we demonstrate that oral treatment with an inhibitor of mitochondrial transcription (IMT)6 shifts whole-animal metabolism towards fatty acid oxidation, which, in turn, leads to rapid normalization of body weight, reversal of hepatosteatosis and restoration of normal glucose tolerance in male mice on a high-fat diet. Paradoxically, the IMT treatment causes a severe reduction of oxidative phosphorylation capacity concomitant with marked upregulation of fatty acid oxidation in the liver, as determined by proteomics and metabolomics analyses. The IMT treatment leads to a marked reduction of complex I, the main dehydrogenase feeding electrons into the ubiquinone (Q) pool, whereas the levels of electron transfer flavoprotein dehydrogenase and other dehydrogenases connected to the Q pool are increased. This rewiring of metabolism caused by reduced mtDNA expression in the liver provides a principle for drug treatment of obesity and obesity-related pathology.

DOI: https://doi.org/10.1038/s42255-024-01038-3
Cold Spring Harb Perspect Med. 2024 May 01. pii: a041534. [Epub ahead of print]

Mitochondria and Cancer.

Timothy C Kenny, Kıvanç Birsoy.

Mitochondria are semiautonomous organelles with diverse metabolic and cellular functions including anabolism and energy production through oxidative phosphorylation. Following the pioneering observations of Otto Warburg nearly a century ago, an immense body of work has examined the role of mitochondria in cancer pathogenesis and progression. Here, we summarize the current state of the field, which has coalesced around the position that functional mitochondria are required for cancer cell proliferation. In this review, we discuss how mitochondria influence tumorigenesis by impacting anabolism, intracellular signaling, and the tumor microenvironment. Consistent with their critical functions in tumor formation, mitochondria have become an attractive target for cancer therapy. We provide a comprehensive update on the numerous therapeutic modalities targeting the mitochondria of cancer cells making their way through clinical trials.

DOI: https://doi.org/10.1101/cshperspect.a041534
Front Oncol. 2024 ;14 1326754

Dual targeting of glutamine and serine metabolism in acute myeloid leukemia.

Kanwal M Hameed, Dominique R Bollino, Amol C Shetty, Brandon Carter-Cooper, Rena G Lapidus, Ashkan Emadi.

  Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy characterized by disrupted blood cell production and function. Recent investigations have highlighted the potential of targeting glutamine metabolism as a promising therapeutic approach for AML. Asparaginases, enzymes that deplete circulating glutamine and asparagine, are approved for the treatment of acute lymphoblastic leukemia, but are also under investigation in AML, with promising results. We previously reported an elevation in plasma serine levels following treatment with Erwinia-derived asparaginase (also called crisantaspase). This led us to hypothesize that AML cells initiate the de novo serine biosynthesis pathway in response to crisantaspase treatment and that inhibiting this pathway in combination with crisantaspase would enhance AML cell death. Here we report that in AML cell lines, treatment with the clinically available crisantaspase, Rylaze, upregulates the serine biosynthesis enzymes phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase (PSAT1) through activation of the Amino Acid Response (AAR) pathway, a cellular stress response mechanism that regulates amino acid metabolism and protein synthesis under conditions of nutrient limitation. Inhibition of serine biosynthesis through CRISPR-Cas9-mediated knockout of PHGDH resulted in a ~250-fold reduction in the half-maximal inhibitory concentration (IC50) for Rylaze, indicating heightened sensitivity to crisantaspase therapy. Treatment of AML cells with a combination of Rylaze and a small molecule inhibitor of PHGDH (BI4916) revealed synergistic anti-proliferative effects in both cell lines and primary AML patient samples. Rylaze-BI4916 treatment in AML cell lines led to the inhibition of cap-dependent mRNA translation and protein synthesis, as well as a marked decrease in intracellular glutathione levels, a critical cellular antioxidant. Collectively, our results highlight the clinical potential of targeting serine biosynthesis in combination with crisantaspase as a novel therapeutic strategy for AML.

Keywords:  asparaginase; cancer metabolism; glutamine; leukemia; serine

DOI:  https://doi.org/10.3389/fonc.2024.1326754
Free Radic Biol Med. 2024 Apr 25. pii: S0891-5849(24)00421-0. [Epub ahead of print]219 195-214

Mitochondrial redox state, bioenergetics, and calcium transport in caloric restriction: A metabolic nexus.

Eloisa A Vilas-Boas, Alicia J Kowaltowski.

Mitochondria congregate central reactions in energy metabolism, many of which involve electron transfer. As such, they are expected to both respond to changes in nutrient supply and demand and also provide signals that integrate energy metabolism intracellularly. In this review, we discuss how mitochondrial bioenergetics and reactive oxygen species production is impacted by dietary interventions that change nutrient availability and impact on aging, such as calorie restriction. We also discuss how dietary interventions alter mitochondrial Ca2+ transport, regulating both mitochondrial and cytosolic processes modulated by this ion. Overall, a plethora of literature data support the idea that mitochondrial oxidants and calcium transport act as integrating signals coordinating the response to changes in nutritional supply and demand in cells, tissues, and animals.

