bims-medica 2024-04-28 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2024–04–28
34 papers selected by
Brett Chrest, East Carolina University

Mitochondria inside acute myeloid leukemia cells hydrolyze ATP to resist chemotherapy.
Raman Imaging-A Valuable Tool for Tracking Fatty Acid Metabolism-Normal and Cancer Human Colon Single-Cell Study.
Venetoclax-Related Neutropenia in Leukemic Patients: A Comprehensive Review of the Underlying Causes, Risk Factors, and Management.
Unique features of β-cell metabolism are lost in type 2 diabetes.
Changes in pediatric referrals after the 2009 ketogenic diet consensus recommendations.
Effect of the Mitochondrial Transaminase (GOT2) on Membrane Potential Sensitive Respiration in Mitochondria of Differentiated C2C12 Muscle Cells.
Beta hydroxybutyrate induces lung cancer cell death, mitochondrial impairment and oxidative stress in a long term glucose-restricted condition.
Sedentary behavior in mice induces metabolic inflexibility by suppressing skeletal muscle pyruvate metabolism.
8-Cl-Ado and 8-NH2-Ado synergize with venetoclax to target the methionine-MAT2A-SAM axis in acute myeloid leukemia.
Molecular biology and novel therapeutics for IDH mutant gliomas: The new era of IDH inhibitors.
Revisiting liver metabolism through acetyl-CoA carboxylase inhibition.
Discovery of Novel Dual Inhibitors Targeting Mutant IDH1 and NAMPT for the Treatment of Glioma with IDH1Mutation.
AML treatment: conventional chemotherapy and emerging novel agents.
Intermittent energy restriction inhibits tumor growth and enhances paclitaxel response in a transgenic mouse model of endometrial cancer.
Hepatic lipid droplet-associated proteome changes distinguish dietary-induced fatty liver from glucose tolerance in male mice.
Vitamin combination promotes ex vivo expansion of NK-92 cells by reprogramming glucose metabolism.
Mitochondrial enzyme FAHD1 reduces ROS in osteosarcoma.
FLT3 and IRAK4 Inhibitor Emavusertib in Combination with BH3-Mimetics in the Treatment of Acute Myeloid Leukemia.
Intermittent fasting, exercise and dietary modification induce unique transcriptomic signatures of multiple tissues governing metabolic homeostasis during weight loss and rebound weight gain.
Glucose Metabolism as a Potential Therapeutic Target in Cytarabine-Resistant Acute Myeloid Leukemia.
Tricarboxylic Acid Cycle Regulation of Metabolic Program, Redox System, and Epigenetic Remodeling for Bone Health and Disease.
Time-Restricted Feeding Attenuates Metabolic Dysfunction-Associated Steatohepatitis and Hepatocellular Carcinoma in Obese Male Mice.
Changes and Significance of Central Carbon Metabolism before and after Metformin Treatment of Type 2 Diabetes Based on Mass Spectrometry.
SCALiR: A Web Application for Automating Absolute Quantification of Mass Spectrometry-Based Metabolomics Data.
Educate, not kill: treating cancer without triggering its defenses.
FLT3 agonists and secondary hematopoietic malignancies: a potential class effect.
Combining sophisticated fast FLIM, confocal microscopy, and STED nanoscopy for live-cell imaging of tunneling nanotubes.
Therapeutic efficacy of RAS inhibitor trametinib using a juvenile myelomonocytic leukemia patient-derived xenograft model.
SMS121, a new inhibitor of CD36, impairs fatty acid uptake and viability of acute myeloid leukemia.
The associations of food environment with gastrointestinal cancer outcomes in the United States.
Muscle weakness and mitochondrial stress occur before metastasis in a novel mouse model of ovarian cancer cachexia.
SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression.
Selected Ion Monitoring for Orbitrap-Based Metabolomics.
Metabolic Alteration Bridging the Prediabetic State and Colorectal Cancer.

bioRxiv. 2024 Apr 15. pii: 2024.04.12.589110. [Epub ahead of print]

Mitochondria inside acute myeloid leukemia cells hydrolyze ATP to resist chemotherapy.

James T Hagen, Mclane M Montgomery, Raphael T Aruleba, Brett R Chrest, Thomas D Green, Miki Kassai, Tonya N Zeczycki, Cameron A Schmidt, Debajit Bhowmick, Su-Fern Tan, David J Feith, Charles E Chalfant, Thomas P Loughran, Darla Liles, Mark D Minden, Aaron D Schimmer, Myles C Cabot, Joseph M Mclung, Kelsey H Fisher-Wellman.

Despite early optimism, therapeutics targeting oxidative phosphorylation (OxPhos) have faced clinical setbacks, stemming from their inability to distinguish healthy from cancerous mitochondria. Herein, we describe an actionable bioenergetic mechanism unique to cancerous mitochondria inside acute myeloid leukemia (AML) cells. Unlike healthy cells which couple respiration to the synthesis of ATP, AML mitochondria were discovered to support inner membrane polarization by consuming ATP. Because matrix ATP consumption allows cells to survive bioenergetic stress, we hypothesized that AML cells may resist cell death induced by OxPhos damaging chemotherapy by reversing the ATP synthase reaction. In support of this, targeted inhibition of BCL-2 with venetoclax abolished OxPhos flux without impacting mitochondrial membrane potential. In surviving AML cells, sustained polarization of the mitochondrial inner membrane was dependent on matrix ATP consumption. Mitochondrial ATP consumption was further enhanced in AML cells made refractory to venetoclax, consequential to downregulations in both the proton-pumping respiratory complexes, as well as the endogenous F 1 -ATPase inhibitor ATP5IF1 . In treatment-naive AML, ATP5IF1 knockdown was sufficient to drive venetoclax resistance, while ATP5IF1 overexpression impaired F 1 -ATPase activity and heightened sensitivity to venetoclax. Collectively, our data identify matrix ATP consumption as a cancer-cell intrinsic bioenergetic vulnerability actionable in the context of mitochondrial damaging chemotherapy.

DOI: https://doi.org/10.1101/2024.04.12.589110
Int J Mol Sci. 2024 Apr 19. pii: 4508. [Epub ahead of print]25(8):

Raman Imaging-A Valuable Tool for Tracking Fatty Acid Metabolism-Normal and Cancer Human Colon Single-Cell Study.

Karolina Beton-Mysur, Monika Kopec, Beata Brozek-Pluska.

  Altered metabolism of lipids is a key factor in many diseases including cancer. Therefore, investigations into the impact of unsaturated and saturated fatty acids (FAs) on human body homeostasis are crucial for understanding the development of lifestyle diseases. In this paper, we focus on the impact of palmitic (PA), linoleic (LA), and eicosapentaenoic (EPA) acids on human colon normal (CCD-18 Co) and cancer (Caco-2) single cells using Raman imaging and spectroscopy. The label-free nature of Raman imaging allowed us to evaluate FAs dynamics without modifying endogenous cellular metabolism. Thanks to the ability of Raman imaging to visualize single-cell substructures, we have analyzed the changes in chemical composition of endoplasmic reticulum (ER), mitochondria, lipid droplets (LDs), and nucleus upon FA supplementation. Analysis of Raman band intensity ratios typical for lipids, proteins, and nucleic acids (I1656/I1444, I1444/I1256, I1444/I750, I1304/I1256) proved that, using Raman mapping, we can observe the metabolic pathways of FAs in ER, which is responsible for the uptake of exogenous FAs, de novo synthesis, elongation, and desaturation of FAs, in mitochondria responsible for energy production via FA oxidation, in LDs specialized in cellular fat storage, and in the nucleus, where FAs are transported via fatty-acid-binding proteins, biomarkers of human colon cancerogenesis. Analysis for membranes showed that the uptake of FAs effectively changed the chemical composition of this organelle, and the strongest effect was noticed for LA. The spectroscopy studies have been completed using XTT tests, which showed that the addition of LA or EPA for Caco-2 cells decreases their viability with a stronger effect observed for LA and the opposite effect observed for PA. For normal cells, CCD-18 Co supplementation using LA or EPA stimulated cells for growing, while PA had the opposite impact.

Keywords:  Raman imaging; Raman spectroscopy; cancer biomarkers; colon cancer; fatty acids; metabolism

DOI:  https://doi.org/10.3390/ijms25084508
Pharmaceuticals (Basel). 2024 Apr 10. pii: 484. [Epub ahead of print]17(4):

Venetoclax-Related Neutropenia in Leukemic Patients: A Comprehensive Review of the Underlying Causes, Risk Factors, and Management.

