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1
Gonzalez, Claudio D., Silvia Alvarez, Alejandro Ropolo, Carla Rosenzvit, Maria F. Gonzalez Bagnes, and Maria I. Vaccaro. "Autophagy, Warburg, and Warburg Reverse Effects in Human Cancer." BioMed Research International 2014 (2014): 1–10. http://dx.doi.org/10.1155/2014/926729.
Повний текст джерелаАнотація:
Autophagy is a highly regulated-cell pathway for degrading long-lived proteins as well as for clearing cytoplasmic organelles. Autophagy is a key contributor to cellular homeostasis and metabolism. Warburg hypothesized that cancer growth is frequently associated with a deviation of a set of energy generation mechanisms to a nonoxidative breakdown of glucose. This cellular phenomenon seems to rely on a respiratory impairment, linked to mitochondrial dysfunction. This mitochondrial dysfunction results in a switch to anaerobic glycolysis. It has been recently suggested that epithelial cancer cells may induce the Warburg effect in neighboring stromal fibroblasts in which autophagy was activated. These series of observations drove to the proposal of a putative reverse Warburg effect of pathophysiological relevance for, at least, some tumor phenotypes. In this review we introduce the autophagy process and its regulation and its selective pathways and role in cancer cell metabolism. We define and describe the Warburg effect and the newly suggested “reverse” hypothesis. We also discuss the potential value of modulating autophagy with several pharmacological agents able to modify the Warburg effect. The association of the Warburg effect in cancer and stromal cells to tumor-related autophagy may be of relevance for further development of experimental therapeutics as well as for cancer prevention.
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Pokorný, Jiří, Jan Pokorný, Jitka Kobilková, Anna Jandová, Jan Vrba, and Jan Vrba. "Targeting Mitochondria for Cancer Treatment – Two Types of Mitochondrial Dysfunction." Prague Medical Report 115, no. 3-4 (2014): 104–19. http://dx.doi.org/10.14712/23362936.2014.41.
Повний текст джерелаАнотація:
Two basic types of cancers were identified – those with the mitochondrial dysfunction in cancer cells (the Warburg effect) or in fibroblasts supplying energy rich metabolites to a cancer cell with functional mitochondria (the reverse Warburg effect). Inner membrane potential of the functional and dysfunctional mitochondria measured by fluorescent dyes (e.g. by Rhodamine 123) displays low and high values (apparent potential), respectively, which is in contrast to the level of oxidative metabolism. Mitochondrial dysfunction (full function) results in reduced (high) oxidative metabolism, low (high) real membrane potential, a simple layer (two layers) of transported protons around mitochondria, and high (low) damping of microtubule electric polar vibrations. Crucial modifications are caused by ordered water layer (exclusion zone). For the high oxidative metabolism one proton layer is at the mitochondrial membrane and the other at the outer rim of the ordered water layer. High and low damping of electric polar vibrations results in decreased and increased electromagnetic activity in cancer cells with the normal and the reverse Warburg effect, respectively. Due to nonlinear properties the electromagnetic frequency spectra of cancer cells and transformed fibroblasts are shifted in directions corresponding to their power deviations resulting in disturbances of interactions and escape from tissue control. The cancer cells and fibroblasts of the reverse Warburg effect tumors display frequency shifts in mutually opposite directions resulting in early generalization. High oxidative metabolism conditions high aggressiveness. Mitochondrial dysfunction, a gate to malignancy along the cancer transformation pathway, forms a narrow neck which could be convenient for cancer treatment.
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Keller, Florian, Roman Bruch, Richard Schneider, Julia Meier-Hubberten, Mathias Hafner, and Rüdiger Rudolf. "A Scaffold-Free 3-D Co-Culture Mimics the Major Features of the Reverse Warburg Effect In Vitro." Cells 9, no. 8 (August 13, 2020): 1900. http://dx.doi.org/10.3390/cells9081900.