DOI: https://doi.org/10.1016/j.freeradbiomed.2024.04.234
Cardiovasc Res. 2024 May 01. pii: cvae092. [Epub ahead of print]

The ketogenic diet does not improve cardiac function and blunts glucose oxidation in ischemic heart failure.

Kim L Ho, Qutuba Karwi, Faqi Wang, Cory Wagg, Liyan Zhang, Sai Panidarapu, Brandon Chen, Simran Pherwani, Amanda A Greenwell, Gavin Oudit, John R Ussher, Gary D Lopaschuk.

AIMS: Cardiac energy metabolism is perturbed in ischemic heart failure and is characterized by a shift from mitochondrial oxidative metabolism to glycolysis. Notably, the failing heart relies more on ketones for energy than a healthy heart, an adaptive mechanism that improves the energy-starved status of the failing heart. However, whether this can be implemented therapeutically remains unknown. Therefore, our aim was to determine if increasing ketone delivery to the heart via a ketogenic diet can improve the outcomes of heart failure.
METHODS: C57BL/6J male mice underwent either a sham surgery or permanent left anterior descending (LAD) coronary artery ligation surgery to induce heart failure. After 2 weeks, mice were then treated with either a control diet or a ketogenic diet for 3 weeks. Transthoracic echocardiography was then carried out to assess in vivo cardiac function and structure. Finally, isolated working hearts from these mice were perfused with appropriately 3H or 14C labelled glucose (5 mM), palmitate (0.8 mM), and ß-hydroxybutyrate (0.6 mM) to assess mitochondrial oxidative metabolism and glycolysis.
RESULTS: Mice with heart failure exhibited a 56% drop in ejection fraction which was not improved with a ketogenic diet feeding. Interestingly, mice fed a ketogenic diet had marked decreases in cardiac glucose oxidation rates. Despite increasing blood ketone levels, cardiac ketone oxidation rates did not increase, probably due to a decreased expression of key ketone oxidation enzymes. Furthermore, in mice on the ketogenic diet no increase in overall cardiac energy production was observed, and instead there was a shift to an increased reliance on fatty acid oxidation as a source of cardiac energy production. This resulted in a decrease in cardiac efficiency in heart failure mice fed a ketogenic diet.
CONCLUSIONS: We conclude that the ketogenic diet does not improve heart function in failing hearts, due to ketogenic diet-induced excessive fatty acid oxidation in the ischemic heart and a decrease in insulin-stimulated glucose oxidation.

DOI: https://doi.org/10.1093/cvr/cvae092
Leuk Res. 2024 Apr 17. pii: S0145-2126(24)00071-7. [Epub ahead of print]141 107505

A systematic review of second-generation FLT3 inhibitors for treatment of patients with relapsed/refractory acute myeloid leukemia.

Alireza Mohebbi, Fahimeh Shahriyary, Vida Farrokhi, Bita Bandar, Najmaldin Saki.

   BACKGROUND: Acute myeloid leukemia (AML) is a complex disease with diverse mutations, including prevalent mutations in the FMS-like receptor tyrosine kinase 3 (FLT3) gene that lead to poor prognosis. Recent advancements have introduced FLT3 inhibitors that have improved outcomes for FLT3-mutated AML patients, however, questions remain on their application in complex conditions such as relapsed/refractory (R/R) disease. Therefore, we aimed to evaluate the clinical effectiveness of second-generation FLT3 inhibitors in treating patients with R/R AML.
METHODS: A systematic literature search of PubMed, MEDLINE, SCOPUS and Google Scholar databases was made to identify relevant studies up to January 30, 2024. This study was conducted following the guidelines of the PRISMA.
RESULTS: The ADMIRAL trial revealed significantly improved overall survival and complete remission rates with gilteritinib compared to salvage chemotherapy, with manageable adverse effects. Ongoing research explores its potential in combination therapies, showing synergistic effects with venetoclax and promising outcomes in various clinical trials. The QuANTUM-R trial suggested longer overall survival with quizartinib compared to standard chemotherapy, although concerns were raised regarding trial design and cardiotoxicity. Ongoing research explores combination therapies involving quizartinib, such as doublet or triplet regimens with venetoclax, showing promising outcomes in FLT3-mutated AML patients.
CONCLUSION: These targeted therapies offer promise for managing this subgroup of AML patients, but further research is needed to optimize their use. This study underscores the importance of personalized treatment based on genetic mutations in AML, paving the way for more effective and tailored approaches to combat the disease.

Keywords:  AML; FLT3; FLT3 Inhibitor; Relapse/Refractory

DOI:  https://doi.org/10.1016/j.leukres.2024.107505
Cell Death Dis. 2024 May 02. 15(5): 311

A novel inhibitor of the mitochondrial respiratory complex I with uncoupling properties exerts potent antitumor activity.