Laura Giuseppina Di Pasqua, Murwan Mahmoud Abdallah, Fausto Feletti, Mariapia Vairetti, Andrea Ferrigno.

  Venetoclax is a Bcl-2 homology domain 3 (BH3) mimetic currently approved for the treatment of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) that has proven to be highly effective in reinstating apoptosis in leukemic cells through the highly selective inhibition of the anti-apoptotic protein B-cell lymphoma-2 (Bcl-2). Clinically, venetoclax has provided lasting remissions through the inhibition of CLL and AML blasts. However, this activity has often come at the cost of grade III/IV neutropenia due to hematopoietic cells' dependence on Bcl-2 for survival. As life-threatening infections are an important complication in these patients, an effective management of neutropenia is indispensable to maximize patient outcomes. While there is general consensus over dose reduction and scheduling modifications to minimize the risk of neutropenia, the impact of these modifications on survival is uncertain. Moreover, guidelines do not yet adequately account for patient-specific and disease-specific risk factors that may predict toxicity, or the role combination treatment plays in exacerbating neutropenia. The objective of this review is to discuss the venetoclax-induced mechanism of hematological toxicity, the potential predictive risk factors that affect patient vulnerability to neutropenia, and the current consensus on practices for management of neutropenia.

Keywords:  AML; BH3 mimetic; Bcl2; CLL; neutropenia; venetoclax

DOI:  https://doi.org/10.3390/ph17040484
Acta Physiol (Oxf). 2024 Apr 24. e14148

Unique features of β-cell metabolism are lost in type 2 diabetes.

Felipe Muñoz, Malin Fex, Thomas Moritz, Hindrik Mulder, Luis Rodrigo Cataldo.

  Pancreatic β cells play an essential role in the control of systemic glucose homeostasis as they sense blood glucose levels and respond by secreting insulin. Upon stimulating glucose uptake in insulin-sensitive tissues post-prandially, this anabolic hormone restores blood glucose levels to pre-prandial levels. Maintaining physiological glucose levels thus relies on proper β-cell function. To fulfill this highly specialized nutrient sensor role, β cells have evolved a unique genetic program that shapes its distinct cellular metabolism. In this review, the unique genetic and metabolic features of β cells will be outlined, including their alterations in type 2 diabetes (T2D). β cells selectively express a set of genes in a cell type-specific manner; for instance, the glucose activating hexokinase IV enzyme or Glucokinase (GCK), whereas other genes are selectively "disallowed", including lactate dehydrogenase A (LDHA) and monocarboxylate transporter 1 (MCT1). This selective gene program equips β cells with a unique metabolic apparatus to ensure that nutrient metabolism is coupled to appropriate insulin secretion, thereby avoiding hyperglycemia, as well as life-threatening hypoglycemia. Unlike most cell types, β cells exhibit specialized bioenergetic features, including supply-driven rather than demand-driven metabolism and a high basal mitochondrial proton leak respiration. The understanding of these unique genetically programmed metabolic features and their alterations that lead to β-cell dysfunction is crucial for a comprehensive understanding of T2D pathophysiology and the development of innovative therapeutic approaches for T2D patients.

Keywords:  disallowed genes; insulin secretion; metabolism; mitochondria; type 2 diabetes; β cells

DOI:  https://doi.org/10.1111/apha.14148
Epilepsy Behav. 2024 Apr 20. pii: S1525-5050(24)00172-0. [Epub ahead of print]155 109791

Changes in pediatric referrals after the 2009 ketogenic diet consensus recommendations.

Rebecca S Stainman, Zahava Turner, Eric H Kossoff.

   BACKGROUND: In 2009, the International Ketogenic Diet Study Group published recommendations for children receiving ketogenic diet (KD) therapy for epilepsy. The document included a table listing epilepsy syndromes and conditions in which the KD has been particularly beneficial, hoping that physicians would refer children for the KD sooner.
PURPOSE: To measure the impact of these 2009 recommendations on referral practice, we compared children initiated on the KD at Johns Hopkins Hospital (JHH) 10 years before and after the recommendations.
RESULTS: Overall, children referred to the KD who met indications increased from the pre- to post-recommendation group, 44 % (112/256) to 69 % (175/255) (p < 0.001), with JHH neurologists specifically referring more frequently (10/112, 9 % to 58/175, 33 %) (p < 0.01). Referrals increased for Glut-1 deficiency (0 % to 2.4 %, p = 0.015), Dravet syndrome (0 % to 6.7 %, p < 0.01), Rett syndrome (0.4 % to 3 %, p = 0.018), and formula-fed only status (16 % to 31 %, p < 0.01). The chances of > 50 % seizure reduction for all children referred improved slightly between decades (56 % to 61 %, p = 0.30).
CONCLUSIONS: Following the 2009 recommendations, our study shows there was an increase in referrals for children with indications at our center. Referrals from neurologists at our own institution increased the most. Ketogenic diet efficacy improved slightly over time but did not reach significance.

Keywords:  Consensus; Diet; Epilepsy; Ketogenic; Pediatric; Referrals

DOI:  https://doi.org/10.1016/j.yebeh.2024.109791
Am J Physiol Cell Physiol. 2024 Apr 22.

Effect of the Mitochondrial Transaminase (GOT2) on Membrane Potential Sensitive Respiration in Mitochondria of Differentiated C2C12 Muscle Cells.

Ritu Som, Brian D Fink, Liping Yu, William I Sivitz.

  We previously showed that the transaminase inhibitor, aminooxyacetic acid, reduced respiration energized at complex II (succinate dehydrogenase, SDH) in mitochondria isolated from mouse hindlimb muscle. The effect required a reduction in membrane potential with resultant accumulation of oxaloacetate (OAA), a potent inhibitor of SDH. To specifically assess the effect of the mitochondrial transaminase, glutamic oxaloacetic transaminase (GOT2) on complex II respiration and to determine the effect in intact cells as well as isolated mitochondria, we performed respiratory and metabolic studies in wildtype (WT) and CRISPR-generated GOT2 knockdown (KD) C2C12 myocytes. Intact cell respiration by GOT2KD cells versus WT was reduced by adding carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP) to lower potential. In mitochondria of C2C12 KD cells, respiration at low potential generated by 1µM FCCP and energized at complex II by 10mM succinate + 0.5mM glutamate, (but not by complex I substrates) was reduced versus WT mitochondria. Although we could not detect OAA, metabolite data suggested that OAA inhibition of SDH may have contributed to the FCCP effect. C2C12 mitochondria differed from skeletal muscle mitochondria in that the effect of FCCP on complex II respiration was not evident with ADP addition. We also observed that C2C12 cells, unlike skeletal muscle, expressed glutamate dehydrogenase, which competes with GOT2 for glutamate metabolism. In summary, GOT2 KD reduced C2C12 respiration in intact cells at low potential. From differential substrate effects, this occurred largely at complex II. Moreover, C2C12 versus muscle mitochondria differ in complex II sensitivity to ADP and differ markedly in expression of glutamate dehydrogenase.

Keywords:  aspartate aminotransferase; mitochondria; myocytes; oxaloacetate; succinate dehydrogenase

DOI:  https://doi.org/10.1152/ajpcell.00576.2023
Mol Biol Rep. 2024 Apr 24. 51(1): 567

Beta hydroxybutyrate induces lung cancer cell death, mitochondrial impairment and oxidative stress in a long term glucose-restricted condition.

Farzad Izak Shirian, Milad Karimi, Maryam Alipour, Siamak Salami, Mitra Nourbakhsh, Samira Nekufar, Nahid Safari-Alighiarloo, Masoumeh Tavakoli-Yaraki.

   BACKGROUND: Metabolic plasticity gives cancer cells the ability to shift between signaling pathways to facilitate their growth and survival. This study investigates the role of glucose deprivation in the presence and absence of beta-hydroxybutyrate (BHB) in growth, death, oxidative stress and the stemness features of lung cancer cells.
METHODS AND RESULTS: A549 cells were exposed to various glucose conditions, both with and without beta-hydroxybutyrate (BHB), to evaluate their effects on apoptosis, mitochondrial membrane potential, reactive oxygen species (ROS) levels using flow cytometry, and the expression of CD133, CD44, SOX-9, and β-Catenin through Quantitative PCR. The activity of superoxide dismutase, glutathione peroxidase, and malondialdehyde was assessed using colorimetric assays. Treatment with therapeutic doses of BHB triggered apoptosis in A549 cells, particularly in cells adapted to glucose deprivation. The elevated ROS levels, combined with reduced levels of SOD and GPx, indicate that oxidative stress contributes to the cell arrest induced by BHB. Notably, BHB treatment under glucose-restricted conditions notably decreased CD133 expression, suggesting a potential inhibition of cell survival through the downregulation of CD133 levels. Additionally, the simultaneous decrease in mitochondrial membrane potential and increase in ROS levels indicate the potential for creating oxidative stress conditions to impede tumor cell growth in such environmental settings.
CONCLUSION: The induced cell death, oxidative stress and mitochondria impairment beside attenuated levels of cancer stem cell markers following BHB administration emphasize on the distinctive role of metabolic plasticity of cancer cells and propose possible therapeutic approaches to control cancer cell growth through metabolic fuels.

