bims-medica 2024-11-17 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2024‒11‒17
thirty-two papers selected by
Brett Chrest, Wake Forest University

Therapeutic potential of β-hydroxybutyrate in the management of pancreatic neoplasms: exploring novel diagnostic and treatment strategies.
Cancer-associated fibroblasts maintain critical pancreatic cancer cell lipid homeostasis in the tumor microenvironment.
Deciphering the Metabolic Basis and Molecular Circuitry of the Warburg Paradox in Lymphoma.
High-Resolution Respirometry Methodology for Bioenergetic and Metabolic Studies in Intact Brain Slices.
Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission.
GlutaR: A High-Performance Fluorescent Protein-Based Sensor for Spatiotemporal Monitoring of Glutamine Dynamics In Vivo.
A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites.
Passage dependence of NADH redox status and reactive oxygen species level in vitro in triple-negative breast cancer cell lines with different invasiveness.
OXPHOS mediators in acute myeloid leukemia patients: Prognostic biomarkers and therapeutic targets for personalized medicine.
Weight Loss, Pathological Changes, and Inflammatory Effects from a Short-Term Ketogenic Diet in Overweight and Obese Men with Untreated Prostate Cancer on Active Surveillance.
A Case-control Study on the Association of Fruit and Vegetable Consumption with Risk of Breast Cancer.
Targeting mitochondrial metabolism with CPI-613 in chemoresistant ovarian tumors.
Ketogenic diet in clinical populations-a narrative review.
Ketone Esters Partially and Selectively Rescue Mitochondrial Bioenergetics After Acute Cervical Spinal Cord Injury in Rats: A Time-Course.
Metabolic landscape of disseminated cancer dormancy.
Spatial metabolomics highlights metabolic reprogramming in acute myeloid leukemia mice through creatine pathway.
Enhancing mitochondrial pyruvate metabolism ameliorates ischemic reperfusion injury in the heart.
Isocitrate dehydrogenase 2 mutation promotes cytarabine resistance in acute myeloid leukemia by Warburg effect.
The Warburg Effect is the result of faster ATP production by glycolysis than respiration.
Mapping Natural Sugars Metabolism in Acute Myeloid Leukaemia Using 2D Nuclear Magnetic Resonance Spectroscopy.
Baseline predictors associated with successful weight loss among breast cancer survivors in the Lifestyle, Exercise, and Nutrition (LEAN) study.
Contribution of glucose and glutamine to hypoxia-induced lipid synthesis decreases, while contribution of acetate increases, during 3T3-L1 differentiation.
Mass Spectrometry Advances in Analysis of Glioblastoma.
Creating Physiological Cell Environments In Vitro: Adjusting Cell Culture Media Composition and Oxygen Levels to Investigate Mitochondrial Function and Cancer Metabolism.
Effects of different types of intermittent fasting on metabolic outcomes: an umbrella review and network meta-analysis.
GC-MS and multivariate analysis reveal partial serum metabolome restoration by bevacizumab in a colon cancer rat model: An untargeted metabolomics investigation.
Association Between Physical Activity and Pancreatic Cancer Risk and Mortality: A Systematic Review and Meta-Analysis.
Unveiling the Genetic and Clinical Differences of Acute Myeloid Leukemia (AML) in Obese Patients.
Fluorescence Lifetime Imaging Enables In vivo Quantification of PD-L1 Expression and Inter-tumoral Heterogeneity.
Mitochondrial Membrane Potential (ΔΨ) Fluctuations Associated with the Metabolic States of Mitochondria.
Targeting ketone body metabolism in mitigating gemcitabine resistance.
The ketogenic diet modulates tumor-associated neutrophil polarization via the AMOT-YAP/TAZ axis to inhibit colorectal cancer progression.

Lipids Health Dis. 2024 Nov 14. 23(1): 376

Therapeutic potential of β-hydroxybutyrate in the management of pancreatic neoplasms: exploring novel diagnostic and treatment strategies.

Mohammad Amin Vaezi, Samira Nekoufar, Ali Karami Robati, Vahid Salimi, Masoumeh Tavakoli-Yaraki.

  Pancreatic neoplasm, a highly aggressive and often fatal cancer, poses challenges due to late detection and nonspecific symptoms. Therefore, both early diagnosis and appropriate therapeutic approaches are necessary to augment the condition of these patients. Cancer cells undergo metabolic deregulation, which enables their proliferation, survival, and invasion. As a result, it is crucial to focus on the metabolic pathways in prevalent cancers and explore treatment strategies that target these pathways to control tumor growth effectively. This is particularly relevant in cancers like pancreatic cancer, which undergo numerous metabolic alterations. The ketogenic regimen, characterized by low carbohydrate and protein contents and high-fat sources, does not involve caloric restriction. This allows for the induction of ketogenesis and an increase in ketone bodies, while insulin and glucose levels remain low even after meals. This unique metabolic state may influence the tumor microenvironment. Given the lack of unanimous agreement on the precise role and mechanism of the ketogenic diet, this review aims to clarify the diagnostic value and accuracy of ketone bodies in various types of pancreatic tumors and explore the potential anti-cancer effects of the ketogenic diet when used alone or in conjunction with chemotherapy, also to determine the potential of the ketogenic diet to be used as adjuvant therapy. The outcomes of this study are instrumental in enhancing our understanding of the benefits and drawbacks associated with employing this diet for the management and diagnosis of pancreatic cancer.

Keywords:  Insulinoma; Ketogenic diet; Ketone body; Pancreatic cancer; Β-hydroxybutyrate

DOI:  https://doi.org/10.1186/s12944-024-02368-7
Cell Rep. 2024 Nov 12. pii: S2211-1247(24)01323-8. [Epub ahead of print]43(11): 114972

Cancer-associated fibroblasts maintain critical pancreatic cancer cell lipid homeostasis in the tumor microenvironment.

Xu Han, Michelle Burrows, Laura C Kim, Jimmy P Xu, Will Vostrejs, Tran Ngoc Van Le, Carson Poltorack, Yanqing Jiang, Edna Cukierman, Ben Z Stanger, Kim A Reiss, Sydney M Shaffer, Clementina Mesaros, Brian Keith, M Celeste Simon.

  Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with abundant cancer-associated fibroblasts (CAFs) creating hallmark desmoplasia that limits oxygen and nutrient delivery. This study explores the importance of lipid homeostasis under stress. Exogenous unsaturated lipids, rather than de novo synthesis, sustain PDAC cell viability by relieving endoplasmic reticulum (ER) stress under nutrient scarcity. Furthermore, CAFs are less hypoxic than adjacent malignant cells in vivo, nominating them as a potential source of unsaturated lipids. CAF-conditioned medium promotes PDAC cell survival upon nutrient and oxygen deprivation, an effect reversed by delipidation. Lysophosphatidylcholines (LPCs) are particularly enriched in CAF-conditioned medium and preferentially taken up by PDAC cells, where they are converted to phosphatidylcholine (PC) to sustain membrane integrity. Blocking LPC-to-PC conversion inhibits PDAC cell survival and increases ER stress. These findings show a critical lipid "cross-feeding" mechanism that promotes PDAC cell survival, offering a potential metabolic target for treatment.

Keywords:  CP: Cancer; CP: Metabolism; fibroblasts; hypoxia; lipids; pancreatic cancer; tumor microenvironment; unsaturated fatty acids

DOI:  https://doi.org/10.1016/j.celrep.2024.114972
Cancers (Basel). 2024 Oct 25. pii: 3606. [Epub ahead of print]16(21):

Deciphering the Metabolic Basis and Molecular Circuitry of the Warburg Paradox in Lymphoma.

Dashnamoorthy Ravi, Athena Kritharis, Andrew M Evens.