Alaa Al Assi, Solène Posty, Frédéric Lamarche, Amel Chebel, Jérôme Guitton, Cécile Cottet-Rousselle, Renaud Prudent, Laurence Lafanechère, Stéphane Giraud, Patrick Dallemagne, Peggy Suzanne, Aurélie Verney, Laurent Genestier, Marie Castets, Eric Fontaine, Marc Billaud, Martine Cordier-Bussat.

Cancer cells are highly dependent on bioenergetic processes to support their growth and survival. Disruption of metabolic pathways, particularly by targeting the mitochondrial electron transport chain complexes (ETC-I to V) has become an attractive therapeutic strategy. As a result, the search for clinically effective new respiratory chain inhibitors with minimized adverse effects is a major goal. Here, we characterize a new OXPHOS inhibitor compound called MS-L6, which behaves as an inhibitor of ETC-I, combining inhibition of NADH oxidation and uncoupling effect. MS-L6 is effective on both intact and sub-mitochondrial particles, indicating that its efficacy does not depend on its accumulation within the mitochondria. MS-L6 reduces ATP synthesis and induces a metabolic shift with increased glucose consumption and lactate production in cancer cell lines. MS-L6 either dose-dependently inhibits cell proliferation or induces cell death in a variety of cancer cell lines, including B-cell and T-cell lymphomas as well as pediatric sarcoma. Ectopic expression of Saccharomyces cerevisiae NADH dehydrogenase (NDI-1) partially restores the viability of B-lymphoma cells treated with MS-L6, demonstrating that the inhibition of NADH oxidation is functionally linked to its cytotoxic effect. Furthermore, MS-L6 administration induces robust inhibition of lymphoma tumor growth in two murine xenograft models without toxicity. Thus, our data present MS-L6 as an inhibitor of OXPHOS, with a dual mechanism of action on the respiratory chain and with potent antitumor properties in preclinical models, positioning it as the pioneering member of a promising drug class to be evaluated for cancer therapy. MS-L6 exerts dual mitochondrial effects: ETC-I inhibition and uncoupling of OXPHOS. In cancer cells, MS-L6 inhibited ETC-I at least 5 times more than in isolated rat hepatocytes. These mitochondrial effects lead to energy collapse in cancer cells, resulting in proliferation arrest and cell death. In contrast, hepatocytes which completely and rapidly inactivated this molecule, restored their energy status and survived exposure to MS-L6 without apparent toxicity.

DOI: https://doi.org/10.1038/s41419-024-06668-9
Cell Metab. 2024 Apr 15. pii: S1550-4131(23)00472-2. [Epub ahead of print]

The mitochondrial multi-omic response to exercise training across rat tissues.

MoTrPAC Study Group

  Mitochondria have diverse functions critical to whole-body metabolic homeostasis. Endurance training alters mitochondrial activity, but systematic characterization of these adaptations is lacking. Here, the Molecular Transducers of Physical Activity Consortium mapped the temporal, multi-omic changes in mitochondrial analytes across 19 tissues in male and female rats trained for 1, 2, 4, or 8 weeks. Training elicited substantial changes in the adrenal gland, brown adipose, colon, heart, and skeletal muscle. The colon showed non-linear response dynamics, whereas mitochondrial pathways were downregulated in brown adipose and adrenal tissues. Protein acetylation increased in the liver, with a shift in lipid metabolism, whereas oxidative proteins increased in striated muscles. Exercise-upregulated networks were downregulated in human diabetes and cirrhosis. Knockdown of the central network protein 17-beta-hydroxysteroid dehydrogenase 10 (HSD17B10) elevated oxygen consumption, indicative of metabolic stress. We provide a multi-omic, multi-tissue, temporal atlas of the mitochondrial response to exercise training and identify candidates linked to mitochondrial dysfunction.

Keywords:  HSD17B10; acetylome; aerobic; exercise; metabolism; metabolomics; mitochondria; multi-omics; proteomics; transcriptomics

DOI:  https://doi.org/10.1016/j.cmet.2023.12.021
Behav Brain Res. 2024 Apr 26. pii: S0166-4328(24)00176-1. [Epub ahead of print] 115020

A shift to a standard diet after exposure to a high-fat, high-sucrose diet from gestation to weaning restores brain metabolism and behavioral flexibility in adult rats.

Saúl Sal-Sarria, Isabel López-Taboada, Héctor González-Pardo, Nélida M Conejo.