Keywords:  A459 cells; Apoptosis; Beta-hydroxybutyrate; Mitochondria membrane potential (ΔΨm); Reactive oxygen species (ROS); Stemness

DOI:  https://doi.org/10.1007/s11033-024-09501-w
J Clin Invest. 2024 Apr 23. pii: e167371. [Epub ahead of print]

Sedentary behavior in mice induces metabolic inflexibility by suppressing skeletal muscle pyruvate metabolism.

Piyarat Siripoksup, Guoshen Cao, Ahmad A Cluntun, J Alan Maschek, Quentinn Pearce, Marisa J Lang, Mi-Young Jeong, Hiroaki Eshima, Patrick J Ferrara, Precious C Opurum, Ziad S Mahmassani, Alek D Peterlin, Shinya Watanabe, Maureen A Walsh, Eric B Taylor, James E Cox, Micah J Drummond, Jared Rutter, Katsuhiko Funai.

  Carbohydrates and lipids provide the majority of substrates to fuel mitochondrial oxidative phosphorylation (OXPHOS). Metabolic inflexibility, defined as an impaired ability to switch between these fuels, is implicated in a number of metabolic diseases. Here we explore the mechanism by which physical inactivity promotes metabolic inflexibility in skeletal muscle. We developed a mouse model of sedentariness, small mouse cage (SMC) that, unlike other classic models of disuse in mice, faithfully recapitulated metabolic responses that occur in humans. Bioenergetic phenotyping of skeletal muscle mitochondria displayed metabolic inflexibility induced by physical inactivity, demonstrated by a reduction in pyruvate-stimulated respiration (JO2) in absence of a change in palmitate-stimulated JO2. Pyruvate resistance in these mitochondria was likely driven by a decrease in phosphatidylethanolamine (PE) abundance in the mitochondrial membrane. Reduction in mitochondrial PE by heterozygous deletion of phosphatidylserine decarboxylase (PSD) was sufficient to induce metabolic inflexibility measured at the whole-body level, as well as at the level of skeletal muscle mitochondria. Low mitochondrial PE in C2C12 myotubes was sufficient to increase glucose flux towards lactate. We further implicate that resistance to pyruvate metabolism is due to attenuated mitochondrial entry via mitochondrial pyruvate carrier (MPC). These findings suggest a mechanism by which mitochondrial PE directly regulates MPC activity to modulate metabolic flexibility in mice.

Keywords:  Metabolism; Mitochondria; Skeletal muscle

DOI:  https://doi.org/10.1172/JCI167371
Leukemia. 2024 Apr 20.

8-Cl-Ado and 8-NH2-Ado synergize with venetoclax to target the methionine-MAT2A-SAM axis in acute myeloid leukemia.

Jiamin Guo, Ralf Buettner, Li Du, Zhenlong Li, Wei Liu, Rui Su, Zhenhua Chen, Yuan Che, Yi Zhang, Rui Ma, Le Xuan Truong Nguyen, Roger E Moore, Pathak Khyatiben, Min-Hsuan Chen, Pirrotte Patrick, Xiwei Wu, Guido Marcucci, Lili Wang, David Horne, Jianjun Chen, Yanzhong Yang, Steven T Rosen.

Targeting the metabolic dependencies of acute myeloid leukemia (AML) cells is a promising therapeutical strategy. In particular, the cysteine and methionine metabolism pathway (C/M) is significantly altered in AML cells compared to healthy blood cells. Moreover, methionine has been identified as one of the dominant amino acid dependencies of AML cells. Through RNA-seq, we found that the two nucleoside analogs 8-chloro-adenosine (8CA) and 8-amino-adenosine (8AA) significantly suppress the C/M pathway in AML cells, and methionine-adenosyltransferase-2A (MAT2A) is one of most significantly downregulated genes. Additionally, mass spectrometry analysis revealed that Venetoclax (VEN), a BCL-2 inhibitor recently approved by the FDA for AML treatment, significantly decreases the intracellular level of methionine in AML cells. Based on these findings, we hypothesized that combining 8CA or 8AA with VEN can efficiently target the Methionine-MAT2A-S-adenosyl-methionine (SAM) axis in AML. Our results demonstrate that VEN and 8CA/8AA synergistically decrease the SAM biosynthesis and effectively target AML cells both in vivo and in vitro. These findings suggest the promising potential of combining 8CA/8AA and VEN for AML treatment by inhibiting Methionine-MAT2A-SAM axis and provide a strong rationale for our recently activated clinical trial.

DOI: https://doi.org/10.1038/s41375-024-02222-w
Biochim Biophys Acta Rev Cancer. 2024 Apr 21. pii: S0304-419X(24)00033-7. [Epub ahead of print]1879(3): 189102

Molecular biology and novel therapeutics for IDH mutant gliomas: The new era of IDH inhibitors.

Yosuke Kitagawa, Ami Kobayashi, Daniel P Cahill, Hiroaki Wakimoto, Shota Tanaka.

  Gliomas with Isocitrate dehydrogenase (IDH) mutation represent a discrete category of primary brain tumors with distinct and unique characteristics, behaviors, and clinical disease outcomes. IDH mutations lead to aberrant high-level production of the oncometabolite D-2-hydroxyglutarate (D-2HG), which act as a competitive inhibitor of enzymes regulating epigenetics, signaling pathways, metabolism, and various other processes. This review summarizes the significance of IDH mutations, resulting upregulation of D-2HG and the associated molecular pathways in gliomagenesis. With the recent finding of clinically effective IDH inhibitors in these gliomas, this article offers a comprehensive overview of the new era of innovative therapeutic approaches based on mechanistic rationales, encompassing both completed and ongoing clinical trials targeting gliomas with IDH mutations.

Keywords:  D2-hydroxyglutarate (D2-HG); Glioma; Isocitrate dehydrogenase (IDH)

DOI:  https://doi.org/10.1016/j.bbcan.2024.189102
Trends Endocrinol Metab. 2024 Apr 24. pii: S1043-2760(24)00093-6. [Epub ahead of print]

Revisiting liver metabolism through acetyl-CoA carboxylase inhibition.

Armando Jesús Pérez-Díaz, María Ángeles Núñez-Sánchez, Bruno Ramos-Molina.

  Liver-targeted acetyl-coenzyme A (CoA) carboxylase (ACC) inhibitors in metabolic dysfunction-associated steatotic liver disease (MASLD) trials reveal notable secondary effects: hypertriglyceridemia and altered glucose metabolism, paradoxically with reduced hepatic steatosis. In their study, Deja et al. explored how hepatic ACC influences metabolism using different pharmacological and genetic methods, coupled with targeted metabolomics and stable isotope-based tracing techniques.

Keywords:  acetyl-CoA carboxylase; autophagy; lipogenesis; liver metabolism; malonyl-CoA

DOI:  https://doi.org/10.1016/j.tem.2024.04.010
J Med Chem. 2024 Apr 23.

Discovery of Novel Dual Inhibitors Targeting Mutant IDH1 and NAMPT for the Treatment of Glioma with IDH1Mutation.

Fei Wen, Gang Gui, Xiaoyu Wang, Anqi Qin, Tianfang Ma, Hui Chen, Chunzheng Li, Xiaoming Zha.

The targeting of cancer cell intrinsic metabolism has emerged as a promising strategy for antitumor intervention. In the study, we identified the first-in-class small molecules that effectively inhibit both mutant isocitrate dehydrogenase 1 (mIDH1) and nicotinamide phosphoribosyltransferase (NAMPT), two crucial targets in cancer metabolism, through structure-based drug design. Notably, compound 23h exhibits excellent and balanced inhibitory activities against both mIDH1 (IC50 = 14.93 nM) and NAMPT (IC50 = 12.56 nM), leading to significant suppression of IDH1-mutated glioma cell (U87 MG-IDH1R132H) proliferation. Significantly, compound 23h has the ability to cross the blood-brain barrier (B/P ratio, 0.76) and demonstrates remarkable in vivo antitumor efficacy (20 mg/kg) in the U87 MG-IDH1R132H orthotopic transplantation mouse models without any notable toxicity. This proof-of-concept investigation substantiates the viability of discovering small molecules that concurrently target mIDH1 and NAMPT, providing valuable leads for the treatment of glioma and an efficient approach for the discovery of multitarget antitumor drugs.