  Background/Objectives: Warburg's metabolic paradox illustrates that malignant cells require both glucose and oxygen to survive, even after converting glucose into lactate. It remains unclear whether sparing glucose from oxidation intersects with TCA cycle continuity and if this confers any metabolic advantage in proliferating cancers. This study seeks to understand the mechanistic basis of Warburg's paradox and its overall implications for lymphomagenesis. Methods: Using metabolomics, we first examined the metabolomic profiles, glucose, and glutamine carbon labeling patterns in the metabolism during the cell cycle. We then investigated proliferation-specific metabolic features of malignant and nonmalignant cells. Finally, through bioinformatics and the identification of appropriate pharmacological targets, we established malignant-specific proliferative implications for the Warburg paradox associated with metabolic features in this study. Results: Our results indicate that pyruvate, lactate, and alanine levels surge during the S phase and are correlated with nucleotide synthesis. By using 13C1,2-Glucose and 13C6,15N2-Glutamine isotope tracers, we observed that the transamination of pyruvate to alanine is elevated in lymphoma and coincides with the entry of glutamine carbon into the TCA cycle. Finally, by using fludarabine as a strong inhibitor of lymphoma, we demonstrate that disrupting the transamination of pyruvate to alanine correlates with the simultaneous suppression of glucose-derived nucleotide biosynthesis and glutamine carbon entry into the TCA cycle. Conclusions: We conclude that the transamination of pyruvate to alanine intersects with reduced glucose oxidation and maintains the TCA cycle as a critical metabolic feature of Warburg's paradox and lymphomagenesis.

Keywords:  Warburg effect; glucose; glutamine; lactate; lymphoma; nucleotides; targeted inhibitors; transaminase

DOI:  https://doi.org/10.3390/cancers16213606
Methods Mol Biol. 2025 ;2878 35-48

High-Resolution Respirometry Methodology for Bioenergetic and Metabolic Studies in Intact Brain Slices.

Cândida Dias, Cátia F Lourenço, João Laranjinha, Ana Ledo.

  The brain is critically dependent on energetic substrates as it consumes circa 20% of glucose and oxygen under normal physiological conditions. Although different cell types and at different locations might experience particular specificities in the utilization of these substrates, overall, mitochondrial oxidative phosphorylation supports the most efficient energy transduction process, enabling the complete oxidation of glucose to CO2 coupled to ATP synthesis in the presence of O2. Impairment of mitochondrial bioenergetics has been identified as an early event in many brain diseases and aging. Thus, novel methodologies to readily assess mitochondrial respiration in brain tissue, while preserving cellular and mitochondrial architecture and overcoming the serious drawbacks of studies using isolated mitochondrial preparations, are needed. Here we describe a methodology for studying functional parameters defining tissue metabolic respiration in brain hippocampal slices. The methodology can be used for physiological, pharmacological, and toxicological studies.

Keywords:  Brain tissue bioenergetics; High-resolution respirometry; Oxidative phosphorylation; Oxygen consumption rate; Whole brain slices

DOI:  https://doi.org/10.1007/978-1-0716-4264-1_2
Sci Adv. 2024 Nov 15. 10(46): eadp7423

Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission.

Anupama Tiwari, Jongyun Myeong, Arsalan Hashemiaghdam, Marion I Stunault, Hao Zhang, Xiangfeng Niu, Marissa A Laramie, Jasmin Sponagel, Leah P Shriver, Gary J Patti, Vitaly A Klyachko, Ghazaleh Ashrafi.

Glucose has long been considered the primary fuel source for the brain. However, glucose levels fluctuate in the brain during sleep or circuit activity, posing major metabolic stress. Here, we demonstrate that the mammalian brain uses pyruvate as a fuel source, and pyruvate can support neuronal viability in the absence of glucose. Nerve terminals are sites of metabolic vulnerability, and we show that mitochondrial pyruvate uptake is a critical step in oxidative ATP production in hippocampal terminals. We find that the mitochondrial pyruvate carrier is post-translationally modified by lysine acetylation, which, in turn, modulates mitochondrial pyruvate uptake. Our data reveal that the mitochondrial pyruvate carrier regulates distinct steps in neurotransmission, namely, the spatiotemporal pattern of synaptic vesicle release and the efficiency of vesicle retrieval-functions that have profound implications for synaptic plasticity. In summary, we identify pyruvate as a potent neuronal fuel and mitochondrial pyruvate uptake as a critical node for the metabolic control of neurotransmission in hippocampal terminals.

DOI: https://doi.org/10.1126/sciadv.adp7423
Angew Chem Int Ed Engl. 2024 Nov 13. e202416608

GlutaR: A High-Performance Fluorescent Protein-Based Sensor for Spatiotemporal Monitoring of Glutamine Dynamics In Vivo.

Bingjie Liu, Zijie Zhao, Pengcheng Wang, Kamiran Aihemaiti, Lixin Zhu, Qingpeng Wei, Wenzhe Li, Xia Yuan, Jing Wu, Changtao Jiang, Min Hao, Jing Wang.

  Glutamine is the most abundant amino acid in human blood and muscle, and is integral to a wide variety of functions in cancer cells. However, the inability to monitor the subcellular distribution of glutamine in real-time has obscured understanding of glutamine metabolism under physiological and pathological conditions. Here, we report the development of a genetically encoded fluorescent sensor and demonstrate how this GlnBP-cpYFP fusion "GlutaR sensor" undergoes glutamine-induced conformational changes reflected in detectable fluorescence responses. Obtained after iterative screening of approximately 1,600 variants, GlutaR exhibits a ratiometric readout, fast response kinetics, and high responsivity, and we demonstrate its selectivity for monitoring glutamine fluctuations in multiple cell types. Additionally, using digitonin permeabilization of GlutaR HeLa cells, we generated a calibration curve and performed in situ titration to quantify free glutamine concentrations in subcellular compartments (cytosol, nucleus, mitochondria). Subsequently, we applied GlutaR to investigate how chemical and genetic inhibition of GS and GLS differentially alter glutamine levels in subcellular compartments. Finally, we demonstrate GlutaR's ability to monitor dynamic glutamine levels in muscle and liver tissues of diabetic mice in vivo. These findings collectively demonstrate GlutaR as a versatile tool for the spatiotemporal characterization of glutamine metabolism in living cells and tissues.

Keywords:  glutamine* biosensor* fluorescence imaging * metabolism* live mice

DOI:  https://doi.org/10.1002/anie.202416608
Cell. 2024 Nov 07. pii: S0092-8674(24)01214-5. [Epub ahead of print]

A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites.

Maria Dolores Moya-Garzon, Mengjie Wang, Veronica L Li, Xuchao Lyu, Wei Wei, Alan Sheng-Hwa Tung, Steffen H Raun, Meng Zhao, Laetitia Coassolo, Hashim Islam, Barbara Oliveira, Yuqin Dai, Jan Spaas, Antonio Delgado-Gonzalez, Kenyi Donoso, Aurora Alvarez-Buylla, Francisco Franco-Montalban, Anudari Letian, Catherine P Ward, Lichao Liu, Katrin J Svensson, Emily L Goldberg, Christopher D Gardner, Jonathan P Little, Steven M Banik, Yong Xu, Jonathan Z Long.

  β-Hydroxybutyrate (BHB) is an abundant ketone body. To date, all known pathways of BHB metabolism involve the interconversion of BHB and primary energy intermediates. Here, we identify a previously undescribed BHB secondary metabolic pathway via CNDP2-dependent enzymatic conjugation of BHB and free amino acids. This BHB shunt pathway generates a family of anti-obesity ketone metabolites, the BHB-amino acids. Genetic ablation of CNDP2 in mice eliminates tissue amino acid BHB-ylation activity and reduces BHB-amino acid levels. The most abundant BHB-amino acid, BHB-Phe, is a ketosis-inducible congener of Lac-Phe that activates hypothalamic and brainstem neurons and suppresses feeding. Conversely, CNDP2-KO mice exhibit increased food intake and body weight following exogenous ketone ester supplementation or a ketogenic diet. CNDP2-dependent amino acid BHB-ylation and BHB-amino acid metabolites are also conserved in humans. Therefore, enzymatic amino acid BHB-ylation defines a ketone shunt pathway and bioactive ketone metabolites linked to energy balance.