  Prolonged consumption of diets high in saturated fat and sugar has been related to obesity and overweight, which in turn are linked to cognitive impairment in both humans and rodents. This has become a current issue, especially in children and adolescents, because these stages are crucial to neurodevelopmental processes and programming of adult behavior. To evaluate the effects of gestational and early exposure to an obesogenic diet, three groups with different dietary patterns were established: high-fat and high-sucrose diet (HFS), standard diet (SD), and a dietary shift from a high-fat, high-sucrose diet to a standard diet after weaning (R). Spatial learning and behavioral flexibility in adult male and female Wistar rats were evaluated using the Morris water maze (MWM) at PND 60. Furthermore, regional brain oxidative metabolism was assessed in the prefrontal cortex and the hippocampus. Contrary to our hypothesis, the HFS diet groups showed similar performance on the spatial learning task as the other groups, although they showed impaired cognitive flexibility. The HFS group had increased brain metabolic capacity compared to that of animals fed the standard diet. Shifting from the HFS diet to the SD diet after weaning restored the brain metabolic capacity in both sexes to levels similar to those observed in animals fed the SD diet. In addition, animals in the R group performed similarly to those fed the SD diet in the Morris water maze in both tasks. However, dietary shift from HFS diet to standard diet after weaning had only moderate sex-dependent effects on body weight and fat distribution. In conclusion, switching from an HFS diet to a balanced diet after weaning would have beneficial effects on behavioral flexibility and brain metabolism, without significant sex differences.

Keywords:  cytochrome c oxidase; high-fat and high-sucrose diet; hippocampus; prefrontal cortex; spatial learning and memory

DOI:  https://doi.org/10.1016/j.bbr.2024.115020
Cancer Metab. 2024 May 03. 12(1): 13

Characterizing OXPHOS inhibitor-mediated alleviation of hypoxia using high-throughput live cell-imaging.

Anne P M Beerkens, Daan F Boreel, James A Nathan, Jiri Neuzil, Gang Cheng, Balaraman Kalyanaraman, Micael Hardy, Gosse J Adema, Sandra Heskamp, Paul N Span, Johan Bussink.

   BACKGROUND: Hypoxia is a common feature of many solid tumors and causes radiotherapy and immunotherapy resistance. Pharmacological inhibition of oxidative phosphorylation (OXPHOS) has emerged as a therapeutic strategy to reduce hypoxia. However, the OXPHOS inhibitors tested in clinical trials caused only moderate responses in hypoxia alleviation or trials were terminated due to dose-limiting toxicities. To improve the therapeutic benefit, FDA approved OXPHOS inhibitors (e.g. atovaquone) were conjugated to triphenylphosphonium (TPP+) to preferentially target cancer cell's mitochondria. In this study, we evaluated the hypoxia reducing effects of several mitochondria-targeted OXPHOS inhibitors and compared them to non-mitochondria-targeted OXPHOS inhibitors using newly developed spheroid models for diffusion-limited hypoxia.
METHODS: B16OVA murine melanoma cells and MC38 murine colon cancer cells expressing a HIF-Responsive Element (HRE)-induced Green Fluorescent Protein (GFP) with an oxygen-dependent degradation domain (HRE-eGFP-ODD) were generated to assess diffusion-limited hypoxia dynamics in spheroids. Spheroids were treated with IACS-010759, atovaquone, metformin, tamoxifen or with mitochondria-targeted atovaquone (Mito-ATO), PEGylated mitochondria-targeted atovaquone (Mito-PEG-ATO) or mitochondria-targeted tamoxifen (MitoTam). Hypoxia dynamics were followed and quantified over time using the IncuCyte Zoom Live Cell-Imaging system.
RESULTS: Hypoxic cores developed in B16OVA.HRE and MC38.HRE spheroids within 24 h hours after seeding. Treatment with IACS-010759, metformin, atovaquone, Mito-PEG-ATO and MitoTam showed a dose-dependent reduction of hypoxia in both B16OVA.HRE and MC38.HRE spheroids. Mito-ATO only alleviated hypoxia in MC38.HRE spheroids while tamoxifen was not able to reduce hypoxia in any of the spheroid models. The mitochondria-targeted OXPHOS inhibitors demonstrated stronger anti-hypoxic effects compared to the non-mito-targeted OXPHOS inhibitors.
CONCLUSIONS: We successfully developed a high-throughput spheroid model in which hypoxia dynamics can be quantified over time. Using this model, we showed that the mitochondria-targeted OXPHOS inhibitors Mito-ATO, Mito-PEG-ATO and MitoTam reduce hypoxia in tumor cells in a dose-dependent manner, potentially sensitizing hypoxic tumor cells for radiotherapy.

Keywords:  Hypoxia; Live cell imaging; Metabolic reprogramming; Mitochondria-targeting; OXPHOS inhibitors; Spheroids

DOI:  https://doi.org/10.1186/s40170-024-00342-6
Blood Adv. 2024 May 03. pii: bloodadvances.2023012041. [Epub ahead of print]

Venetoclax, a new player in the treatment of children with high-risk myeloid malignancies?

Riccardo Masetti, Francesco Baccelli, Davide Leardini, Franco Locatelli.