DOI: https://doi.org/10.1021/acs.jmedchem.3c02482
Trends Pharmacol Sci. 2024 Apr 19. pii: S0165-6147(24)00064-6. [Epub ahead of print]

AML treatment: conventional chemotherapy and emerging novel agents.

Mark Forsberg, Marina Konopleva.

  Acute myeloid leukemia (AML) is driven by complex mutations and cytogenetic abnormalities with profound tumoral heterogeneity, making it challenging to treat. Ten years ago, the 5-year survival rate of patients with AML was only 29% with conventional chemotherapy and stem cell transplantation. All attempts to improve conventional therapy over the previous 40 years had failed. Now, new genomic, immunological, and molecular insights have led to a renaissance in AML therapy. Improvements to standard chemotherapy and a wave of new targeted therapies have been developed. However, how best to incorporate these advances into frontline therapy and sequence them in relapse is not firmly established. In this review, we highlight current treatments of AML, targeted agents, and pioneering attempts to synthesize these developments into a rational standard of care (SoC).

Keywords:  acute myeloid leukemia; chemotherapy; precision medicine; targeted combinatorial strategies

DOI:  https://doi.org/10.1016/j.tips.2024.03.005
Gynecol Oncol. 2024 Apr 25. pii: S0090-8258(24)00197-5. [Epub ahead of print]186 126-136

Intermittent energy restriction inhibits tumor growth and enhances paclitaxel response in a transgenic mouse model of endometrial cancer.

Ziyi Zhao, Jiandong Wang, Weimin Kong, Ziwei Fang, Michael F Coleman, Ginger L Milne, Wesley C Burkett, Meredith A Newton, Olivia Lara, Douglas Lee, Boer Deng, Xiaochang Shen, Hongyan Suo, Wenchuan Sun, Stephen D Hursting, Chunxiao Zhou, Victoria L Bae-Jump.

   OBJECTIVE: Overweight/obesity is the strongest risk factor for endometrial cancer (EC), and weight management can reduce that risk and improve survival. We aimed to establish the differential benefits of intermittent energy restriction (IER) and low-fat diet (LFD), alone and in combination with paclitaxel, to reverse the procancer effects of high-fat diet (HFD)-induced obesity in a mouse model of EC.
METHODS: Lkb1fl/flp53fl/fl mice were fed HFD or LFD to generate obese and lean phenotypes, respectively. Obese mice were maintained on a HFD or switched to a LFD (HFD-LFD) or IER (HFD-IER). Ten weeks after induction of endometrial cancer, mice in each group received paclitaxel or placebo for 4 weeks. Body and tumor weights; tumoral transcriptomic, metabolomic and oxylipin profiles; and serum metabolic hormones and chemocytokines were assessed.
RESULTS: HFD-IER and HFD-LFD, relative to HFD, reduced body weight; reversed obesity-induced alterations in serum insulin, leptin and inflammatory factors; and decreased tumor incidence and mass, often to levels emulating those associated with continuous LFD. Concurrent paclitaxel, versus placebo, enhanced tumor suppression in each group, with greatest benefit in HFD-IER. The diets produced distinct tumoral gene expression and metabolic profiles, with HFD-IER associated with a more favorable (antitumor) metabolic and inflammatory environment.
CONCLUSION: In Lkb1fl/flp53fl/fl mice, IER is generally more effective than LFD in promoting weight loss, inhibiting obesity-related endometrial tumor growth (particularly in combination with paclitaxel), and reversing detrimental obesity-related metabolic effects. These findings lay the foundation for further investigations of IER as an EC prevention and treatment strategies in overweight/obesity women.

Keywords:  Gene expression; Intermittent energy restriction (IER); Metabolites; Paclitaxel; Tumor growth

DOI:  https://doi.org/10.1016/j.ygyno.2024.04.012
Am J Physiol Endocrinol Metab. 2024 Apr 24.

Hepatic lipid droplet-associated proteome changes distinguish dietary-induced fatty liver from glucose tolerance in male mice.

Andries Van Woerkom, Dylan J Harney, Shilpa R Nagarajan, Mariam F Hakeem-Sanni, Jinfeng Lin, Matthew Hooke, Tamara Pilpitel, Gregory J Cooney, Mark Larance, Darren N Saunders, Amanda E Brandon, Andrew J Hoy.

  Fatty liver is characterized by the expansion of lipid droplets (LDs) and is associated with the development of many metabolic diseases. We assessed the morphology of hepatic LDs and performed quantitative proteomics in lean, glucose-tolerant mice compared to high-fat diet (HFD) fed mice that displayed hepatic steatosis and glucose intolerance as well as high-starch diet (HStD) fed mice who exhibited similar levels of hepatic steatosis but remained glucose tolerant. Both HFD and HStD-fed mice had more and larger LDs than Chow-fed animals. We observed striking differences in liver LD proteomes of HFD and HStD-fed mice compared to Chow-fed mice, with fewer differences between HFD and HStD. Taking advantage of our diet strategy, we identified a fatty liver LD proteome consisting of proteins common in HFD- and HStD-fed mice, as well as a proteome associated with glucose tolerance that included proteins shared in Chow and HStD but not HFD-fed mice. Notably, glucose intolerance was associated with changes in the ratio of adipose triglyceride lipase to perilipin 5 in the LD proteome, suggesting dysregulation of neutral lipid homeostasis in glucose-intolerant fatty liver. We conclude that our novel dietary approach uncouples ectopic lipid burden from insulin resistance-associated changes in the hepatic lipid droplet proteome.

Keywords:  Lipid droplet; fatty liver; glucose tolerance; mice; proteomics

DOI:  https://doi.org/10.1152/ajpendo.00013.2024
Bioresour Bioprocess. 2022 Aug 26. 9(1): 87

Vitamin combination promotes ex vivo expansion of NK-92 cells by reprogramming glucose metabolism.

Yan Fu, Yuying Chen, Zhepei Xie, Huimin Huang, Wen-Song Tan, Haibo Cai.

  Robust ex vivo expansion of NK-92 cells is essential for clinical immunotherapy. The vitamin B group is critical for the expansion and function of immune cells. This study optimized a vitamin combination by response surface methodology based on an in-house designed chemically defined serum-free medium EM. The serum-free medium EM-V4 with an optimal vitamin combination favoured ex vivo expansion of NK-92 cells. The characteristics of glucose metabolism of NK-92 cells in EM-V4 and the relationships between cell expansion and metabolism were investigated. NK-92 cells in EM-V4 underwent metabolic reprogramming. An elevated ratio of glucose-6-phosphate dehydrogenase/phosphofructokinase (G6PDH/PFK) indicated that NK-92 cells shifted towards the pentose phosphate pathway (PPP). An increase in the ratio of pyruvate dehydrogenase/lactate dehydrogenase (PDH/LDH) suggested that the cells shifted towards the Krebs (TCA) cycle, i.e., from glycolysis to aerobic metabolism. The enhanced ratio of oxygen consumption rate/extracellular acidification rate (OCR/ECAR) indicated that NK-92 cells were more reliant on mitochondrial respiration than on glycolysis. This shift provided more intermediate metabolites and energy for biosynthesis. Thus, EM-V4 accelerated biomass accumulation and energy production to promote NK-92 cell expansion by regulating the metabolic distribution. Our results provide valuable insight for the large-scale ex vivo expansion of clinically available NK-92 cells.

Keywords:  Ex vivo expansion; Glucose metabolism; NK-92 cells; Response surface methodology; Vitamin concentration optimization

DOI:  https://doi.org/10.1186/s40643-022-00578-4
Sci Rep. 2024 Apr 22. 14(1): 9231

Mitochondrial enzyme FAHD1 reduces ROS in osteosarcoma.

Anne Heberle, Elia Cappuccio, Andreas Andric, Tatjana Kuen, Anna Simonini, Alexander K H Weiss.