Повний текст джерелаАнотація:
Most tumors consume large amounts of glucose. Concepts to explain the mechanisms that mediate the achievement of this metabolic need have proposed a switch of the tumor mass to aerobic glycolysis. Depending on whether primarily tumor or stroma cells undergo such a commutation, the terms ‘Warburg effect’ or ‘reverse Warburg effect’ were coined to describe the underlying biological phenomena. However, current in vitro systems relying on 2-D culture, single cell-type spheroids, or basal-membrane extract (BME/Matrigel)-containing 3-D structures do not thoroughly reflect these processes. Here, we aimed to establish a BME/Matrigel-free 3-D microarray cancer model to recapitulate the metabolic interplay between cancer and stromal cells that allows mechanistic analyses and drug testing. Human HT-29 colon cancer and CCD-1137Sk fibroblast cells were used in mono- and co-cultures as 2-D monolayers, spheroids, and in a cell-chip format. Metabolic patterns were studied with immunofluorescence and confocal microscopy. In chip-based co-cultures, HT-29 cells showed facilitated 3-D growth and increased levels of hexokinase-2, TP53-induced glycolysis and apoptosis regulator (TIGAR), lactate dehydrogenase, and: translocase of outer mitochondrial membrane 20 (TOMM20), when compared with HT-29 mono-cultures. Fibroblasts co-cultured with HT-29 cells expressed higher levels of mono-carboxylate transporter 4, hexokinase-2, microtubule-associated proteins 1A/1B light chain 3, and ubiquitin-binding protein p62 than in fibroblast mono-cultures, in both 2-D cultures and chips. Tetramethylrhodamin-methylester (TMRM) live-cell imaging of chip co-cultures revealed a higher mitochondrial potential in cancer cells than in fibroblasts. The findings demonstrate a crosstalk between cancer cells and fibroblasts that affects cellular growth and metabolism. Chip-based 3-D co-cultures of cancer cells and fibroblasts mimicked features of the reverse Warburg effect.
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Schiliro, Chelsea, and Bonnie L. Firestein. "Mechanisms of Metabolic Reprogramming in Cancer Cells Supporting Enhanced Growth and Proliferation." Cells 10, no. 5 (April 29, 2021): 1056. http://dx.doi.org/10.3390/cells10051056.
Повний текст джерелаАнотація:
Cancer cells alter metabolic processes to sustain their characteristic uncontrolled growth and proliferation. These metabolic alterations include (1) a shift from oxidative phosphorylation to aerobic glycolysis to support the increased need for ATP, (2) increased glutaminolysis for NADPH regeneration, (3) altered flux through the pentose phosphate pathway and the tricarboxylic acid cycle for macromolecule generation, (4) increased lipid uptake, lipogenesis, and cholesterol synthesis, (5) upregulation of one-carbon metabolism for the production of ATP, NADH/NADPH, nucleotides, and glutathione, (6) altered amino acid metabolism, (7) metabolism-based regulation of apoptosis, and (8) the utilization of alternative substrates, such as lactate and acetate. Altered metabolic flux in cancer is controlled by tumor-host cell interactions, key oncogenes, tumor suppressors, and other regulatory molecules, including non-coding RNAs. Changes to metabolic pathways in cancer are dynamic, exhibit plasticity, and are often dependent on the type of tumor and the tumor microenvironment, leading in a shift of thought from the Warburg Effect and the “reverse Warburg Effect” to metabolic plasticity. Understanding the complex nature of altered flux through these multiple pathways in cancer cells can support the development of new therapies.
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Evans, Laura A., Emilie I. Anderson, Xuan-Mai Petterson, Shaji Kumar, and Wilson I. Gonsalves. "Disrupting the Reverse Warburg Effect As a Therapeutic Strategy in Multiple Myeloma." Blood 138, Supplement 1 (November 5, 2021): 2649. http://dx.doi.org/10.1182/blood-2021-147970.