Keywords:  BHB; enzyme; ketone; metabolite; metabolomics; obesity

DOI:  https://doi.org/10.1016/j.cell.2024.10.032
Transl Breast Cancer Res. 2024 ;5 27

Passage dependence of NADH redox status and reactive oxygen species level in vitro in triple-negative breast cancer cell lines with different invasiveness.

Allison Podsednik, He N Xu, Lin Z Li.

  Background: The redox status of nicotinamide adenine dinucleotide (NAD; including oxidized form NAD+ and reduced form NADH) plays key roles in both health and disease and has been actively studied to develop cancer biomarkers and therapeutic strategies. With the optical redox imaging (ORI) technique, we have been investigating the relationship of NADH redox status, reactive oxygen species (ROS), and invasiveness in breast cancer cell cultures, and have associated higher invasiveness with more oxidized NADH redox state. However, the cell cultures may have phenotypic drift and metabolic change with increased passage numbers.Methods: We investigated the passage-dependence of NADH redox status and ROS levels in two triple-negative breast cancer (TNBC) cell cultures: the more invasive/metastatic MDA-MB-231 and the less invasive/metastatic HCC1806 cell lines. We measured the NADH redox status, redox plasticity, and cytoplasmic and mitochondrial ROS levels under the basal condition and metabolic perturbations of the mitochondrial electron transport chain. We evaluated the dependence of redox and ROS profiles on the cell passage number by comparing the early (<20 passages) with the late (>60 passages) passage cells.
Results: (I) NADH redox and ROS baselines are stable and independent of cell passage number, but can vary with passage number under metabolic perturbations depending on specific perturbation and cell line; (II) NADH redox status and intracellular ROS levels can change discordantly in cancer cells; (III) under both basal and metabolically perturbed conditions, the more invasive cell line has a more oxidized NADH redox status with a higher basal cytoplasmic ROS level than the less invasive line, regardless of passage number.
Conclusions: The general correlation between redox, ROS, and invasiveness in studied TNBC cells is not very sensitive to passage number. These results indicate that NADH redox and basal ROS status in TNBC likely reflect the intrinsic progressive nature of TNBC cells.

Keywords:  Optical redox imaging (ORI); flavin adenine dinucleotide (FAD); nicotinamide adenine dinucleotide reduced form (NADH); oxidized flavoproteins (Fp); prognostic biomarker

DOI:  https://doi.org/10.21037/tbcr-24-36
World J Surg Oncol. 2024 Nov 12. 22(1): 298

OXPHOS mediators in acute myeloid leukemia patients: Prognostic biomarkers and therapeutic targets for personalized medicine.

Amal Kamal Abdel-Aziz.

  BACKGROUND: Despite significant advances in comprehending its tumorigenic role, the prognostic and therapeutic potential of targeting oxidative phosphorylation (OXPHOS) in acute myeloid leukemia (AML) remain obscure.METHODS: The prognostic value of ~ 200 mitochondrial/OXPHOS genes as candidate biomarkers was examined in AML patients over ~ 10 years follow-up using Kaplan-Meier and Cox regression analyses. Furthermore, the transcript levels of the assessed markers were inspected in healthy bone marrow tissues and the dependencies of AML cells on the assessed genes were examined.
RESULTS: Elevated levels of NADH:ubiquinone oxidoreductase subunit A6 (NDUFA6), succinate dehydrogenase complex flavoprotein subunit A (SDHA), solute carrier family 25 member 12 (SLC25A12), electron transfer flavoprotein subunit beta (ETFB), carnitine palmitoyltransferase 1A (CPT1A) and glutathione peroxidase 4 (GPX4) were associated with poor overall survival of AML patients. SLC25A12, ETFB and CPT1A were overexpressed in AML compared to healthy tissues. Cytochrome B5 type A (CYB5A)high, SLC25A12high and GPX4high AML patients displayed higher levels of circulating and engrafted blasts compared to low-expressing cohorts. NPM1 and SRSF2 mutations were frequent in SDHAlow and CPT1Alow AML patients respectively. FLT3-ITD, NPM1 and IDH1 mutations were prevalent in CPT1Ahigh AML patients. FLT3-ITD AMLs were more dependent on OXPHOS.
CONCLUSIONS: This study identifies NDUFA6 and SDHA as novel companion prognostic biomarkers which might present a rational strategy for personalized therapy of AML patients.

Keywords:  Acute myeloid leukemia; Mitochondrial biomarker; Oxidative phosphorylation; Prognosis

DOI:  https://doi.org/10.1186/s12957-024-03581-5
Nutrients. 2024 Oct 30. pii: 3716. [Epub ahead of print]16(21):

Weight Loss, Pathological Changes, and Inflammatory Effects from a Short-Term Ketogenic Diet in Overweight and Obese Men with Untreated Prostate Cancer on Active Surveillance.

Adeel Kaiser, Mohummad M Siddiqui, Jason Bosley-Smith, Shu Wang, Joseph Aryankalayil, Mark V Mishra, Alice S Ryan, Christopher R D'Adamo.

  BACKGROUND AND AIMS: Active Surveillance (AS) is a favored strategy for the management of indolent prostate cancers (PCs). Overweight and obese men harbor an increased risk of cancer progression during AS. We aim to prospectively evaluate the feasibility and outcomes of a ketogenic diet (KD) weight-loss intervention in overweight men with PC.MATERIALS AND METHODS: Men with PC and a BMI > 25 kg/m2 undergoing AS were placed on an 8-week ad libitum KD program before a scheduled surveillance biopsy to assess the impact on clinical grade group (CGG). Blood ketone levels were tracked to ensure compliance. BMI, PSA, and inflammatory marker data (TNF-α, TNFR1, TNFR2, sICAM-1, sVCAM-1, IL-6, IL1-RA, CRP, and SAA) were collected before and after the KD intervention. A Shapiro-Wilk test was performed to assess the normality of all continuous study variables. Paired t-tests and Wilcoxon rank sum tests were utilized to compare normally and non-normally distributed study outcomes, respectively.
RESULTS: Ten AS patients aged 62.1 (±5.4) years were enrolled with an average BMI of 31.7 kg/m2 (±11.8). Post-KD intervention mean blood ketone levels were 0.32 (±0.12) mmol/L with a mean BMI reduction of 7.4% (p < 0.0003). There were no meaningful changes in PSA or inflammatory biomarkers (p > 0.05). Nine patients completed re-biopsy following a KD with four patients showing no evidence of cancer; one downgraded to a lower CGG; two had unchanged CGG scores; and two had higher CGG scores compared to baseline.
CONCLUSIONS: Short-term KD interventions for BMI reduction are feasible in men undergoing AS for PC and may result in favorable pathological effects without inflammatory marker changes. Larger studies with longer follow-up are needed to explore whether KD-induced weight loss can improve clinical outcomes with AS in PC.

Keywords:  active surveillance; inflammation; ketogenic diet; obesity; overweight; prostate cancer

DOI:  https://doi.org/10.3390/nu16213716
Int J Prev Med. 2024 ;15 56

A Case-control Study on the Association of Fruit and Vegetable Consumption with Risk of Breast Cancer.

Reza Ramezani, Leila Azadbakht, Sanaz Benisi-Kohansal, Ahmad Esmaillzadeh, Alireza Milajerdi.

  Background: Limited data are available linking dietary intake of fruit and vegetables to breast cancer, in particular among the Middle Eastern population. The present study was done to investigate the association of fruit and vegetable consumption with the risk of breast cancer in Iranian adult women.Methods: Dietary intake of fruit and vegetables was assessed using a validated 106-item Willett-format semi-quantitative dish-based food frequency questionnaire. Logistic regression was used to determine the association between fruit and vegetable consumption and breast cancer. Women aged >30 years, residing in Isfahan, Iran from July 2013 to July 2015. Breast cancer was diagnosed during the maximum of the last 6 months by physical examination and mammography findings.
Results: Overall, data on 350 cases and 700 controls were analyzed. After controlling for potential confounders, participants with the highest dietary intake of fruits had higher odds of breast cancer than those with the lowest intake (odds ratio [OR]: 8.23; 95% confidence interval [CI]: 4.37-15.50), while those who consumed highest amounts of vegetables were less likely to have breast cancer than their counterparts (OR: 0.12; 95% CI: 0.06-0.24). Although no significant associations were found between dietary intakes of fruits and vegetables and risk of breast cancer in premenopausal women, significant positive association between fruit consumption and breast cancer (OR: 16.80; 95% CI: 7.80, 36.21; P < .001) was observed in postmenopausal women.
Conclusions: We found an inverse association between dietary intake of vegetables and breast cancer. Fruit consumption was significantly associated with greater odds of breast cancer in this study.