This study investigated the impact of overexpressing the mitochondrial enzyme Fumarylacetoacetate hydrolase domain-containing protein 1 (FAHD1) in human osteosarcoma epithelial cells (U2OS) in vitro. While the downregulation or knockdown of FAHD1 has been extensively researched in various cell types, this study aimed to pioneer the exploration of how increased catalytic activity of human FAHD1 isoform 1 (hFAHD1.1) affects human cell metabolism. Our hypothesis posited that elevation in FAHD1 activity would lead to depletion of mitochondrial oxaloacetate levels. This depletion could potentially result in a decrease in the flux of the tricarboxylic acid (TCA) cycle, thereby accompanied by reduced ROS production. In addition to hFAHD1.1 overexpression, stable U2OS cell lines were established overexpressing a catalytically enhanced variant (T192S) and a loss-of-function variant (K123A) of hFAHD1. It is noteworthy that homologs of the T192S variant are present in animals exhibiting increased resistance to oxidative stress and cancer. Our findings demonstrate that heightened activity of the mitochondrial enzyme FAHD1 decreases cellular ROS levels in U2OS cells. However, these results also prompt a series of intriguing questions regarding the potential role of FAHD1 in mitochondrial metabolism and cellular development.

DOI: https://doi.org/10.1038/s41598-024-60012-x
Curr Issues Mol Biol. 2024 Mar 29. 46(4): 2946-2960

FLT3 and IRAK4 Inhibitor Emavusertib in Combination with BH3-Mimetics in the Treatment of Acute Myeloid Leukemia.

Katja Seipel, Harpreet Mandhair, Ulrike Bacher, Thomas Pabst.

  Targeting the FLT3 receptor and the IL-1R associated kinase 4 as well as the anti-apoptotic proteins MCL1 and BCL2 may be a promising novel approach in the treatment of acute myeloid leukemia (AML). The FLT3 and IRAK4 inhibitor emavusertib (CA4948), the MCL1 inhibitor S63845, the BCL2 inhibitor venetoclax, and the HSP90 inhibitor PU-H71 were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells in vitro. AML cells represented all major morphologic and molecular subtypes, including FLT3-ITD and NPM1 mutant AML cell lines and a variety of patient-derived AML cells. Emavusertib in combination with MCL1 inhibitor S63845 or BCL2 inhibitor venetoclax induced cell cycle arrest and apoptosis in MOLM-13 cells. In primary AML cells, the response to emavusertib was associated with the presence of the FLT3 gene mutation with an allelic ratio >0.5 and the presence of NPM1 gene mutations. S63845 was effective in all tested AML cell lines and primary AML samples. Blast cell percentage was positively associated with the response to CA4948, S63845, and venetoclax, with elevated susceptibility of primary AML with blast cell fraction >80%. Biomarkers of the response to venetoclax included the blast cell percentage and bone marrow infiltration rate, as well as the expression levels of CD11b, CD64, and CD117. Elevated susceptibility to CA4948 combination treatments with S63845 or PU-H71 was associated with FLT3-mutated AML and CD34 < 30%. The combination of CA4948 and BH3-mimetics may be effective in the treatment in FLT3-mutated AML with differential target specificity for MCL1 and BCL2 inhibitors. Moreover, the combination of CA4948 and PU-H71 may be a candidate combination treatment in FLT3-mutated AML.

Keywords:  B-cell lymphoma 2 (BCL2); BCL2 homology domain 3 (BH3); BCL2 inhibitor venetoclax; HSP90 inhibitor PU-H71; IRAK4 inhibitor emavusetib (CA4948); MCL1 inhibitor S63845; acute myeloid leukemia (AML); cell surface glycoprotein CD34; heat-shock protein 90 (HSP90); interleukin-1 receptor-associated kinase 4 (IRAK4); leukocyte integrin CD11B; myeloid cell leukemia 1 (MCL1); stem cell factor receptor c-KIT (CD117)

DOI:  https://doi.org/10.3390/cimb46040184
J Nutr Biochem. 2024 Apr 18. pii: S0955-2863(24)00082-2. [Epub ahead of print] 109649

Intermittent fasting, exercise and dietary modification induce unique transcriptomic signatures of multiple tissues governing metabolic homeostasis during weight loss and rebound weight gain.

Tianqi Liu, Yuan Liu, Tao Yan, Baobao Zhang, Lanqi Zhou, Wanyu Zhu, Guoze Wang, Jie Kang, Wen Peng, Lin Shi.

  Obesity and its related metabolic diseases bring great challenges to public health. In-depth understanding on the efficacy of weight-loss interventions is critical for long-term weight control. Our study demonstrated the comparable efficacy of exercise (EX), intermittent fasting (IF), or the change of daily diet from an unhealthy to a normal chow (DR) for weight reduction, but largely divergently affected metabolic status and transcriptome of subcutaneous fat, scapular brown fat, skeletal muscles and liver in high-fat-high-fructose diet (HFHF) induced obese mice. EX and IF reduced systematic inflammation, improved glucose and lipid metabolism in liver and muscle, and amino acid metabolism and thermogenesis in adipose tissues. EX exhibited broad regulatory effects on TCA cycle, carbon metabolism, thermogenesis, propanoate-, fatty acid and amino acid metabolism across multiple tissues. IF prominently affected genes involved in mitophagy and autophagy in adipose tissues and core genes involved in butanoate metabolism in liver. DR however failed to improve metabolic homeostasis and biological dysfunctions in obese mice. Notably, by exploring potential inter-organ communication, we identified an obesity-resistant-like gene profile that were strongly correlated with HFHF induced metabolic derangements and could predict the degree of weight regain induced by the follow-up HFHF diet. Among them, 12 genes (e.g., Gdf15, Tfrc, Cdv3, Map2k4 and Nqo1) were causally associated with human metabolic traits, i.e., BMI, body fat mass, HbA1C, fasting glucose and cholesterol. Our findings provide critical groundwork for improved understanding the impacts of weight-loss interventions on host metabolism. The identified genes predicting weight regain may be considered regulatory targets for improving the long-term weight control.

Keywords:  Obesity; multi-tissue transcriptome; obesity-resistant-like gene profile; weight loss; weight regain

DOI:  https://doi.org/10.1016/j.jnutbio.2024.109649
Pharmaceutics. 2024 Mar 22. pii: 442. [Epub ahead of print]16(4):

Glucose Metabolism as a Potential Therapeutic Target in Cytarabine-Resistant Acute Myeloid Leukemia.

Joana Pereira-Vieira, Daniela D Weber, Sâmia Silva, Catarina Barbosa-Matos, Sara Granja, Rui Manuel Reis, Odília Queirós, Young H Ko, Barbara Kofler, Margarida Casal, Fátima Baltazar.

  Altered glycolytic metabolism has been associated with chemoresistance in acute myeloid leukemia (AML). However, there are still aspects that need clarification, as well as how to explore these metabolic alterations in therapy. In the present study, we aimed to elucidate the role of glucose metabolism in the acquired resistance of AML cells to cytarabine (Ara-C) and to explore it as a therapeutic target. Resistance was induced by stepwise exposure of AML cells to increasing concentrations of Ara-C. Ara-C-resistant cells were characterized for their growth capacity, genetic alterations, metabolic profile, and sensitivity to different metabolic inhibitors. Ara-C-resistant AML cell lines, KG-1 Ara-R, and MOLM13 Ara-R presented different metabolic profiles. KG-1 Ara-R cells exhibited a more pronounced glycolytic phenotype than parental cells, with a weaker acute response to 3-bromopyruvate (3-BP) but higher sensitivity after 48 h. KG-1 Ara-R cells also display increased respiration rates and are more sensitive to phenformin than parental cells. On the other hand, MOLM13 Ara-R cells display a glucose metabolism profile similar to parental cells, as well as sensitivity to glycolytic inhibitors. These results indicate that acquired resistance to Ara-C in AML may involve metabolic adaptations, which can be explored therapeutically in the AML patient setting who developed resistance to therapy.

Keywords:  3-bromopyruvate; acute myeloid leukemia; chemoresistance; cytarabine; glucose metabolism; metabolic inhibitors; phenformin; seahorse

DOI:  https://doi.org/10.3390/pharmaceutics16040442
Antioxidants (Basel). 2024 Apr 17. pii: 470. [Epub ahead of print]13(4):

Tricarboxylic Acid Cycle Regulation of Metabolic Program, Redox System, and Epigenetic Remodeling for Bone Health and Disease.

Wei-Shiung Lian, Re-Wen Wu, Yu-Han Lin, Yu-Shan Chen, Holger Jahr, Feng-Sheng Wang.