Повний текст джерелаАнотація:
Abstract Introduction: Altered cellular metabolism is a hallmark of every cancer cell. Aerobic glycolysis ("The Warburg Effect") is one of the earliest recognized metabolic abnormalities in cancer cells whereby extracellular glucose is preferentially metabolized and eventually processed to generate lactate and energy in the form of ATP before the former is released extracellularly, irrespective of oxygen availability. While extracellular lactate produced and released from cancer cells has traditionally been considered a waste metabolic by-product, recent understanding of cell metabolism suggests that it can also serve as a primary metabolic fuel for cancer cells via uptake by monocarboxylate transporters (MCTs). Our goal was to evaluate this "Reverse Warburg Effect" phenomenon in multiple myeloma (MM) cells and determine if it can be exploited for therapeutic purposes. Methods: All HMCLs, MM1S, RPMI-8226 and U266, were grown in RPMI-1640 cell culture medium containing 11 mM glucose and supplemented with 10% dialyzed fetal bovine serum (FBS) and 2 mM Glutamine. Primary MM cells were extracted using magnetic bead CD138 positive selection from MM patient bone marrow aspirates. For 13C-labeling experiments, HMCLs and primary MM cells were suspended in RPMI-1640 cell culture media containing 13C-labeled isotopes. Isotopomer analysis of glycolytic and tricarboxylic acid (TCA) cycle metabolites from HMCL and primary MM cell pellets was performed using Agilent Technologies 5975C gas chromatography-mass spectrometry. Small molecule inhibitors, AZD3965 and syrosingopine, were purchased from Selleck Chemicals and Sigma respectively. Cellular viability and proliferation were measured using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrasodium bromide (MTT) and CCK-8 assays respectively. MCT-1 and MCT-4 antibodies for western blotting were utilized to evaluate their cell membrane expression on HMCLs. Results: The HMCLs, MM1S and RPMI-8226 as well as primary CD138+ cells from MM patient bone marrow were cultured in cell culture media containing physiological levels (1 mM) of U-13C-Lactate. The incorporation of extracellular 13C into the intracellular glycolytic and TCA cycle metabolite pool was observed (Fig 1) based on the expected isotopomeric patterns, demonstrating the Reverse Warburg Effect in MM cells. The relative contribution of carbon substrate by extracellular lactate compared to extracellular glucose was assessed in the following HMCLs: MM1S, RPMI-8226 and U266 cells by culturing in cell culture media containing 3-13C-Lactate and U-13C-Glucose. Extracellular lactate (yellow bar) contribution to the formation of TCA metabolites equaled that of glucose (red bar) based on the expected isotopomer patterns, suggesting the relative importance of extracellular lactate as an essential nutrient like glucose (Fig 2). Since MCT-1 and MCT-4 are key bidirectional cell membrane transporters of lactate in and out of cells, we explored the clinical significance of their gene expression level on clinical outcomes using the COMMPASS dataset provided by the Multiple Myeloma Research Foundation (MMRF). When MM patients were dichotomized at above or below the median of the expression levels of fragments per kilobase of transcript per million (FPKM), MCT-1 and MCT-4 overexpression conferred a worse progression free survival and overall survival (Fig 3). The MCT-1/MCT-4 protein expression was detectable across the various HMCLs: MM1S, U266 and RPMI-8226 (Fig 4). Inhibition of MCT-1 by specific inhibitor AZD3965 was able to reduce proliferation but not affect viability of HMCLs at 48 hours (Fig 5). However, dual inhibition of MCT-1/MCT-4 using syrosingopine was able to significantly reduce proliferation and decrease viability of HMCLs in a dose dependent fashion (Fig 6). Finally, dual inhibition of MCT-1/MCT-4 using syrosingopine reduced the utilization of extracellular lactate into the TCA cycle pool by HMCLs in media containing 3-13C-Lactate (Fig 7). Conclusion: Utilization of extracellular lactate via Reverse Warburg Effect phenomenon appears highly active in MM cells. Disrupting the utilization of extracellular lactate by dual inhibition of both MCT-1 and MCT-4 appears therapeutic. In the future, dual inhibition of MCT-1/MCT-4 in combination with other anti-MM therapies should be evaluated to determine synergistic therapeutic potential. Figure 1 Figure 1. Disclosures Kumar: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Antengene: Consultancy, Honoraria; Beigene: Consultancy; Bluebird Bio: Consultancy; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Roche-Genentech: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding.
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Parkinson, E. Kenneth, Jerzy Adamski, Grit Zahn, Andreas Gaumann, Fabian Flores-Borja, Christine Ziegler, and Maria E. Mycielska. "Extracellular citrate and metabolic adaptations of cancer cells." Cancer and Metastasis Reviews 40, no. 4 (December 2021): 1073–91. http://dx.doi.org/10.1007/s10555-021-10007-1.