Keywords:  Breast cancer; case-control study; fruits; vegetables

DOI:  https://doi.org/10.4103/ijpvm.ijpvm_129_23
J Ovarian Res. 2024 Nov 14. 17(1): 226

Targeting mitochondrial metabolism with CPI-613 in chemoresistant ovarian tumors.

Mary P Udumula, Faraz Rashid, Harshit Singh, Tim Pardee, Sanjeev Luther, Tanya Bhardwaj, Km Anjaly, Sofia Piloni, Miriana Hijaz, Radhika Gogoi, Philip A Philip, Adnan R Munkarah, Shailendra Giri, Ramandeep Rattan.

  BACKGROUND: There is evidence indicating that chemoresistance in tumor cells is mediated by the reconfiguration of the tricarboxylic acid cycle, leading to heightened mitochondrial activity and oxidative phosphorylation (OXPHOS). Previously, we have shown that ovarian cancer cells that are resistant to chemotherapy display increased OXPHOS, mitochondrial function, and metabolic flexibility. To exploit this weakness in chemoresistant ovarian cancer cells, we examined the effectiveness of the mitochondrial inhibitor CPI-613 in treating preclinical ovarian cancer.METHODS: Chemosensitive OVCAR3, and chemoresistant CAOV3 and F2 ovarian cancer cells lines and their xenografts in nude mice were used. Functional metabolic studies were performed using Seahorse instrument. Metabolite quantification was performed using LC/MS/MS.
RESULTS: Mice treated with CPI-613 exhibited a notable increase in overall survival and a reduction in tumor development and burden in OVCAR3, F2, and CAOV3 xenografts. CPI-613 suppressed the activity of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase complex, which are two of its targets. This led to a reduction in OXPHOS and tricarboxylic acid cycle activity in all 3 xenografts. The addition of CPI-613 enhanced the responsiveness of chemotherapy in the chemoresistant F2 and CAOV3 tumors, resulting in a notable improvement in survival rates and a reduction in tumor size as compared to using chemotherapy alone. CPI-613 reduced the chemotherapy-induced OXPHOS in chemoresistant tumors. The study revealed that the mechanism by which CPI-613 inhibits tumor growth is through mitochondrial collapse. This is evidenced by an increase in superoxide production within the mitochondria, a decrease in ATP generation, and the release of cytochrome C, which triggers mitochondria-induced apoptosis.
CONCLUSION: Our study demonstrates the translational potential of CPI-613 against chemoresistant ovarian tumors.

Keywords:  Apoptosis; CPI-613; Mitochondria; Ovarian cancer

DOI:  https://doi.org/10.1186/s13048-024-01546-6
Front Med (Lausanne). 2024 ;11 1432717

Ketogenic diet in clinical populations-a narrative review.

Alon Zemer, Shabnam Samaei, Uri Yoel, Aya Biderman, Yair Pincu.

  Ketogenic diet (KD) is a high-fat, low-carbohydrate (CHO) diet, designed to induce a metabolic state of ketosis in which the body metabolizes primarily lipids for energy production. Various forms of KD are being promoted as promising treatments for numerous health conditions from chronic headaches to weight-loss and even different forms of cancer and are becoming increasingly more popular. KD appears to be an efficacious approach for weight-loss, and maintenance, improved glycemia, cognitive function and cancer prognosis. However, there is a controversy regarding the safety of KD, and the potential health risks that might be associated with long-term exposure to KD. There is a gap between the acceptance and utilization of KD in individuals with health conditions and the criticism and negative attitudes toward KD by some clinicians. Many individuals choose to follow KD and are encouraged by the positive results they experience. Although the medical establishment does not endorse KD as a first line of treatment, clinicians need to be informed about KD, and offer support and medical supervision for patients who self-select to follow KD. This can ensure that within the boundaries of KD, patients will make good and healthy dietary choices and prevent clinical disengagement in extreme cases. To that end, there is an urgent need for good quality research to address the issues of long-term safety of KD in different clinical populations and for standardization of KD both in research and in the clinic.

Keywords:  cancer; diabetes; intractable pediatric epilepsy; neurodegenerative disease; obesity; very-low-carbohydrate-diet; weight-loss

DOI:  https://doi.org/10.3389/fmed.2024.1432717
Cells. 2024 Oct 22. pii: 1746. [Epub ahead of print]13(21):

Ketone Esters Partially and Selectively Rescue Mitochondrial Bioenergetics After Acute Cervical Spinal Cord Injury in Rats: A Time-Course.

Oscar Seira, HyoJoon David Park, Jie Liu, Michelle Poovathukaran, Kieran Clarke, Robert Boushel, Wolfram Tetzlaff.

  Spinal cord injury (SCI) pathology and pathophysiology can be attributed to both primary physical injury and secondary injury cascades. Secondary injury cascades involve dysregulated metabolism and energetic deficits directly linked to compromised mitochondrial bioenergetics. Rescuing mitochondrial function and reducing oxidative stress are associated with neuroprotection. In this regard, ketosis after traumatic brain injury (TBI), or after SCI, improves secondary neuropathology by decreasing oxidative stress, increasing antioxidants, reducing inflammation, and improving mitochondrial bioenergetics. Here, we follow up on our previous study and have used an exogenous ketone monoester, (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (KE), as an alternative to a ketogenic diet, focusing on mitochondrial function between 1 and 14 days after injury. Starting 3 h following a cervical level 5 (C5) hemi-contusion injury, animals were fed either a standard control diet (SD) or a ketone ester diet (KED) combined with KE administered orally (OKE). We found that mitochondrial function was reduced after SCI at all times post-SCI, accompanied by reduced expression of most of the components of the electron transport chain (ETC). The KE rescued some of the bioenergetic parameters 1 day after SCI when D-β-Hydroxybutyrate (BHB) concentrations were ~2 mM. Still, most of the beneficial effects were observed 14 days after injury, with BHB concentrations reaching values of 4-6 mM. To our knowledge, this is the first report to show the beneficial effects of KE in rescuing mitochondrial function after SCI and demonstrates the suitability of KE in ameliorating the metabolic dysregulation that occurs after traumatic SCI without requiring a restrictive dietary regime.

Keywords:  D-β-hydroxybutyrate; dietary treatment; metabolism; neurotrauma; respirometry

DOI:  https://doi.org/10.3390/cells13211746
Trends Cancer. 2024 Nov 06. pii: S2405-8033(24)00224-3. [Epub ahead of print]

Metabolic landscape of disseminated cancer dormancy.

Stanislav Drapela, Bruna M Garcia, Ana P Gomes, Ana Luísa Correia.

  Cancer dormancy is a phenomenon defined by the entry of cancer cells into a reversible quiescent, nonproliferative state, and represents an essential part of the metastatic cascade responsible for cancer recurrence and mortality. Emerging evidence suggests that metabolic reprogramming plays a pivotal role in enabling entry, maintenance, and exit from dormancy in the face of the different environments of the metastatic cascade. Here, we review the current literature to understand the dynamics of metabolism during dormancy, highlighting its fine-tuning by the host micro- and macroenvironment, and put forward the importance of identifying metabolic vulnerabilities of the dormant state as therapeutic targets to eradicate recurrent disease.

Keywords:  dormancy; metabolism; metastasis; metastatic microenvironment

DOI:  https://doi.org/10.1016/j.trecan.2024.10.005
Acta Pharm Sin B. 2024 Oct;14(10): 4461-4477

Spatial metabolomics highlights metabolic reprogramming in acute myeloid leukemia mice through creatine pathway.