Venetoclax selectively inhibits BCL-2 and restores apoptotic signaling of hematological malignant cells. Venetoclax in combination with hypomethylating and low-dose cytotoxic agents has revolutionized the management of elderly patients affected by acute myeloid leukemia (AML), as well as that of patients unfit to receive intensive chemotherapy. In a single phase 1 pediatric trial conducted on relapsed/refractory AML, the combination of venetoclax with intensive chemotherapy was shown to be safe and yielded promising response rates. In addition, several retrospective studies in children with AML reported that venetoclax combined with hypomethylating agents and cytotoxic drugs appears a safe and efficacious bridge to transplant. Promising results on the use of venetoclax combinations in advanced myelodysplastic syndromes (MDS) and therapy-related MDS/AML have also been reported in small case series. This review summarizes the available current knowledge about venetoclax use in childhood high-risk myeloid neoplasms, discussing a possible integration of BCL-2 inhibition in the current treatment algorithm of these children. It also focuses on specific genetic subgroups potentially associated with response in preclinical and clinical studies.

DOI: https://doi.org/10.1182/bloodadvances.2023012041
Sci Rep. 2024 04 29. 14(1): 9865

Switching diets after 6-months does not result in renewed weight loss: a secondary analysis of a 12-month crossover randomized trial.

Matthew J Landry, Catherine P Ward, Kristen M Cunanan, Priya Fielding-Singh, Anthony Crimarco, Christopher D Gardner.

Weight change trajectory from diet and lifestyle interventions typically involves rapid weight loss followed by a weight plateau after approximately 6 months. Changing from one weight-loss diet to another at the time of the plateau could instigate renewed weight loss. Therefore, our secondary analysis aimed to assess trajectory of weight loss in a 12-month, randomized, cross-over study. Forty-two adults were randomized to eat a healthy low-fat or healthy low-carbohydrate diet for 6 months then switched to the opposite diet for an additional 6 months. Regardless of diet assignment, participants experienced rapid initial weight loss, which slowed between 3 to 6 months. After switching diets at 6 months, weight modestly decreased until 9 months, but at a rate slower than the initial 3 months and slower than the rate from 3 to 6 months. This suggests that the weight loss plateau typically seen at 6 months is physiological and cannot be overcome by simply switching to a different weight-loss diet.

DOI: https://doi.org/10.1038/s41598-024-60547-z
Methods Mol Biol. 2024 ;2806 31-40

Patient-Derived Xenograft Models for Leukemias.

Fiona C Brown, Catherine L Carmichael.

  Patient-derived xenograft (PDX) modeling is a valuable tool for the study of leukemia pathogenesis, progression, and therapy response. Engraftment of human leukemia cells occurs following injection into the tail vein (or retro-orbital vein) of preconditioned immunocompromised mice. Injected mice are maintained in a sterile and supportive housing environment until leukemia engraftment is observed, at which time studies such as drug treatments or leukemia sampling can occur. Here, we outline a method for generating PDXs from Acute Myeloid Leukemia (AML) patient samples using tail vein injection; however it can also be readily applied to T- and B- Acute Lymphoblastic Leukemia (ALL) samples.

Keywords:  Bone marrow; Immunocompromised; Irradiation; Leukemia; Mouse model; Peripheral blood; Spleen; Tail vein injection; Xenograft

DOI:  https://doi.org/10.1007/978-1-0716-3858-3_4
J Clin Invest. 2024 Apr 30. pii: e174186. [Epub ahead of print]

Dietary dicarboxylic acids provide a non-storable alternative fat source that protects mice against obesity.

Eric S Goetzman, Bob B Zhang, Yuxun Zhang, Sivakama S Bharathi, Joanna Bons, Jacob Rose, Samah Shah, Keaton J Solo, Alexandra V Schmidt, Adam C Richert, Steven J Mullett, Stacy L Gelhaus, Krithika S Rao, Sruti S Shiva, Katherine E Pfister, Anne Silva Barbosa, Sunder Sims-Lucas, Steven F Dobrowolski, Birgit Schilling.

  Dicarboxylic fatty acids are generated in the liver and kidney in a minor pathway called fatty acid ω-oxidation. The effects of consuming dicarboxylic fatty acids as an alternative source of dietary fat have not been explored. Here, we fed dodecanedioic acid, a 12-carbon dicarboxylic (DC12), to mice at 20% of daily caloric intake for nine weeks. DC12 increased metabolic rate, reduced body fat, reduced liver fat, and improved glucose tolerance. We observed DC12-specific breakdown products in liver, kidney, muscle, heart, and brain, indicating that oral DC12 escaped first-pass liver metabolism and was utilized by many tissues. In tissues expressing the "a" isoform of acyl-CoA oxidase-1 (ACOX1), a key peroxisomal fatty acid oxidation enzyme, DC12 was chain shortened to the TCA cycle intermediate succinyl-CoA. In tissues with low peroxisomal fatty acid oxidation capacity, DC12 was oxidized by mitochondria. In vitro, DC12 was catabolized even by adipose tissue and was not stored intracellularly. We conclude that DC12 and other dicarboxylic acids may be useful for combatting obesity and for treating metabolic disorders.