Повний текст джерелаАнотація:
Abstract It is well established that cancer cells acquire energy via the Warburg effect and oxidative phosphorylation. Citrate is considered to play a crucial role in cancer metabolism by virtue of its production in the reverse Krebs cycle from glutamine. Here, we review the evidence that extracellular citrate is one of the key metabolites of the metabolic pathways present in cancer cells. We review the different mechanisms by which pathways involved in keeping redox balance respond to the need of intracellular citrate synthesis under different extracellular metabolic conditions. In this context, we further discuss the hypothesis that extracellular citrate plays a role in switching between oxidative phosphorylation and the Warburg effect while citrate uptake enhances metastatic activities and therapy resistance. We also present the possibility that organs rich in citrate such as the liver, brain and bones might form a perfect niche for the secondary tumour growth and improve survival of colonising cancer cells. Consistently, metabolic support provided by cancer-associated and senescent cells is also discussed. Finally, we highlight evidence on the role of citrate on immune cells and its potential to modulate the biological functions of pro- and anti-tumour immune cells in the tumour microenvironment. Collectively, we review intriguing evidence supporting the potential role of extracellular citrate in the regulation of the overall cancer metabolism and metastatic activity.
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Duda, Przemysław, Jakub Janczara, James A. McCubrey, Agnieszka Gizak та Dariusz Rakus. "The Reverse Warburg Effect Is Associated with Fbp2-Dependent Hif1α Regulation in Cancer Cells Stimulated by Fibroblasts". Cells 9, № 1 (14 січня 2020): 205. http://dx.doi.org/10.3390/cells9010205.
Повний текст джерелаАнотація:
Fibroblasts are important contributors to cancer development. They create a tumor microenvironment and modulate our metabolism and treatment resistance. In the present paper, we demonstrate that healthy fibroblasts induce metabolic coupling with non-small cell lung cancer cells by down-regulating the expression of glycolytic enzymes in cancer cells and increasing the fibroblasts’ ability to release lactate and thus support cancer cells with energy-rich glucose-derived metabolites, such as lactate and pyruvate—a process known as the reverse Warburg effect. We demonstrate that these changes result from a fibroblasts-stimulated increase in the expression of fructose bisphosphatase (Fbp) in cancer cells and the consequent modulation of Hif1α function. We show that, in contrast to current beliefs, in lung cancer cells, the predominant and strong interaction with the Hif1α form of Fbp is not the liver (Fbp1) but in the muscle (Fbp2) isoform. Since Fbp2 oligomerization state and thus, its role is regulated by AMP and NAD+—crucial indicators of cellular metabolic conditions—we hypothesize that the Hif1α-dependent regulation of the metabolism in cancer is modulated through Fbp2, a sensor of the energy and redox state of a cell.
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Nagpal, Seema, Tulin Dadali, Taichang Jang, Milton Merchant, Anne R. Diers, Stephane Gesta, Janice Stevens, et al. "Effect of BPM31510 on radiosensitivity of temozolomide-resistant glioblastoma cell model and survival in in vivo C6 glioma rat model supporting phase I clinical investigation in GBM." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e13509-e13509. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e13509.
Повний текст джерелаАнотація:
e13509 Background: Glioblastoma (GB) is characterized by dysregulated metabolism, utilizing glycolysis for energy production to support unrestricted growth. BPM 31510, an ubidecarenone containing lipid nanodispersion effectuates a switch in cancer energy sourcing from glycolysis towards mitochondrial OXPHOS, i.e. reverses Warburg effect, providing rationale for its potential utility in treatment of GB. The current study investigated utility of BPM31510 alone and in combination with temozolomide. Methods: In vitro (U251-MG human GB cell line) and in vivo (C6 glioma rat model) preclinical models of GB were used to assess the anti-cancer activity of BPM 31510 alone (100 mg/kg/d) and combination with TMZ/bevacizumab (BEV). In addition, an in vitro model of acquired TMZ chemo-resistance was established by progressive adaptation of parental U251-MG cells to increasing doses of TMZ. Parental and resistant subclones (TMZ-R) were used to define activity of BPM31510 in the TMZ-refractory setting. Results: In vitro results demonstrated that BPM 31510 has anti-cancer activity in both parental and TMZ-R U251-MG cells with EC50 values of ~400 µM and 800 µM, respectively. Importantly, BPM 31510 treatment also resensitized TMZ-R cell lines to TMZ. In vivo, BPM 31510 treatment was associated with increasing duration of survival; one fifth of the rats treated achieved survival greater than 15 days post implantation, a response not observed in the control or irradiation arms of the study. Assessment of the combination of BPM 31510 with TMZ or BEV in the in vivoC6 glioma rat model is ongoing. A phase I open-label, non-randomized clinical trial to evaluate the safety and tolerability of BPM31510 in patients with recurrent BEV-refractory GB, as well as the changes in GB metabolism by SUV-PET imaging in response to treatment is under investigation. Conclusions: Preclinical data demonstrate that BPM 31510 has potential anti-cancer activity alone and in combination with standard therapy regimens and alleviates TMZ chemo-resistance in preclinical models of GB. These results provide support of a Phase 1 clinical study of BPM31510 in GB; this study is actively enrolling.