Yucheng Bao, Jing Qiao, Wenjie Gong, Ruihong Zhang, Yanting Zhou, Yinyin Xie, Yuan Xie, Jiuming He, Tong Yin.

  Acute myeloid leukemia (AML) is recognized as an aggressive cancer that is characterized by significant metabolic reprogramming. Here, we applied spatial metabolomics to achieve high-throughput, in situ identification of metabolites within the liver metastases of AML mice. Alterations at metabolite and protein levels were further mapped out and validated by integrating untargeted metabolomics and proteomics. This study showed a downregulation in arginine's contribution to polyamine biosynthesis and urea cycle, coupled with an upregulation of the creatine metabolism. The upregulation of creatine synthetases Gatm and Gamt, as well as the creatine transporter Slc6a8, resulted in a marked accumulation of creatine within tumor foci. This process further enhances oxidative phosphorylation and glycolysis of leukemia cells, thereby boosting ATP production to foster proliferation and infiltration. Importantly, we discovered that inhibiting Slc6a8 can counter these detrimental effects, offering a new strategy for treating AML by targeting metabolic pathways.

Keywords:  Acute myeloid leukemia; Creatine; Glycolysis; Metabolic reprogramming; Metastasis; Oxidative phosphorylation; Slc6a8; Spatial metabolomics

DOI:  https://doi.org/10.1016/j.apsb.2024.07.004
JCI Insight. 2024 Nov 08. pii: e187849. [Epub ahead of print]9(21):

Enhancing mitochondrial pyruvate metabolism ameliorates ischemic reperfusion injury in the heart.

Joseph R Visker, Ahmad A Cluntun, Jesse N Velasco-Silva, David R Eberhardt, Luis Cedeño-Rosario, Thirupura S Shankar, Rana Hamouche, Jing Ling, Hyoin Kwak, J Yanni Hillas, Ian Aist, Eleni Tseliou, Sutip Navankasattusas, Dipayan Chaudhuri, Gregory S Ducker, Stavros G Drakos, Jared Rutter.

DOI: https://doi.org/10.1172/jci.insight.187849
Hematol Oncol. 2024 Nov;42(6): e3316

Isocitrate dehydrogenase 2 mutation promotes cytarabine resistance in acute myeloid leukemia by Warburg effect.

Jinrong Yang, Zixu Wang, Kun Wu, Bo Nie, Liyin Li, Jingyan Ruan, Qiang Zhou, Yun Zeng, Mingxia Shi.

  Mutation of isocitrate dehydrogenase 2 (IDH2) is a key factor in promoting cytarabine (Ara-C) resistance in acute myeloid leukemia (AML), however the underly mechanism remains unclear. Acute myeloid leukemia cells, were cultured with either IDH2 knockdown (KD-IDH2) or overexpression (OE-IDH2) to elucidate the role of IDH2 in these leukemic cell lines. Additionally, mutant cell lines were engineered to replicate clinically relevant IDH2 mutations. To investigate cellular responses, the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) was administered to the cells. Cell proliferation was quantified using a Cell Counting Kit-8 (CCK-8), while apoptosis was evaluated through propidium iodide staining followed by flow cytometry. Glycolytic metabolism levels were measured using a specific reagent kit, and Western blotting was employed to determine the expression levels of glycolysis-related proteins. Transcriptome sequencing was conducted to elucidate the mechanisms by which IDH2 mutations influence glycolysis. Furthermore, both in vitro cell experiments and in vivo subcutaneous transplantation tumor models in nude mice were utilized to validate these mechanisms. OE-IDH2 in AML cells, enhances resistance to the Ara-C, promotes cell proliferation and glycolysis, and inhibits apoptosis. KD-IDH2 exhibits opposite effects. Both IDH2 mutations and OE-IDH2 produce similar effects on these cellular processes. The increase in glycolysis levels following IDH2 mutation may contribute to the reduced efficacy of Enasidenib in inhibiting the proliferation of IDH-mutant AML cells. Transcriptome sequencing results indicate an enrichment of the PI3K/Akt signaling pathway in IDH2-mutant AML cells. BEZ235 significantly inhibits the expression of phosphorylated PI3K (p-PI3K), phosphorylated Akt (p-Akt), mTOR, glycolytic metabolism, and Ara-C resistance both in vitro and in vivo. Overexpression and mutation of IDH2 coordinate with the Warburg effect through the PI3K/Akt/mTOR pathway to promote Ara-C resistance in AML.

Keywords:  AML cell; Ara‐C resistant; IDH2 mutation; Warburg effect; acute myeloid leukemia

DOI:  https://doi.org/10.1002/hon.3316
Proc Natl Acad Sci U S A. 2024 Nov 12. 121(46): e2409509121

The Warburg Effect is the result of faster ATP production by glycolysis than respiration.

Matthew A Kukurugya, Saharon Rosset, Denis V Titov.

  Many prokaryotic and eukaryotic cells metabolize glucose to organism-specific by-products instead of fully oxidizing it to carbon dioxide and water-a phenomenon referred to as the Warburg Effect. The benefit to a cell is not fully understood, given that partial metabolism of glucose yields an order of magnitude less adenosine triphosphate (ATP) per molecule of glucose than complete oxidation. Here, we test a previously formulated hypothesis that the benefit of the Warburg Effect is to increase ATP production rate by switching from high-yielding respiration to faster glycolysis when excess glucose is available and respiration rate becomes limited by proteome occupancy. We show that glycolysis produces ATP faster per gram of pathway protein than respiration in Escherichia coli, Saccharomyces cerevisiae, and mammalian cells. We then develop a simple mathematical model of energy metabolism that uses five experimentally estimated parameters and show that this model can accurately predict absolute rates of glycolysis and respiration in all three organisms under diverse conditions, providing strong support for the validity of the ATP production rate maximization hypothesis. In addition, our measurements show that mammalian respiration produces ATP up to 10-fold slower than respiration in E. coli or S. cerevisiae, suggesting that the ATP production rate per gram of pathway protein is a highly evolvable trait that is heavily optimized in microbes. We also find that E. coli respiration is faster than fermentation, explaining the observation that E. coli, unlike S. cerevisiae or mammalian cells, never switch to pure fermentation in the presence of oxygen.

Keywords:  Warburg Effect; cancer metabolism; energy metabolism; modeling; systems biology

DOI:  https://doi.org/10.1073/pnas.2409509121
Cancers (Basel). 2024 Oct 23. pii: 3576. [Epub ahead of print]16(21):

Mapping Natural Sugars Metabolism in Acute Myeloid Leukaemia Using 2D Nuclear Magnetic Resonance Spectroscopy.

Christina Muhs, Islam Alshamleh, Christian Richter, Hubert Serve, Harald Schwalbe.

  Metabolism plays a central role in cancer progression. Rewiring glucose metabolism is essential for fulfilling the high energy and biosynthetic demands as well as for the development of drug resistance. Nevertheless, the role of other diet-abundant natural sugars is not fully understood. In this study, we performed a comprehensive 2D NMR spectroscopy tracer-based assay with a panel of 13C-labelled sugars (glucose, fructose, galactose, mannose and xylose). We assigned over 100 NMR signals from metabolites derived from each sugar and mapped them to metabolic pathways, uncovering two novel findings. First, we demonstrated that mannose has a semi-identical metabolic profile to that of glucose with similar label incorporation patterns. Second, next to the known role of fructose in driving one-carbon metabolism, we explained the equally important contribution of galactose to this pathway. Interestingly, we demonstrated that cells growing with either fructose or galactose became less sensitive to certain one-carbon metabolism inhibitors such as 5-Flurouracil and SHIN1. In summary, this study presents the differential metabolism of natural sugars, demonstrating that mannose has a comparable profile to that of glucose. Conversely, galactose and fructose contribute to a greater extent to one-carbon metabolism, which makes them important modulators for inhibitors targeting this pathway. To our knowledge, this is the first NMR study to comprehensively investigate the metabolism of key natural sugars in AML and cancer.

Keywords:  AML; NMR spectroscopy; isotope tracing; sugar metabolism

DOI:  https://doi.org/10.3390/cancers16213576
J Cancer Surviv. 2024 Nov 11.