Keywords:  Fatty acid oxidation; Metabolism; Mitochondria; Obesity

DOI:  https://doi.org/10.1172/JCI174186
Sci Adv. 2024 May 03. 10(18): eadn3448

Spatially resolved analysis of microenvironmental gradient impact on cancer cell phenotypes.

Jamie Auxillos, Roxane Crouigneau, Yan-Fang Li, Yifan Dai, Arnaud Stigliani, Isabella Tavernaro, Ute Resch-Genger, Albin Sandelin, Rodolphe Marie, Stine F Pedersen.

Despite the physiological and pathophysiological significance of microenvironmental gradients, e.g., for diseases such as cancer, tools for generating such gradients and analyzing their impact are lacking. Here, we present an integrated microfluidic-based workflow that mimics extracellular pH gradients characteristic of solid tumors while enabling high-resolution live imaging of, e.g., cell motility and chemotaxis, and preserving the capacity to capture the spatial transcriptome. Our microfluidic device generates a pH gradient that can be rapidly controlled to mimic spatiotemporal microenvironmental changes over cancer cells embedded in a 3D matrix. The device can be reopened allowing immunofluorescence analysis of selected phenotypes, as well as the transfer of cells and matrix to a Visium slide for spatially resolved analysis of transcriptional changes across the pH gradient. This workflow is easily adaptable to other gradients and multiple cell types and can therefore prove invaluable for integrated analysis of roles of microenvironmental gradients in biology.

DOI: https://doi.org/10.1126/sciadv.adn3448
Metabolism. 2024 Apr 25. pii: S0026-0495(24)00147-1. [Epub ahead of print] 155920

Statin treatment reduces leucine turnover, but does not affect endogenous production of beta-hydroxy-beta-methylbutyrate (HMB).

Martin Hagve, Suzette L Pereira, Dillon K Walker, Marielle P K J Engelen, Nicolaas E P Deutz.

   BACKGROUND: Statins, or hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, are one of the most commonly prescribed medications for lowering cholesterol. Myopathic side-effects ranging from pain and soreness to critical rhabdomyolysis are commonly reported and often lead to discontinuation. The pathophysiological mechanism is, in general, ascribed to a downstream reduction of Coenzyme Q10 synthesis, resulting in mitochondrial dysfunction. HMG-CoA is a metabolite of leucine and its corresponding keto acid α-ketoisocaproic acid (KIC) and beta-hydroxy-beta-methylbutyrate (HMB), however little is known about the changes in the metabolism of leucine and its metabolites in response to statins.
OBJECTIVE: We aimed to investigate if statin treatment has implications on the upstream metabolism of leucine to KIC and HMB, as well as on other branched chain amino acids (BCAA).
DESIGN: 12 hyperlipidemic older adults under statin treatment were recruited. The study was conducted as a paired prospective study. Included participants discontinued their statin treatment for 4 weeks before they returned for baseline measurements (before). Statin treatment was then reintroduced, and the participants returned for a second study day 7 days after reintroduction (after statin). On study days, participants were injected with stable isotope pulses for measurement of the whole-body production (WBP) of all BCAA (leucine, isoleucine and valine) along with their respective keto acids and HMB.
RESULTS: We found a reduced leucine WBP (22 %, p = 0.0033), along with a reduction in valine WBP (13 %, p = 0.0224). All other WBP of BCAA and keto acids were unchanged. There were no changes in the WBP of HMB.
CONCLUSIONS: Our study shows that statin inhibition of HMG-CoA reductase has an upstream impact on the turnover of leucine and valine. Whether this impairment in WBP of leucine may contribute to the known pathophysiological side effects of statins on muscle remains to be further investigated.

Keywords:  Amino acids; Isotope pulse; Leucine; Statins; beta-hydroxy-beta-methylbutyrate

DOI:  https://doi.org/10.1016/j.metabol.2024.155920
Front Oncol. 2024 ;14 1370405

Efficacy and safety of venetoclax plus hypomethylating agents in relapsed/refractory acute myeloid leukemia: a multicenter real-life experience.

Francesco Angotzi, Federica Lessi, Matteo Leoncin, Carla Filì, Mauro Endri, Albana Lico, Andrea Visentin, Stefano Pravato, Anna Candoni, Livio Trentin, Carmela Gurrieri.