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Li, Na, and Xianquan Zhan. "Multiomics-based energy metabolism heterogeneity and its regulation by antiparasite drug ivermectin." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e18080-e18080. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e18080.
Повний текст джерелаАнотація:
e18080 Background: Energy metabolism heterogeneity is a hallmark in ovarian cancer, namely the Warburg effect and the reverse Warburg effects coexist in ovarian cancer. Exploration of energy metabolism heterogeneity benefits for discovery of the effective biomarkers for ovarian cancers. Methods: Comprehensive analysis of mitochondrial proteomics data (1198 mitochondrial differentially expressed proteins), mitochondrial phosphorpoteomics data (67 mitochondrial phosphorproteins), proteomics data (205 differentially expressed proteins), and transcriptomics data (20115 genes in 419 ovarian cancer samples) was useful. Results: It revealed (i) the upregulations of rate-limiting enzymes PKM2 in glycolysis, IDH2 in Kreb’s cycle, and UQCRH in oxidative phosphorylation (OXPHOS) pathways, (ii) the upregulation of PDHB that converts pyruvate from glycolysis into acetyl-CoA in Kreb’s cycle. Anti-parasite drug ivermectin demonstrated its strong abilities to inhibit proliferation and cell cycle progression and promote apoptosis in EOC cells, through molecular networks to target PFKP in glycolysis, IDH2 and IDH3B in Kreb’s cycle, ND2, ND5, CYTB, and UQCRH in OXPHOS, and MCT1 and MCT4 in lactate shuttle to inhibit EOC growth. Those results were further confirmed in the ovarian cancer cell models and tissues. Conclusions: It clearly concluded that ivermectin might have new potential for ovarian cancer treatment through regulating energy metabolism pathways. These findings provide more accurate understanding of molecular mechanisms of ovarian cancers and discovery of effective energy-metabolism-heterogeneity-based therapeutic drugs for ovarian cancers.
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Reiter, Russel J., Ramaswamy Sharma, Qiang Ma, Sergio Rosales-Corral, Dario Acuna-Castroviejo, and Germaine Escames. "Inhibition of mitochondrial pyruvate dehydrogenase kinase: a proposed mechanism by which melatonin causes cancer cells to overcome cytosolic glycolysis, reduce tumor biomass and reverse insensitivity to chemotherapy." Melatonin Research 2, no. 3 (August 31, 2019): 105–19. http://dx.doi.org/10.32794/mr11250033.
Повний текст джерелаАнотація:
This review presents a hypothesis to explain the role of melatonin in regulating glucose metabolism in cancer cells. Many cancer cells use cytosolic glycolysis (the Warburg effect) to produce energy (ATP). Under these conditions, glucose is primarily converted to lactate which is released into the blood in large quantities. The Warburg effect gives cancer cells advantages in terms of enhanced macromolecule synthesis required for accelerated cellular proliferation, reduced cellular apoptosis which enhances tumor biomass and a greater likelihood of metastasis. Based on available data, high circulating melatonin levels at night serve as a signal for breast cancer cells to switch from cytosolic glycolysis to mitochondrial glucose oxidation and oxidative phosphorylation for ATP production. In this situation, melatonin promotes the synthesis of acetyl-CoA from pyruvate; we speculate that melatonin does this by inhibiting the mitochondrial enzyme pyruvate dehydrogenase kinase (PDK) which normally inhibits pyruvate dehydrogenase complex (PDC), the enzyme that controls the pyruvate to acetyl-CoA conversion. Acetyl-CoA has several important functions in the mitochondria; it feeds into the citric acid cycle which improves oxidative phosphorylation and, additionally, it is a necessary co-factor for the rate limiting enzyme, arylalkylamine N-acetyltransferase, in mitochondrial melatonin synthesis. When breast cancer cells are using cytosolic glycolysis (during the day) they are of the cancer phenotype; at night when they are using mitochondria to produce ATP via oxidative phosphorylation, they have a normal cell phenotype. If this day:night difference in tumor cell metabolism is common in other cancers, it indicates that these tumor cells are only cancerous part of the time. We also speculate that high nighttime melatonin levels also reverse the insensitivity of tumors to chemotherapy.