Baseline predictors associated with successful weight loss among breast cancer survivors in the Lifestyle, Exercise, and Nutrition (LEAN) study.

Rachel Hoobler, Leah S Puklin, Maura Harrigan, Brenda Cartmel, Fang-Yong Li, Tara Sanft, Leah M Ferrucci, Melinda L Irwin, Mary C Playdon.

  PURPOSE: To investigate participant characteristics associated with clinically meaningful weight loss (≥ 5% weight loss) among breast cancer survivors participating in the Lifestyle, Exercise, and Nutrition (LEAN) study.METHODS: Female breast cancer survivors with a body mass index ≥ 25 kg/m2 were enrolled in a 6-month weight loss intervention. Univariate and multivariable logistic regression were used to determine baseline predictors of clinically meaningful weight loss (< vs. ≥ 5%) among those in the intervention arm. The area under the receiver operator characteristic curve (ROC-AUC) C-statistic evaluated the final model's ability to classify weight loss success.
RESULTS: Baseline data were available for 77 participants. Having a history of weight gain during breast cancer treatment was associated with lower odds of achieving ≥ 5% weight loss (OR = 0.36, 95% CI 0.13 - 0.99) compared to women with no history of weight gain during cancer treatment.
CONCLUSION: Breast cancer survivors with overweight or obesity who gained weight during their cancer treatment were less likely to achieve clinically meaningful weight loss during a post-treatment weight loss intervention.
IMPLICATION FOR CANCER SURVIVORS: Breast cancer survivors are encouraged to achieve and maintain a healthy body weight to minimize the risk for cancer recurrence and comorbidity. Our results indicate that programs aimed at prevention of weight gain during treatment could aid in this goal. Understanding characteristics that increase or decrease the likelihood of achieving clinically meaningful weight loss will inform the design of programs that better support breast cancer survivors' weight loss success.

Keywords:  Baseline predictors; Breast cancer; Lifestyle intervention; Weight loss

DOI:  https://doi.org/10.1007/s11764-024-01702-3
Sci Rep. 2024 Nov 15. 14(1): 28193

Contribution of glucose and glutamine to hypoxia-induced lipid synthesis decreases, while contribution of acetate increases, during 3T3-L1 differentiation.

Lucie Ryskova, Katerina Pospisilova, Jiri Vavra, Tomas Wolf, Ales Dvorak, Libor Vitek, Jan Polak.

The molecular mechanisms linking obstructive sleep apnea syndrome (OSA) to obesity and the development of metabolic diseases are still poorly understood. The role of hypoxia (a characteristic feature of OSA) in excessive fat accumulation has been proposed. The present study investigated the possible effects of hypoxia (4% oxygen) on de novo lipogenesis by tracking the major carbon sources in differentiating 3T3-L1 adipocytes. Gas-permeable cultuware was employed to cultivate 3T3-L1 adipocytes in hypoxia (4%) for 7 or 14 days of differentiation. We investigated the contribution of glutamine, glucose or acetate using 13C or 14C labelled carbons to the newly synthesized lipid pool, changes in intracellular lipid content after inhibiting citrate- or acetate-dependent pathways and gene expression of involved key enzymes. The results demonstrate that, in differentiating adipocytes, hypoxia decreased the synthesis of lipids from glucose (44.1 ± 8.8 to 27.5 ± 3.0 pmol/mg of protein, p < 0.01) and partially decreased the contribution of glutamine metabolized through the reverse tricarboxylic acid cycle (4.6% ± 0.2-4.2% ± 0.1%, p < 0.01). Conversely, the contribution of acetate, a citrate- and mitochondria-independent source of carbons, increased upon hypoxia (356.5 ± 71.4 to 649.8 ± 117.5 pmol/mg of protein, p < 0.01). Further, inhibiting the citrate- or acetate-dependent pathways decreased the intracellular lipid content by 58% and 73%, respectively (p < 0.01) showing the importance of de novo lipogenesis in hypoxia-exposed adipocytes. Altogether, hypoxia modified the utilization of carbon sources, leading to alterations in de novo lipogenesis in differentiating adipocytes and increased intracellular lipid content.

DOI: https://doi.org/10.1038/s41598-024-79458-0
Mass Spectrom Rev. 2024 Nov 11.

Mass Spectrometry Advances in Analysis of Glioblastoma.

Sofian Al Shboul, Ashita Singh, Renata Kobetic, David R Goodlett, Paul M Brennan, Ted Hupp, Irena Dapic.

  Some cancers such as glioblastoma (GBM), show minimal response to medical interventions, often only capable of mitigating tumor growth or alleviating symptoms. High metabolic activity in the tumor microenvironment marked by immune responses and hypoxia, is a crucial factor driving tumor progression. The many developments in mass spectrometry (MS) over the last decades have provided a pivotal tool for studying proteins, along with their posttranslational modifications. It is known that the proteomic landscape of GBM comprises a wide range of proteins involved in cell proliferation, survival, migration, and immune evasion. Combination of MS imaging and microscopy has potential to reveal the spatial and molecular characteristics of pathological tissue sections. Moreover, integration of MS in the surgical process in form of techniques such as DESI-MS or rapid evaporative ionization MS has been shown as an effective tool for rapid measurement of metabolite profiles, providing detailed information within seconds. In immunotherapy-related research, MS plays an indispensable role in detection and targeting of cancer antigens which serve as a base for antigen-specific therapies. In this review, we aim to provide detailed information on molecular profile in GBM and to discuss recent MS advances and their clinical benefits for targeting this aggressive disease.

Keywords:  glioblastoma; glycans; lipids; mass spectrometry; proteomics; tissues

DOI:  https://doi.org/10.1002/mas.21912
Methods Mol Biol. 2025 ;2878 163-199

Creating Physiological Cell Environments In Vitro: Adjusting Cell Culture Media Composition and Oxygen Levels to Investigate Mitochondrial Function and Cancer Metabolism.

Sónia A Pinho, Georgina L Gardner, Ricardo Alva, Jeff A Stuart, Teresa Cunha-Oliveira.

  In vitro and ex vivo studies are crucial for mitochondrial research, offering valuable insights into cellular mechanisms and aiding in diagnostic and therapeutic strategies. Accurate in vitro models rely on adequate cell culture conditions, such as the composition of culture media and oxygenation levels. These conditions can influence energy metabolism and mitochondrial activities, thus impacting studies involving mitochondrial components, such as the effectiveness of anticancer drugs. This chapter focuses on practical guidance for creating setups that replicate in vivo microenvironments, capturing the original metabolic context of cells. We explore protocols to better mimic the physiological cell environment, promote cellular reconfiguration, and prime cells according to the modeled context. The first part is dedicated to the use of human dermal fibroblasts, which are a promising model for pre-clinical mitochondrial research due to their adaptability and relevance to human mitochondrial physiology. We present an optimized protocol for gradually adjusting extracellular glucose levels, which demonstrated significant mitochondrial, metabolic, and redox remodeling in normal adult dermal fibroblasts. The second part is dedicated to replication of tumor microenvironments, which are relevant for studies targeting cellular energy metabolism to inhibit tumor growth. Currently available physiological media can mimic blood plasma metabolome but not the specific tumor microenvironment. To address this, we describe optimized media formulation and oxygenation protocols, which can simulate the tumor microenvironment in cell culture experiments. Replicating in vivo microenvironments in in vitro and ex vivo studies can enhance our understanding of cellular processes, facilitate drug development, and advance personalized therapeutics in mitochondrial medicine.

Keywords:  Cell culture media; Energy metabolism; Fibroblasts; Glucose; Hypoxia; Mitochondrial function; Mitochondrial medicine; Nutrient composition; Oxidative phosphorylation; Pericellular oxygen levels; Tumor microenvironment

DOI:  https://doi.org/10.1007/978-1-0716-4264-1_9
BMC Med. 2024 Nov 13. 22(1): 529

Effects of different types of intermittent fasting on metabolic outcomes: an umbrella review and network meta-analysis.