  Imbalanced osteogenic cell-mediated bone gain and osteoclastic remodeling accelerates the development of osteoporosis, which is the leading risk factor of disability in the elderly. Harmonizing the metabolic actions of bone-making cells and bone resorbing cells to the mineralized matrix network is required to maintain bone mass homeostasis. The tricarboxylic acid (TCA) cycle in mitochondria is a crucial process for cellular energy production and redox homeostasis. The canonical actions of TCA cycle enzymes and intermediates are indispensable in oxidative phosphorylation and adenosine triphosphate (ATP) biosynthesis for osteogenic differentiation and osteoclast formation. Knockout mouse models identify these enzymes' roles in bone mass and microarchitecture. In the noncanonical processes, the metabolites as a co-factor or a substrate involve epigenetic modification, including histone acetyltransferases, DNA demethylases, RNA m6A demethylases, and histone demethylases, which affect genomic stability or chromatin accessibility for cell metabolism and bone formation and resorption. The genetic manipulation of these epigenetic regulators or TCA cycle intermediate supplementation compromises age, estrogen deficiency, or inflammation-induced bone mass loss and microstructure deterioration. This review sheds light on the metabolic functions of the TCA cycle in terms of bone integrity and highlights the crosstalk of the TCA cycle and redox and epigenetic pathways in skeletal tissue metabolism and the intermediates as treatment options for delaying osteoporosis.

Keywords:  DNA demethylases; RNA m6A demethylases; TCA cycle; bone homeostasis; histone demethylases; osteoporosis; redox; α-ketoglutarate

DOI:  https://doi.org/10.3390/antiox13040470
Cancers (Basel). 2024 Apr 16. pii: 1513. [Epub ahead of print]16(8):

Time-Restricted Feeding Attenuates Metabolic Dysfunction-Associated Steatohepatitis and Hepatocellular Carcinoma in Obese Male Mice.

Manasi Das, Deepak Kumar, Consuelo Sauceda, Alexis Oberg, Lesley G Ellies, Liping Zeng, Lily J Jih, Isabel G Newton, Nicholas J G Webster.

  Metabolic dysfunction-associated steatotic liver disease (MASLD) has surpassed the hepatitis B virus and hepatitis C virus as the leading cause of chronic liver disease in most parts of the Western world. MASLD (formerly known as NAFLD) encompasses both simple steatosis and more aggressive metabolic dysfunction-associated steatohepatitis (MASH), which is accompanied by inflammation, fibrosis, and cirrhosis, and ultimately can lead to hepatocellular carcinoma (HCC). There are currently very few approved therapies for MASH. Weight loss strategies such as caloric restriction can ameliorate the harmful metabolic effect of MASH and inhibit HCC; however, it is difficult to implement and maintain in daily life, especially in individuals diagnosed with HCC. In this study, we tested a time-restricted feeding (TRF) nutritional intervention in mouse models of MASH and HCC. We show that TRF abrogated metabolic dysregulation induced by a Western diet without any calorie restriction or weight loss. TRF improved insulin sensitivity and reduced hyperinsulinemia, liver steatosis, inflammation, and fibrosis. Importantly, TRF inhibited liver tumors in two mouse models of obesity-driven HCC. Our data suggest that TRF is likely to be effective in abrogating MASH and HCC and warrant further studies of time-restricted eating in humans with MASH who are at higher risk of developing HCC.

Keywords:  dietary intervention; hepatocellular cancer; metabolic dysfunction-associated steatohepatitis; mouse model; non-alcoholic fatty liver disease; time-restricted feeding

DOI:  https://doi.org/10.3390/cancers16081513
Discov Med. 2024 Apr;36(183): 678-689

Changes and Significance of Central Carbon Metabolism before and after Metformin Treatment of Type 2 Diabetes Based on Mass Spectrometry.

Yang Shu, Fujie Yang, Weidong Li, Lisha Li, Qiongying Hu, Daqian Xiong.

   BACKGROUND: An imbalance in energy metabolism serves as a causal factor for type 2 diabetes (T2D). Although metformin has been known to ameliorate the overall energy metabolism imbalance, but the direct correlation between metformin and central carbon metabolism (CCM) has not been thoroughly investigated. In this study, we employed a high-performance ion chromatography-tandem mass spectrometry (HPIC-MS/MS) technique to examine the alterations and significance of CCM both before and after metformin treatment for T2D.
METHODS: We recruited 29 participants, comprising 10 individuals recently diagnosed with T2D (T2D group). Among these, 10 patients underwent a 4-6-week treatment with metformin (MET group). Additionally, we included 9 healthy subjects (CON group). Employing HPIC-MS/MS, we quantitatively analyzed 56 metabolites across 18 biologically relevant metabolic pathways associated with CCM. Univariate and multivariate statistical analyses were utilized to identify differential metabolites. Subsequently, correlation analyses and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted on the identified differential metabolites.
RESULTS: We identified seven distinct metabolites in individuals with T2D (p < 0.05). Notably, cyclic 3',5'-Adenosine MonoPhosphate (AMP), Glucose 6-phosphate, L-lactic acid, Maleic acid, and Malic acid exhibited a reversal to normal levels following metformin treatment. Furthermore, Malic acid demonstrated a positive correlation with L-lactic acid (r = 0.94, p < 0.05), as did succinic acid with malic acid (r = 0.81, p < 0.05), L-lactic acid with succinic acid (r = 0.78, p < 0.05), and L-lactic acid with glucose-6-phosphate (r = 0.72, p < 0.05). These metabolites were notably enriched in pyruvate metabolism (p = 0.005), tricarboxylic acid cycle (TCA) (p = 0.007), propanoate metabolism (p = 0.007), and glycolysis or gluconeogenesis (p = 0.009), respectively.
CONCLUSIONS: We employed HPIC-MS/MS to uncover alterations in CCM among individuals recently diagnosed with T2D before and after metformin treatment. The findings suggest that metformin may ameliorate the energy metabolism imbalance in T2D by reducing intermediates within the CCM pathway.

Keywords:  HPIC-MS/MS; central carbon metabolism; metabolites; type 2 diabetes: metformin

DOI:  https://doi.org/10.24976/Discov.Med.202436183.64
Anal Chem. 2024 Apr 20.

SCALiR: A Web Application for Automating Absolute Quantification of Mass Spectrometry-Based Metabolomics Data.

Luis F Ponce, Stephanie L Bishop, Soren Wacker, Ryan A Groves, Ian A Lewis.

Quantitative liquid chromatography-mass spectrometry (LC-MS)-based metabolomics is becoming an important approach for studying complex biological systems but presents several technical challenges that limit its widespread use. Computing metabolite concentrations using standard curves generated from standard mixtures of known concentrations is a labor-intensive process that is often performed manually. Currently, there are few options for open-source software tools that can automatically calculate metabolite concentrations. Herein, we introduce SCALiR (standard curve application for determining linear ranges), a new web-based software tool specifically built for this task, which allows users to automatically transform LC-MS signals into absolute quantitative data (https://www.lewisresearchgroup.org/software). SCALiR uses an algorithm that automatically finds the equation of the line of best fit for each standard curve and uses this equation to calculate compound concentrations from the LC-MS signal. Using a standard mix containing 77 metabolites, we show a close correlation between the concentrations calculated by SCALiR and the expected concentrations of each compound (R2 = 0.99 for a y = x curve fitting). Moreover, we demonstrate that SCALiR reproducibly calculates concentrations of midrange standards across ten analytical batches (average coefficient of variation 0.091). SCALiR can be used to calculate metabolite concentrations either using external calibration curves or by using internal standards to correct for matrix effects. This open-source and vendor agnostic software offers users several advantages in that (1) it requires only 10 s of analysis time to compute concentrations of >75 compounds, (2) it facilitates automation of quantitative workflows, and (3) it performs deterministic evaluations of compound quantification limits. SCALiR therefore provides the metabolomics community with a simple and rapid tool that enables rigorous and reproducible quantitative metabolomics studies.

DOI: https://doi.org/10.1021/acs.analchem.3c04988
Trends Mol Med. 2024 Apr 23. pii: S1471-4914(24)00091-1. [Epub ahead of print]

Educate, not kill: treating cancer without triggering its defenses.

Aneta Škarková, Mariano Bizzarri, Radoslav Janoštiak, Jan Mašek, Daniel Rosel, Jan Brábek.

  Traditionally, anticancer therapies focus on restraining uncontrolled proliferation. However, these cytotoxic therapies expose cancer cells to direct killing, instigating the process of natural selection favoring survival of resistant cells that become the foundation for tumor progression and therapy failure. Recognizing this phenomenon has prompted the development of alternative therapeutic strategies. Here we propose strategies targeting cancer hallmarks beyond proliferation, aiming at re-educating cancer cells towards a less malignant phenotype. These strategies include controlling cell dormancy, transdifferentiation therapy, normalizing the cancer microenvironment, and using migrastatic therapy. Adaptive resistance to these educative strategies does not confer a direct proliferative advantage to resistant cells, as non-resistant cells are not subject to eradication, thereby delaying or preventing the development of therapy-resistant tumors.