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Ordway, Bryce, Michal Tomaszewski, Samantha Byrne, Dominique Abrahams, Pawel Swietach, Robert J. Gillies, and Mehdi Damaghi. "Targeting of Evolutionarily Acquired Cancer Cell Phenotype by Exploiting pHi-Metabolic Vulnerabilities." Cancers 13, no. 1 (December 28, 2020): 64. http://dx.doi.org/10.3390/cancers13010064.
Повний текст джерелаАнотація:
Evolutionary dynamics can be used to control cancers when a cure is not clinically considered to be achievable. Understanding Darwinian intratumoral interactions of microenvironmental selection forces can be used to steer tumor progression towards a less invasive trajectory. Here, we approach intratumoral heterogeneity and evolution as a dynamic interaction among subpopulations through the application of small, but selective biological forces such as intracellular pH (pHi) and/or extracellular pH (pHe) vulnerabilities. Increased glycolysis is a prominent phenotype of cancer cells under hypoxia or normoxia (Warburg effect). Glycolysis leads to an important aspect of cancer metabolism: reduced pHe and higher pHi. We recently showed that decreasing pHi and targeting pHi sensitive enzymes can reverse the Warburg effect (WE) phenotype and inhibit tumor progression. Herein, we used diclofenac (DIC) repurposed to control MCT activity, and Koningic acid (KA) that is a GAPDH partial inhibitor, and observed that we can control the subpopulation of cancer cells with WE phenotype within a tumor in favor of a less aggressive phenotype without a WE to control progression and metastasis. In a 3D spheroid co-cultures, we showed that our strategy can control the growth of more aggressive MDA-MB-231 cells, while sparing the less aggressive MCF7 cells. In an animal model, we show that our approach can reduce tumor growth and metastasis. We thus propose that evolutionary dynamics can be used to control tumor cells’ clonal or sub-clonal populations in favor of slower growth and less damage to patients. We propose that this can result in cancer control for tumors where cure is not an option.
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Peng, Bo, Si-Yuan Zhang, Ka Iong Chan, Zhang-Feng Zhong, and Yi-Tao Wang. "Novel Anti-Cancer Products Targeting AMPK: Natural Herbal Medicine against Breast Cancer." Molecules 28, no. 2 (January 11, 2023): 740. http://dx.doi.org/10.3390/molecules28020740.
Повний текст джерелаАнотація:
Breast cancer is a common cancer in women worldwide. The existing clinical treatment strategies have been able to limit the progression of breast cancer and cancer metastasis, but abnormal metabolism, immunosuppression, and multidrug resistance involving multiple regulators remain the major challenges for the treatment of breast cancer. Adenosine 5′-monophosphate (AMP)-Activated Protein Kinase (AMPK) can regulate metabolic reprogramming and reverse the “Warburg effect” via multiple metabolic signaling pathways in breast cancer. Previous studies suggest that the activation of AMPK suppresses the growth and metastasis of breast cancer cells, as well as stimulating the responses of immune cells. However, some other reports claim that the development and poor prognosis of breast cancer are related to the overexpression and aberrant activation of AMPK. Thus, the role of AMPK in the progression of breast cancer is still controversial. In this review, we summarize the current understanding of AMPK, particularly the comprehensive bidirectional functions of AMPK in cancer progression; discuss the pharmacological activators of AMPK and some specific molecules, including the natural products (including berberine, curcumin, (−)-epigallocatechin-3-gallate, ginsenosides, and paclitaxel) that influence the efficacy of these activators in cancer therapy; and elaborate the role of AMPK as a potential therapeutic target for the treatment of breast cancer.