Yu-En Chen, Hui-Li Tsai, Yu-Kang Tu, Ling-Wei Chen.

  BACKGROUND: Intermittent fasting (IF) holds promise for enhancing metabolic health. However, the optimum IF forms and their superiority over continuous energy restriction (CER) remain unclear due to disconnected findings.METHODS: We systematically searched PubMed, Embase, and the Cochrane databases for meta-analyses of randomized controlled trials (RCTs) investigating the association between IF and metabolic health outcomes. Subsequently, we performed an umbrella review and network meta-analysis (NMA) to evaluate the efficacy of different forms of IF (time-restricted eating (TRE), alternate-day fasting (ADF), and 5:2 diet (regular eating for 5 days and energy restriction for 2 days per week)) compared to CER and usual diets on metabolic health outcomes. To assess the certainty of both direct and indirect estimates, we employed the Confidence in Network Meta-Analysis (CINeMA) approach. Additionally, we calculated the surface under the cumulative ranking curve (SUCRA) for each dietary strategy to determine their ranking in terms of metabolic health benefits.
RESULTS: Ten of the best and non-redundant meta-analysis studies, involving 153 original studies and 9846 participants, were included. When considering direct evidence only, all IF forms significantly reduced body weight compared to usual diets. In NMA incorporating indirect evidence, all IF regimens also significantly reduced body weight compared to usual diets. In the SUCRA of NMA, IF ranked higher than usual diets or CER in 85.4% and 56.1% of the outcomes, respectively. ADF had the highest overall ranking for improving metabolic health (ranked first: 64.3%, ranked second: 14.3%).
CONCLUSIONS: Overall, all IF forms demonstrate potentials to improve metabolic health, with ADF appearing to produce better outcomes across investigated outcomes. Further high-quality trials are warranted to confirm the (relative) efficacy of IF on metabolic health.
TRIAL REGISTRATION: PROSPERO (record no: CRD42022302690).

Keywords:  Alternate-day fasting; Continuous energy restriction; Intermittent fasting; Metabolic health; Time-restricted eating

DOI:  https://doi.org/10.1186/s12916-024-03716-1
J Pharm Biomed Anal. 2024 Nov 04. pii: S0731-7085(24)00604-6. [Epub ahead of print]253 116562

GC-MS and multivariate analysis reveal partial serum metabolome restoration by bevacizumab in a colon cancer rat model: An untargeted metabolomics investigation.

Maram H Abduljabbar, Yusuf S Althobaiti, Reem M Alnemari, Farooq M Almutairi, Muneef M Aldhafeeri, Ahmed Serag, Atiah H Almalki.

  Bevacizumab is an anti-angiogenic therapeutic agent that targets vascular endothelial growth factor (VEGF) and has been approved for the treatment of several types of cancer, including colon cancer. Herein, a GC-MS based metabolomics approach was employed to investigate the impact of bevacizumab on the serum metabolome of colon cancer rats. Multivariate chemometric analysis models such as PCA and PLS-DA showed a clear separation between the control, cancer and bevacizumab-treated groups, suggesting that bevacizumab administration induced significant metabolic alterations. Furthermore, pairwise comparisons between the studied groups using the OPLS-DA model in addition to univariate analysis identified several discriminatory metabolites belonged to various chemical classes including amino acids, organic acids and fatty acids that were perturbed between the studied groups. Interestingly, bevacizumab treatment was able to partially restore some of the cancer-induced metabolic disturbances, indicating its potential therapeutic efficacy via improving the tumor vasculature and nutrient delivery. Besides, pathway analysis of the differential metabolites identified key metabolic pathways affected by bevacizumab, which included valine, leucine and isoleucine metabolism, pyruvate metabolism and butanoate metabolism. However, little effects were observed on lipid metabolites such as palmitic acid and stearic acid and consequently their related metabolic pathways such as fatty acid biosynthesis metabolism suggesting that bevacizumab has more prominent effect on energy and amino acid metabolisms as compared to fatty acid metabolism in colon cancer rats. Overall, our study provided novel insights into the metabolic mechanisms underlying the therapeutic effects of bevacizumab in colon cancer rats via the use of a comprehensive GC-MS metabolomics approach.

Keywords:  Bevacizumab; Colon cancer; GC-MS; Metabolomics; Multivariate analysis

DOI:  https://doi.org/10.1016/j.jpba.2024.116562
Cancers (Basel). 2024 Oct 24. pii: 3594. [Epub ahead of print]16(21):

Association Between Physical Activity and Pancreatic Cancer Risk and Mortality: A Systematic Review and Meta-Analysis.

Mylena D Bos, Jelmer E Oor, Lucas Goense, N Helge Meyer, Maximilian Bockhorn, Frederik J H Hoogwater, Joost M Klaase, Maarten W Nijkamp.

  Background: Physical activity has been associated with a lower risk of various types of cancer and reduced cancer-specific mortality. Less is known about its impact on pancreatic cancer. The aim of this systematic review and meta-analysis was to summarize evidence on the association between physical activity and pancreatic cancer risk and mortality. Methods: PubMed and Embase were searched until May 2024 for studies examining physical activity in relation to pancreatic cancer incidence and mortality. Summary risk estimates for highest vs. lowest physical activity levels were calculated using a random-effects model. The risk of publication bias was assessed with a funnel plot and Egger's regression test. Results: A total of seven case-control and eighteen prospective cohort studies were included that investigated the association between physical activity and pancreatic cancer incidence. Our meta-analysis showed a summary estimate of 0.75 (95% CI 0.64-0.88) for case-control studies (I2 = 23%, n = 7) and a summary estimate of 0.91 (95% CI 0.86-0.97) for prospective cohort studies (I2 = 5%, n = 18). Among the six prospective cohort studies that assessed pancreatic cancer mortality, the summary estimate was 1.03 (95% CI 0.83-1.27), I2 = 50%. Conclusions: Higher levels of physical activity were associated with reduced pancreatic cancer risk. Evidence from a limited number of studies suggests that pre-diagnosis physical activity does not affect pancreatic cancer mortality.

Keywords:  mortality; pancreatic cancer; physical activity; risk

DOI:  https://doi.org/10.3390/cancers16213594
Eur J Haematol. 2024 Nov 13.

Unveiling the Genetic and Clinical Differences of Acute Myeloid Leukemia (AML) in Obese Patients.

Fevzi F Yalniz, Anna Johnson, Yanal Alnimer, Zena Chahine, Trevor Morris, Rina Yadav, Hiffsa Taj, Chaitanya Iragavarapu, Reinhold Munker, Gregory Monohan, Sainan Wai, Shulin Zhang, Sahar Nozad, Ayman Qasrawi.

  BACKGROUND: The molecular architecture of acute myeloid leukemia (AML) is heterogeneous. Obesity has been identified as a risk factor for the development of AML. There remains a scarcity of data elucidating the specific genetic profile of AML in obese patients.METHODS: We conducted a review of adult patients treated at our institution for newly diagnosed AML from January 1, 2017, to January 1, 2023. Obesity is defined as BMI > 30 kg/m2. Demographic, clinical, laboratory, and pathologic data were collected retrospectively. The primary outcome of interest was the molecular features of obese compared to non-obese AML patients. The secondary outcome was overall survival (OS). Inverse probability of treatment weights (IPTW) used to balance both groups on several confounding variables.
RESULTS: A total of 185 patients were included in the analysis. 90 (49%) were obese. Compared with non-obese patients, obese patients were younger and more likely to be females (55 vs. 63, p = 0.04, 55% vs. 38%, p value, p = 0.02, respectively). After matching on age, gender, and ethnicity, obese patients exhibit lower rates of total number of gene mutations (median 2.7 vs. 3.2, p = 0.05), significantly lower rates of mutations in transcriptional factor genes (15.7% vs. 33.2%, p = 0.01), and near-significant in spliceosome genes (12% vs. 22.3%, p = 0.08), and higher rates of NPM1 mutation (23.3% vs. 12.6%, p = 0.08). Median OS was not significantly different in the matched cohort.
CONCLUSIONS: The molecular features of obese AML patients significantly differ from non-obese counterparts. These findings suggest distinct underlying mechanisms in leukemogenesis in obese patients.