Keywords:  dormancy; metastasis; migrastatics; resistance; transdifferentiation; tumor reversion

DOI:  https://doi.org/10.1016/j.molmed.2024.04.003
Clin Cancer Res. 2024 Apr 23.

FLT3 agonists and secondary hematopoietic malignancies: a potential class effect.

Henry W Raeder, Michael W Drazer.

Expansion of cDC cells via FLT3 agonism has promising therapeutic potential in the treatment of advanced solid tumors. Here, we discuss the results of a clinical trial using GS-3583, an FLT3 agonist, that was stopped after a patient in the study developed acute myeloid leukemia.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-0460
Life Sci Alliance. 2024 Jul;pii: e202302398. [Epub ahead of print]7(7):

Combining sophisticated fast FLIM, confocal microscopy, and STED nanoscopy for live-cell imaging of tunneling nanotubes.

Magalie Bénard, Christophe Chamot, Damien Schapman, Aurélien Debonne, Alexis Lebon, Fatéméh Dubois, Guénaëlle Levallet, Hitoshi Komuro, Ludovic Galas.

Cell-to-cell communication via tunneling nanotubes (TNTs) is a challenging topic with a growing interest. In this work, we proposed several innovative tools that use red/near-infrared dye labeling and employ lifetime-based imaging strategies to investigate the dynamics of TNTs in a living mesothelial H28 cell line that exhibits spontaneously TNT1 and TNT2 subtypes. Thanks to a fluorescence lifetime imaging microscopy module being integrated into confocal microscopy and stimulated emission depletion nanoscopy, we applied lifetime imaging, lifetime dye unmixing, and lifetime denoising techniques to perform multiplexing experiments and time-lapses of tens of minutes, revealing therefore structural and functional characteristics of living TNTs that were preserved from light exposure. In these conditions, vesicle-like structures, and tubular- and round-shaped mitochondria were identified within living TNT1. In addition, mitochondrial dynamic studies revealed linear and stepwise mitochondrial migrations, bidirectional movements, transient backtracking, and fission events in TNT1. Transfer of Nile Red-positive puncta via both TNT1 and TNT2 was also detected between living H28 cells.

DOI: https://doi.org/10.26508/lsa.202302398
Pediatr Hematol Oncol. 2024 Apr 22. 1-9

Therapeutic efficacy of RAS inhibitor trametinib using a juvenile myelomonocytic leukemia patient-derived xenograft model.

Alex Q Lee, Hiroaki Konishi, Masami Ijiri, Yueju Li, Arun Panigrahi, Jeremy Chien, Noriko Satake.

  Juvenile myelomonocytic leukemia (JMML) is an aggressive pediatric leukemia with few effective treatments and poor outcomes even after stem cell transplantation, the only current curative treatment. We developed a JMML patient-derived xenograft (PDX) mouse model and demonstrated the in vivo therapeutic efficacy and confirmed the target of trametinib, a RAS-RAF-MEK-ERK pathway inhibitor, in this model. A PDX model was created through transplantation of patient JMML cells into mice, up to the second generation, and successful engraftment was confirmed using flow cytometry. JMML PDX mice were treated with trametinib versus vehicle control, with a median survival of 194 days in the treatment group versus 124 days in the control group (p = 0.02). Trametinib's target as a RAS pathway inhibitor was verified by showing inhibition of ERK phosphorylation using immunoblot assays. In conclusion, trametinib monotherapy significantly prolongs survival in our JMML PDX model by inhibiting the RAS pathway. Our model can be effectively used for assessment of novel targeted treatments, including potential combination therapies, to improve JMML outcomes.

Keywords:  Juvenile myelomonocytic leukemia; RAS inhibitor; patient-derived xenograft; targeted therapy; trametinib

DOI:  https://doi.org/10.1080/08880018.2024.2343688
Sci Rep. 2024 04 20. 14(1): 9104

SMS121, a new inhibitor of CD36, impairs fatty acid uptake and viability of acute myeloid leukemia.

Hannah Åbacka, Samuele Masoni, Giulio Poli, Peng Huang, Francesco Gusso, Carlotta Granchi, Filippo Minutolo, Tiziano Tuccinardi, Anna K Hagström-Andersson, Karin Lindkvist-Petersson.

  Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults and the second most common among children. AML is characterized by aberrant proliferation of myeloid blasts in the bone marrow and impaired normal hematopoiesis. Despite the introduction of new drugs and allogeneic bone marrow transplantation, patients have poor overall survival rate with relapse as the major challenge, driving the demand for new therapeutic strategies. AML patients with high expression of the very long/long chain fatty acid transporter CD36 have poorer survival and very long chain fatty acid metabolism is critical for AML cell survival. Here we show that fatty acids are transferred from human primary adipocytes to AML cells upon co-culturing. A drug-like small molecule (SMS121) was identified by receptor-based virtual screening and experimentally demonstrated to target the lipid uptake protein CD36. SMS121 reduced the uptake of fatty acid into AML cells that could be reversed by addition of free fatty acids and caused decreased cell viability. The data presented here serves as a framework for the development of CD36 inhibitors to be used as future therapeutics against AML.

Keywords:  AML; Acute myeloid leukemia; Adipocyte; CD36; Fatty acid

DOI:  https://doi.org/10.1038/s41598-024-58689-1
J Surg Oncol. 2024 Apr 22.

The associations of food environment with gastrointestinal cancer outcomes in the United States.

David J Fei-Zhang, Samuel J Schellenberg, David J Bentrem, Jeffrey D Wayne, Timothy M Pawlik.

   BACKGROUND: Social conditions and dietary behaviors have been implicated in the rising burden of gastrointestinal cancers (GIC). The "food environment" reflects influences on a community level relative to food availability, nutritional assistance, and social determinants of health. Using the US Department of Agriculture-Food Environment Atlas (FEA), we sought to characterize the association of food environment on GIC presenting stage and long-term survival.
METHODS: Patients diagnosed with GIC between 2013 and 2017 were identified using the SEER database. FEA-scores were based on 282 county-level food security variables, store-restaurant availability, SNAP/WIC enrollment, pricing/taxes, and producer vicinity adjusted-for factors of socioeconomic status, race-ethnicity, transportation access, and comorbidities. Relative FEA rankings across US counties were averaged into a composite score and assigned to patients by county-of-residence. The association of FEA, cancer stage, and survival were analyzed using multiple logistic regression and cox-proportional hazard models relative to White/non-White race/ethnicity.
RESULTS: Among 287,148 patients, the most common GIC-sites were colon (n = 97,942, 34%), pancreas (n = 49,785, 17.3%), liver (n = 31,098, 11.0%) and esophagus (n = 16,271, 5.7%). A worse food environment was independently associated with increased odds of late-stage diagnosis (esophageal odds ratio [OR]: 1.03, 95% confidence interval [CI]: 1.01-1.05; hepatic OR: 1.06, 95% CI: 1.03-1.08; pancreatic OR: 1.04, 95% CI: 1.01-1.06) among all patients; in contrast, food environment was associated with colorectal cancer stage among non-White patients only (OR: 1.04, 95% CI: 1.03-1.06). Worse food environment was associated with worse 3-year survival (colon OR: 1.03, 95% CI: 1.01-1.04; hepatic OR: 1.12, 95% CI: 1.08-1.17; gastric OR: 1.07, 95% CI: 1.01-1.13). Similar associations were noted relative to overall survival among the entire cohort (biliary tract hazard ratio [HR]: 1.03, 95% CI: 1.01-1.05; esophageal HR: 1.02, 95% CI: 1.01-1.04; hepatic HR: 1.07, 95% CI: 1.06-1.09; pancreatic HR: 1.04, 95% CI: 1.02-1.05; rectum HR: 1.03, 95% CI: 1.01-1.04; gastric HR: 1.05, 95% CI: 1.03-1.07), as well as among non-White patients (biliary HR: 1.04, 95% CI: 1.01-1.07; colon HR: 1.03, 95% CI: 1.01-1.05; esophageal HR: 1.05, 95% CI: 1.02-1.08; hepatic HR: 1.08, 95% CI: 1.06-1.10) (all p < 0.003).
CONCLUSIONS: Food environment was independently associated with late-stage tumor presentation and worse 3-year and overall survival among GIC patients. Interventions to address inequities across communities relative to food environments are needed to alleviate disparities in cancer care.

Keywords:  food environment; gastrointestinal cancer; social determinants of health; social vulnerability

DOI:  https://doi.org/10.1002/jso.27656
bioRxiv. 2024 Apr 08. pii: 2024.04.08.588639. [Epub ahead of print]

Muscle weakness and mitochondrial stress occur before metastasis in a novel mouse model of ovarian cancer cachexia.