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Pfeilstocker, Michael, Peter Wihlidal, Franz Varga, Elisabeth Pittermann, and Heidrun Karlic. "Imatinib Mesylate Induced Reversal of Leukemic Gene Phenotype in HL60 Cells Coincides with Stimulation of Oxidative Metabolism." Blood 110, no. 11 (November 16, 2007): 4190. http://dx.doi.org/10.1182/blood.v110.11.4190.4190.
Повний текст джерелаАнотація:
Abstract Besides blockade of tyrosine kinases such as c-kit, Imatinib mesylate (IM) regulates glucose flux through downregulation of GLUT-1 transporters in human leukemia cells. This mechanism has the potential to induce regression of type 2 diabetes and hyperlipidemia as observed in patients with chronic myeloid leukemia or hypereosinophilic syndrome. In addition, there is a stimulatory effect of IM on differentiation of human mesenchymal stem cells. Its synergism with retinoic acid or low dose Ara-C is applied in treatment of acute myeloid leukemia (AML). Thus, the AML-derived c-kit positive cell line HL60 was chosen for studying the effect of IM on expression of genes associated with differentiation and metabolism. We analysed the possible feedback on transcription factors (AML1 and AML3) and consequences regarding differentiation and metabolism - associated genes. Quantitative reverse transcriptase PCR analyses revealed that IM treatment of HL60 cells downregulates mRNA synthesis of AML1 and AML3 by 70% without affecting transcription of the c-abl tyrosine kinase. IM reduces expression of CD34 mRNA from 20% to 6% of the housekeeping gene G6PD. The appearance of differentiated cells was accompanied by a remarkable stimulation of mRNAs from CD11b and CD14 (monocyte markers) reaching 4-fold higher expression levels relative to G6PD. This was associated with an increased proportion of osteocalcin (OCN), which has recently been shown to enhance mitochondrial activity. A 2-fold stimulation of a fat-metabolism associated mitochondrial palmitoyltransferase (CPT1B) and 10-fold stimulation of microsomal carnitine palmitoyltransferase and the carnitine transporter OCTN2 supports previous data indicating an IM-associated stimulation of oxidative metabolism resulting in a regression of type-2 diabetes and hyperlipidemia. Our current investigations show that IM-associated attenuation of cell proliferation inhibited transcription factors AML1 and AML3 and triggered differentiation in the leukemic cell line HL60, as reflected by altered mRNA expression of surface marker genes. The IM - induced stimulation of lipid metabolism in HL60 confirms previous data indicating a reversal of the Warburg effect in K562 cells without cytocidal activity. This indicates a similar mechanism as known for other drugs and strategies targeting glucose or fat metabolism, which are discussed in the context of cancer prevention and treatment.
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Johnson, Suzanne M., Clare Dempsey, Amy Chadwick, Stephanie Harrison, Jizhong Liu, Yujun Di, Owen McGinn, et al. "Metabolic Reprogramming of Bone Marrow Stromal Cells By Leukemic Extracellular Vesicles in Acute Lymphoblastic Leukemia (ALL)." Blood 126, no. 23 (December 3, 2015): 1430. http://dx.doi.org/10.1182/blood.v126.23.1430.1430.