Keywords:  acute myeloid leukemia; molecular architecture; obesity

DOI:  https://doi.org/10.1111/ejh.14338
Cancer Res. 2024 Nov 08.

Fluorescence Lifetime Imaging Enables In vivo Quantification of PD-L1 Expression and Inter-tumoral Heterogeneity.

Rahul Pal, Murali Krishnamoorthy, Aya Matsui, Homan Kang, Satoru Morita, Hajime Taniguchi, Tatsuya Kobayashi, Atsuyo Morita, Hak Soo Choi, Dan G Duda, Anand T N Kumar.

Patient selection for cancer immunotherapy requires precise, quantitative readouts of biomarker expression in intact tumors that can be reliably compared across multiple subjects over time. The current clinical standard biomarker for assessing immunotherapy response is programmed death-ligand-1 (PD-L1) expression, typically quantified using immunohistochemistry. This method, however, only provides snapshots of PD-L1 expression status in microscopic regions of ex vivo specimens. While various targeted probes have been investigated for in vivo imaging of PD-L1, non-specific probe accumulation within the tumor microenvironment (TME) has hindered accurate quantification, limiting the utility for preclinical and clinical studies. Here, we demonstrated that in vivo time-domain (TD) fluorescence imaging of an anti-PD-L1 antibody tagged with the near-infrared fluorophore IRDye 800CW (αPDL1-800) can yield quantitative estimates of baseline tumor PD-L1 heterogeneity across untreated mice, as well as variations in PD-L1 expression in mice undergoing clinically relevant anti-PD1 treatment. The fluorescence lifetime (FLT) of PD-L1 bound αPDL1-800 was significantly longer than the FLT of nonspecifically accumulated αPDL1-800 in the TME. This FLT contrast allowed quantification of PD-L1 expression across mice both in superficial breast tumors using planar FLT imaging and in deep-seated liver tumors (>5 mm depth) using the asymptotic TD algorithm for fluorescence tomography. These findings suggest that fluorescence lifetime imaging can accelerate the preclinical investigation and clinical translation of new immunotherapy treatments by enabling robust quantification of receptor expression across subjects.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-0880
Methods Mol Biol. 2025 ;2878 117-131

Mitochondrial Membrane Potential (ΔΨ) Fluctuations Associated with the Metabolic States of Mitochondria.

Ivo F Machado, Raul G Miranda, João S Teodoro, Daniel J Dorta, Anabela P Rolo, Carlos M Palmeira.

  The proton electrochemical gradient generated by the respiratory chain activity accounts for over 90% of the available respiratory energy and, as such, its evaluation and accurate measurement regarding total values and fluctuations are an invaluable component of the understanding of mitochondrial function. Consequently, alterations in electric potential across the inner mitochondrial membrane generated by differential protonic accumulation and transport are known as the mitochondrial membrane potential, or Δψ, and are reflective of the functional metabolic status of mitochondria. There are several experimental approaches to measure Δψ, ranging from fluorometric evaluations to electrochemical probes. In this chapter, we describe how Δψ may be evaluated in isolated mitochondria and live cells using electrochemical and fluorescent methods, such as tetraphenylphosphonium (TPP+) and tetramethylrhodamine methyl ester (TMRM), respectively. These methods are dependent on the accumulation of cationic probes within mitochondria, which are assessed by using a TPP+-selective electrode or instruments that measure fluorescence (microplate reader and flow cytometer).

Keywords:  Flow cytometry; Membrane potential; Metabolic states; Mitochondria; TMRM; TPP+-selective electrode

DOI:  https://doi.org/10.1007/978-1-0716-4264-1_7
JCI Insight. 2024 Nov 07. pii: e177840. [Epub ahead of print]

Targeting ketone body metabolism in mitigating gemcitabine resistance.

Krizia Rohena-Rivera, Sungyong You, Minhyung Kim, Sandrine Billet, Johanna Ten Hoeve, Gabrielle Gonzales, Chengqun Huang, Ashley Heard, Keith Syson Chan, Neil A Bhowmick.

  Chemotherapy is often combined with surgery for muscle invasive and non-muscle invasive bladder cancer. However, 70% of the patients recur within 5 years. Metabolic reprogramming is an emerging hallmark in cancer chemoresistance. Here, we report a gemcitabine resistance mechanism which promotes cancer reprogramming via the metabolic enzyme, OXCT1. This mitochondrial enzyme, responsible for the rate-limiting step in β-hydroxybutyrate (βHB) catabolism, was elevated in muscle invasive disease and in chemo-resistant bladder cancer patients. Resistant orthotopic tumors presented an OXCT1-dependent rise in mitochondrial oxygen consumption rate, ATP, and nucleotide biosynthesis. In resistant bladder cancer, knocking out OXCT1 restored gemcitabine sensitivity, and administering the non-metabolizable βHB, enantiomer (S-βHB) only partially restored gemcitabine sensitivity. Suggesting an extra-metabolic role for OXCT1, multi-omics analysis of gemcitabine sensitive and resistant cells revealed an OXCT1-dependent signature with the transcriptional repressor, OVOL1, as a master regulator of epithelial differentiation. The elevation of OVOL1 target genes was associated with its cytoplasmic translocation and poor prognosis in a chemotherapy-treated BCa patient cohort. The knockout of OXCT1 restored OVOL1 transcriptional repressive activity by its nuclear translocation. Orthotopic mouse models of bladder cancer supported OXCT1 as a mediator of gemcitabine sensitivity through ketone metabolism and regulating cancer stem cell differentiation.

Keywords:  Cancer; Drug therapy; Oncology; Urology

DOI:  https://doi.org/10.1172/jci.insight.177840
Pharmacol Res. 2024 Nov 05. pii: S1043-6618(24)00439-0. [Epub ahead of print]210 107494

The ketogenic diet modulates tumor-associated neutrophil polarization via the AMOT-YAP/TAZ axis to inhibit colorectal cancer progression.

Xiuwei Mi, Yudong Duan, Jiying Sun, Qingliang Tai, Huihui Yao, Lijun Meng, Xiaoshan Yang, Xinyu Shi, Bo Shi, Junjie Chen, Liang Sun, Diyuan Zhou, Sheng Xiao, Yizhou Yao, Songbing He.

  Despite significant advances in the diagnosis and treatment of colorectal cancer (CRC), the prognosis for late-stage patients remains poor, highlighting the urgent need for new preventive and therapeutic strategies. Recent studies have focused on the ketogenic diet (KD) and its metabolite, β-hydroxybutyrate (BHB), for their tumor-suppressive effects and modulation of inflammatory responses. Using the azoxymethane (AOM) / dextran sulfate sodium (DSS)-induced mouse CRC model, we found that the ketogenic diet and BHB inhibit pro-tumor N2-type tumor-associated neutrophils (TANs) while promoting the polarization of TANs towards the anti-tumor N1 type. This shift in TANs polarization affects tumor growth and metastasis. The underlying mechanism involves BHB acting on the intracellular receptor histone deacetylases 3 (HDAC3), which modulates the activation of the AMOT-YAP/TAZ axis, leading to the inhibition of pro-carcinogenic factor transcription and release. Moreover, clinical cohort data corroborate these findings, showing that CRC patients with elevated BHB levels have significantly lower rates of lymph node involvement, which is associated with a higher infiltration ratio of anti-carcinogenic N1-type TANs in the tumor microenvironment (TME). These results suggest that BHB levels could serve as a prognostic biomarker for CRC. In conclusion, our findings indicate that BHB derived from KD regulates TANs polarization in CRC via the HDAC3-AMOT-YAP/TAZ axis, effectively inhibiting tumor growth and metastasis. These insights establish a novel theoretical basis for employing the KD in the treatment of CRC and for developing cancer adjuvant immunotherapy strategy based on the polarization of neutrophils.

Keywords:  Colorectal cancer; Ketogenic diet; N1/N2 polarization; Neutrophils; β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.phrs.2024.107494