Luca J Delfinis, Leslie M Ogilvie, Shahrzad Khajehzadehshoushtar, Shivam Gandhi, Madison C Garibotti, Arshdeep K Thuhan, Kathy Matuszewska, Madison Pereira, Ronald G Jones, Arthur J Cheng, Thomas J Hawke, Nicholas P Greene, Kevin A Murach, Jeremy A Simpson, Jim Petrik, Christopher G R Perry.

   Objectives: A high proportion of women with advanced epithelial ovarian cancer (EOC) experience weakness and cachexia. This relationship is associated with increased morbidity and mortality. EOC is the most lethal gynecological cancer, yet no preclinical cachexia model has demonstrated the combined hallmark features of metastasis, ascites development, muscle loss and weakness in adult immunocompetent mice.
Methods: Here, we evaluated a new model of ovarian cancer-induced cachexia with the advantages of inducing cancer in adult immunocompetent C57BL/6J mice through orthotopic injections of EOC cells in the ovarian bursa. We characterized the development of metastasis, ascites, muscle atrophy, muscle weakness, markers of inflammation, and mitochondrial stress in the tibialis anterior (TA) and diaphragm ~45, ~75 and ~90 days after EOC injection.
Results: Primary ovarian tumour sizes were progressively larger at each time point while robust metastasis, ascites development, and reductions in body, fat and muscle weights occurred by 90 Days. There were no changes in certain inflammatory (TNFα), atrogene (MURF1 and Atrogin) or GDF15 markers within both muscles whereas IL-6 was increased at 45 and 90 Day groups in the diaphragm. TA weakness in 45 Day preceded atrophy and metastasis that were observed later (75 and 90 Day, respectively). The diaphragm demonstrated both weakness and atrophy in 45 Day. In both muscles, this pre-metastatic muscle weakness corresponded with considerable reprogramming of gene pathways related to mitochondrial bioenergetics as well as reduced functional measures of mitochondrial pyruvate oxidation and creatine-dependent ADP/ATP cycling as well as increased reactive oxygen species emission (hydrogen peroxide). Remarkably, muscle force per unit mass at 90 days was partially restored in the TA despite the presence of atrophy and metastasis. In contrast, the diaphragm demonstrated progressive weakness. At this advanced stage, mitochondrial pyruvate oxidation in both muscles exceeded control mice suggesting an apparent metabolic super-compensation corresponding with restored indices of creatine-dependent adenylate cycling.
Conclusion: This mouse model demonstrates the concurrent development of cachexia and metastasis that occurs in women with EOC. The model provides physiologically relevant advantages of inducing tumour development within the ovarian bursa in immunocompetent adult mice. Moreover, the model reveals that muscle weakness in both TA and diaphragm precedes metastasis while weakness also precedes atrophy in the TA. An underlying mitochondrial bioenergetic stress corresponded with this early weakness. Collectively, these discoveries can direct new research towards the development of therapies that target pre-atrophy and pre-metastatic weakness during EOC in addition to therapies targeting cachexia.

Keywords:  Ovarian cancer cachexia; metastasis; mitochondria; skeletal muscle

DOI:  https://doi.org/10.1101/2024.04.08.588639
EMBO J. 2024 Apr 22.

SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression.

Weiwei Yan, Chengmei Xie, Sijun Sun, Quan Zheng, Jingyi Wang, Zihao Wang, Cheuk-Him Man, Haiyan Wang, Yunfan Yang, Tianshi Wang, Leilei Shi, Shengjie Zhang, Chen Huang, Shuangnian Xu, Yi-Ping Wang.

  Mitochondria are cellular powerhouses that generate energy through the electron transport chain (ETC). The mitochondrial genome (mtDNA) encodes essential ETC proteins in a compartmentalized manner, however, the mechanism underlying metabolic regulation of mtDNA function remains unknown. Here, we report that expression of tricarboxylic acid cycle enzyme succinate-CoA ligase SUCLG1 strongly correlates with ETC genes across various TCGA cancer transcriptomes. Mechanistically, SUCLG1 restricts succinyl-CoA levels to suppress the succinylation of mitochondrial RNA polymerase (POLRMT). Lysine 622 succinylation disrupts the interaction of POLRMT with mtDNA and mitochondrial transcription factors. SUCLG1-mediated POLRMT hyposuccinylation maintains mtDNA transcription, mitochondrial biogenesis, and leukemia cell proliferation. Specifically, leukemia-promoting FMS-like tyrosine kinase 3 (FLT3) mutations modulate nuclear transcription and upregulate SUCLG1 expression to reduce succinyl-CoA and POLRMT succinylation, resulting in enhanced mitobiogenesis. In line, genetic depletion of POLRMT or SUCLG1 significantly delays disease progression in mouse and humanized leukemia models. Importantly, succinyl-CoA level and POLRMT succinylation are downregulated in FLT3-mutated clinical leukemia samples, linking enhanced mitobiogenesis to cancer progression. Together, SUCLG1 connects succinyl-CoA with POLRMT succinylation to modulate mitochondrial function and cancer development.

Keywords:  FMS-like Tyrosine Kinase 3; Lysine Succinylation; Mitochondrial Biogenesis; Mitochondrial RNA Polymerase; Succinate-CoA Ligase

DOI:  https://doi.org/10.1038/s44318-024-00101-9
Metabolites. 2024 Mar 25. pii: 184. [Epub ahead of print]14(4):

Selected Ion Monitoring for Orbitrap-Based Metabolomics.

Wenyun Lu, Matthew J McBride, Won Dong Lee, Xi Xing, Xincheng Xu, Xi Li, Anna M Oschmann, Yihui Shen, Caroline Bartman, Joshua D Rabinowitz.

  Orbitrap mass spectrometry in full scan mode enables the simultaneous detection of hundreds of metabolites and their isotope-labeled forms. Yet, sensitivity remains limiting for many metabolites, including low-concentration species, poor ionizers, and low-fractional-abundance isotope-labeled forms in isotope-tracing studies. Here, we explore selected ion monitoring (SIM) as a means of sensitivity enhancement. The analytes of interest are enriched in the orbitrap analyzer by using the quadrupole as a mass filter to select particular ions. In tissue extracts, SIM significantly enhances the detection of ions of low intensity, as indicated by improved signal-to-noise (S/N) ratios and measurement precision. In addition, SIM improves the accuracy of isotope-ratio measurements. SIM, however, must be deployed with care, as excessive accumulation in the orbitrap of similar m/z ions can lead, via space-charge effects, to decreased performance (signal loss, mass shift, and ion coalescence). Ion accumulation can be controlled by adjusting settings including injection time and target ion quantity. Overall, we suggest using a full scan to ensure broad metabolic coverage, in tandem with SIM, for the accurate quantitation of targeted low-intensity ions, and provide methods deploying this approach to enhance metabolome coverage.

Keywords:  SIM; fluxomics; full scan; isotope labeling; isotope tracing; metabolomics; orbitrap; relative standard deviation; selected ion monitoring; signal-to-noise ratio

DOI:  https://doi.org/10.3390/metabo14040184
Cells. 2024 Apr 09. pii: 663. [Epub ahead of print]13(8):

Metabolic Alteration Bridging the Prediabetic State and Colorectal Cancer.

Antonino Colloca, Isabella Donisi, Camilla Anastasio, Maria Luisa Balestrieri, Nunzia D'Onofrio.

  Prediabetes and colorectal cancer (CRC) represent compelling health burdens responsible for high mortality and morbidity rates, sharing several modifiable risk factors. It has been hypothesized that metabolic abnormalities linking prediabetes and CRC are hyperglycemia, hyperinsulinemia, and adipokines imbalance. The chronic stimulation related to these metabolic signatures can favor CRC onset and development, as well as negatively influence CRC prognosis. To date, the growing burden of prediabetes and CRC has generated a global interest in defining their epidemiological and molecular relationships. Therefore, a deeper knowledge of the metabolic impairment determinants is compelling to identify the pathological mechanisms promoting the onset of prediabetes and CRC. In this scenario, this review aims to provide a comprehensive overview on the metabolic alterations of prediabetes and CRC as well as an overview of recent preventive and therapeutic approaches for both diseases, focusing on the role of the metabolic state as a pivotal contributor to consider for the development of future preventive and therapeutic strategies.

Keywords:  chronic inflammation; colorectal cancer; hormone dysregulation; metabolic alteration; microbiota; nutrition; obesity; pharmacotherapy; physical activity; prediabetes

DOI:  https://doi.org/10.3390/cells13080663