  Venetoclax (VEN) has been shown to play a synergistic effect in combination with hypomethylating agents (HMAs) in the frontline treatment of acute myeloid leukemia (AML). However, the potential role of this therapy in the relapsed/refractory (R/R) AML setting, still needs to be further unveiled. The aim of the current study was to retrospectively outline the safety profile, response and survival outcomes of R/R AML patients treated with VEN in association with HMAs. Clinical, biological, and molecular data were collected from 57 patients with R/R AML treated with VEN combined with azacitidine or decitabine between 2018 and 2023. The median age of patients was 63 years, 38 (66.7%) received treatment for relapsed disease while 19 (33.3%) for refractory disease, 5 (8.7%) were treated for molecular relapse. A consistent proportion of the cohort was represented by patients with unfavorable prognostic factors such as complex karyotype (36.8%), secondary AML (29.8%), previous exposure to HMAs (38.6%), and relapse after allogeneic stem cell transplant (22.8%). A total of 14 patients achieved CR (24.6%), 3 (5.3%) CRi, 3 (5.3%) MLFS, and 3 (5.3%) PR, accounting for an ORR of 40.4%. The CR/CRi rate was higher in the group treated with azacitidine than in the group treated with decitabine (37.8% vs. 15%). The median OS was 8.2 months, reaching 20.1 months among responding patients. VEN-HMAs treatment allowed to bridge to allogeneic stem cell transplantation 11 (23.9%) of eligible patients, for which a median OS of 19.8 months was shown. On multivariate analysis, ECOG performance status ≥2, complex karyotype and not proceeding to allogeneic stem cell transplantation after therapy with VEN-HMAs were the factors independently associated with shorter OS. Patients treated with the azacitidine rather than the decitabine containing regimen generally displayed a trend toward superior outcomes. The major toxicities were prolonged neutropenia and infections. In conclusion, this study showed how VEN-HMAs could represent an effective salvage therapy in patients with R/R AML, even among some of those patients harboring dismal prognostic features, with a good toxicity profile. Further prospective studies are thus warranted.

Keywords:  acute myeloid leukemia; azacitidine; decitabine; hypomethylating agents; relapsed/refractory acute myeloid leukemia; venetoclax

DOI:  https://doi.org/10.3389/fonc.2024.1370405
Int J Cancer. 2024 May 01.

Post-diagnosis dietary factors, supplement use and colorectal cancer prognosis: A Global Cancer Update Programme (CUP Global) systematic literature review and meta-analysis.

Doris S M Chan, Margarita Cariolou, Georgios Markozannes, Katia Balducci, Rita Vieira, Sonia Kiss, Nerea Becerra-Tomás, Dagfinn Aune, Darren C Greenwood, Esther M González-Gil, Ellen Copson, Andrew G Renehan, Martijn Bours, Wendy Demark-Wahnefried, Melissa M Hudson, Anne M May, Folakemi T Odedina, Roderick Skinner, Karen Steindorf, Anne Tjønneland, Galina Velikova, Monica L Baskin, Rajiv Chowdhury, Lynette Hill, Sarah J Lewis, Jaap Seidell, Matty P Weijenberg, John Krebs, Amanda J Cross, Konstantinos K Tsilidis.

  The role of diet in colorectal cancer prognosis is not well understood and specific lifestyle recommendations are lacking. We searched for randomised controlled trials (RCTs) and longitudinal observational studies on post-diagnosis dietary factors, supplement use and colorectal cancer survival outcomes in PubMed and Embase from inception until 28th February 2022. Random-effects dose-response meta-analyses were conducted when at least three studies had sufficient information. The evidence was interpreted and graded by the CUP Global independent Expert Committee on Cancer Survivorship and Expert Panel. Five RCTs and 35 observational studies were included (30,242 cases, over 8700 all-cause and 2100 colorectal cancer deaths, 3700 progression, recurrence, or disease-free events). Meta-analyses, including 3-10 observational studies each, were conducted for: whole grains, nuts/peanuts, red and processed meat, dairy products, sugary drinks, artificially sweetened beverages, coffee, alcohol, dietary glycaemic load/index, insulin load/index, marine omega-3 polyunsaturated fatty acids, supplemental calcium, circulating 25-hydroxyvitamin D (25[OH]D) and all-cause mortality; for alcohol, supplemental calcium, circulating 25(OH)D and colorectal cancer-specific mortality; and for circulating 25(OH)D and recurrence/disease-free survival. The overall evidence was graded as 'limited'. The inverse associations between healthy dietary and/or lifestyle patterns (including diets that comprised plant-based foods), whole grains, total, caffeinated, or decaffeinated coffee and all-cause mortality and the positive associations between unhealthy dietary patterns, sugary drinks and all-cause mortality provided 'limited-suggestive' evidence. All other exposure-outcome associations provided 'limited-no conclusion' evidence. Additional, well-conducted cohort studies and carefully designed RCTs are needed to develop specific lifestyle recommendations for colorectal cancer survivors.

Keywords:  colorectal cancer survival; diet; evidence grading; food; systematic review

DOI:  https://doi.org/10.1002/ijc.34906
Int J Cancer. 2024 May 01.

Post-diagnosis adiposity, physical activity, sedentary behaviour, dietary factors, supplement use and colorectal cancer prognosis: Global Cancer Update Programme (CUP Global) summary of evidence grading.

Konstantinos K Tsilidis, Georgios Markozannes, Nerea Becerra-Tomás, Margarita Cariolou, Katia Balducci, Rita Vieira, Sonia Kiss, Dagfinn Aune, Darren C Greenwood, Laure Dossus, Esther M González-Gil, Marc J Gunter, Kate Allen, Nigel T Brockton, Helen Croker, Vanessa L Gordon-Dseagu, Panagiota Mitrou, Nicole Musuwo, Martin J Wiseman, Ellen Copson, Andrew G Renehan, Martijn Bours, Wendy Demark-Wahnefried, Melissa M Hudson, Anne M May, Folakemi T Odedina, Roderick Skinner, Karen Steindorf, Anne Tjønneland, Galina Velikova, Monica L Baskin, Rajiv Chowdhury, Lynette Hill, Sarah J Lewis, Jaap Seidell, Matty P Weijenberg, John Krebs, Amanda J Cross, Doris S M Chan.

  Based on the World Cancer Research Fund Global Cancer Update Programme, we performed systematic reviews and meta-analyses to investigate the association of post-diagnosis adiposity, physical activity, sedentary behaviour, and dietary factors with colorectal cancer prognosis. We searched PubMed and Embase until 28th February, 2022. An independent expert committee and expert panel graded the quality of evidence. A total of 167 unique publications were reviewed, and all but five were observational studies. The quality of the evidence was graded conservatively due to the high risk of several biases. There was evidence of non-linearity in the associations between body mass index and colorectal cancer prognosis. The associations appeared reverse J-shaped, and the quality of this evidence was graded as limited (likelihood of causality: limited-no conclusion). The evidence on recreational physical activity and lower risk of all-cause mortality (relative risk [RR] highest vs. lowest: 0.69, 95% confidence interval [CI]: 0.62-0.77) and recurrence/disease-free survival (RR: 0.80, 95% CI: 0.70-0.92) was graded as limited-suggestive. There was limited-suggestive evidence for the associations between healthy dietary and/or lifestyle patterns (including diets that comprised plant-based foods), intake of whole grains and coffee with lower risk of all-cause mortality, and between unhealthy dietary patterns and intake of sugary drinks with higher risk of all-cause mortality. The evidence for other exposures on colorectal cancer outcomes was sparse and graded as limited-no conclusion. Analyses were conducted excluding cancer patients with metastases without substantial changes in the findings. Well-designed intervention and cohort studies are needed to support the development of lifestyle recommendations for colorectal cancer patients.

Keywords:  adiposity; colorectal cancer; diet; evidence grading; physical activity; prognosis; sedentary behaviour; survival; systematic review

DOI:  https://doi.org/10.1002/ijc.34904
Ann Med Surg (Lond). 2024 May;86(5): 2399-2401

Glutamate-reduced diet and ketogenic diet for pediatric drug-resistant epilepsy: a novel approach to treatment.

Zaib Un Nisa Mughal, Abdul Malik, Burhanuddin Sohail Rangwala, Hussain Sohail Rangwala, Hareer Fatima, Mirha Ali, Asma A Farah.

DOI: https://doi.org/10.1097/MS9.0000000000001972
BMC Mol Cell Biol. 2024 Apr 30. 25(1): 14

High-fat diet enhances cell proliferation and compromises intestinal permeability in a translational canine intestinal organoid model.

Itsuma Nagao, Yoko M Ambrosini.

   BACKGROUND: Emerging evidence underscores the responsiveness of the mammalian intestine to dietary cues, notably through the involvement of LGR5 + intestinal stem cells in orchestrating responses to diet-driven signals. However, the effects of high-fat diet (HFD) on these cellular dynamics and their impact on gut integrity remain insufficiently understood. Our study aims to assess the multifaceted interactions between palmitic acid (PA), cell proliferation, and the intestinal epithelial barrier using a canine colonoid model. Canine models, due to their relevance in simulating human intestinal diseases, offer a unique platform to explore the molecular mechanisms underlying HFD derived intestinal dysfunction.
RESULTS: Canine colonoids were subjected to PA exposure, a surrogate for the effects of HFD. This intervention revealed a remarkable augmentation of cell proliferative activity. Furthermore, we observed a parallel reduction in transepithelial electrical resistance (TEER), indicating altered epithelium barrier integrity. While E-cadherin exhibited consistency, ZO-1 displayed a noteworthy reduction in fluorescence intensity within the PA-exposed group.
CONCLUSIONS: By employing canine intestinal organoid systems, we provide compelling insights into the impact of PA on intestinal physiology. These findings underscore the importance of considering both cell proliferative activity and epithelial integrity in comprehending the repercussions of HFDs on intestinal health. Our study contributes to a deeper understanding of the consequences of HFD on intestinal homeostasis, utilizing valuable translational in vitro models derived from dogs.

Keywords:  Canine; High-fat diet; Intestinal organoids; Palmitic acid

DOI:  https://doi.org/10.1186/s12860-024-00512-w