Повний текст джерелаАнотація:
Abstract In ALL, leukemic cells have been shown to modulate the bone marrow microenvironment through aberrant cytokine production favoring leukemic cell survival. Extracellular vesicles have also been recognised as key mediators of non-paracrine cellular interactions in cancer. This mechanism of tumor-stromal interaction has been described in chronic lymphocytic leukemia where recipient stromal cells undergo phenotypic changes. We now report a similar phenomenon in ALL. Light microscopy showed that primary ALL blasts and cell lines, released anucleate extracellular vesicles into extracellular fluids. On transmission electron microscopy, leukemic extracellular vesicles (LEVs) were observed to be heterogeneous, ranging from 100nm exosome-like particles to large 6µm particles. Larger LEVs were enclosed in lipid-rich membranes and contained several organelles including ribosomes, lysosomes, golgi bodies and mitochondria. On fluorescent immunostaining, LEVs demonstrated an organized cytoskeleton with expression of actin, vinculin and talin. On imaging flow cytometry, a relative excess of circulating CD19-positive LEVs were observed in patient samples at diagnosis compared to post-treatment; these were readily distinguished from CD61-expressing platelets. On time-lapse microscopy, LEVs generated by green fluorescent labeled ALL cells, appeared as dynamic particles and were internalized by both leukemic and bone marrow stromal cells. Confocal microscopy revealed internalized labeled LEVs located in the perinuclear region of recipient cells for up to a week. Lipophilic tracer labeled LEVs, ALL cell lines and primary cells were transplanted intrafemorally in NSG mice as independent experiments. Transplanted LEVs were observed in peripheral blood at day 9 of transplantation and in marrow stromal cells in contralateral femurs at day 14 of injection. Bilateral femoral flushes at day 14 in both LEV and ALL xenografts, showed free LEVs in extracellular spaces as well as internalization of LEVs by murine mesenchymal cells. While internalization of LEVs by heterogeneous leukemic cell lines led to phenotypic transformation to the cell of origin, recipient marrow stromal cells did not demonstrate change in phenotype, viability or proliferation. In keeping with this, both control and LEV internalized stromal cells had similar ATP levels. Instead, metabolic analyses using an extracellular flux analyzer indicated that recipient stromal cells demonstrated altered normoxic metabolism, with decreased mitochondrial respiration, and increased extracellular acidification associated with raised lactate production. Thus indicating aerobic glycolysis as the main source of energy. In concordance with this, megakaryocytes, granulocytes and endothelial cells but not lymphoblasts in leukemic murine and human bone marrow demonstrated perimembranous expression of the lactate export protein MCT4 (monocarboxylate transporter 4). In contrast, in normal and remission marrow, while granulocytes express membranous MCT4, endothelial cells do not express MCT4 and megakaryocytes showed a predominant cytoplasmic expression. Thus internalized LEVs triggered a metabolic switch from oxidative phosphorylation to aerobic glycolysis in recipient stromal cells resulting in extracellular lactate generation. We speculate that extracellular lactate in the microenvironment serves as the preferred energy substrate for ALL cells, a phenomenon reported in other cancers and termed the reverse Warburg effect. Targeting lactate-dependent metabolism may therefore represent a novel common therapeutic strategy in ALL and other cancers. Disclosures No relevant conflicts of interest to declare.
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Ji, Lijiang, Weixing Shen, Feng Zhang, Jie Qian, Jie Jiang, Liping Weng, Jiani Tan та ін. "Worenine reverses the Warburg effect and inhibits colon cancer cell growth by negatively regulating HIF-1α". Cellular & Molecular Biology Letters 26, № 1 (18 травня 2021). http://dx.doi.org/10.1186/s11658-021-00263-y.
Повний текст джерелаАнотація:
Abstract Background Some natural compounds inhibit cancer cell growth in various cancer cell lines with fewer side effects than traditional chemotherapy. Here, we explore the pharmacological effects and mechanisms of worenine (isolated from Coptis chinensis) against colorectal cancer. Methods The effects of worenine on colorectal cancer cell proliferation, colony formation and cell cycle distribution were measured. Glycolysis was investigated by examining glucose uptake and consumption, lactate production, and the activities and expressions of glycolysis enzymes (PFK-L, HK2 and PKM2). HIF-1α was knocked down and stimulated in vitro to investigate the underlying mechanisms. Results Worenine somewhat altered the glucose metabolism and glycolysis (Warburg effect) of cancer cells. Its anti-cancer effects and capability to reverse the Warburg effect were similar to those of HIF-1α siRNA and weakened by deferoxamine (an HIF-1α agonist). Conclusion It is suggested that worenine targets HIF-1α to inhibit colorectal cancer cell growth, proliferation, cell cycle progression and the Warburg effect.
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Shin, Eunah, and Ja Seung Koo. "Glucose Metabolism and Glucose Transporters in Breast Cancer." Frontiers in Cell and Developmental Biology 9 (September 6, 2021). http://dx.doi.org/10.3389/fcell.2021.728759.
Повний текст джерелаАнотація:
Breast cancer is the most common malignancy in women worldwide and is associated with high mortality rates despite the continuously advancing treatment strategies. Glucose is essential for cancer cell metabolism owing to the Warburg effect. During the process of glucose metabolism, various glycolytic metabolites, such as serine and glycine metabolites, are produced and other metabolic pathways, such as the pentose phosphate pathway (PPP), are associated with the process. Glucose is transported into the cell by glucose transporters, such as GLUT. Breast cancer shows high expressions of glucose metabolism-related enzymes and GLUT, which are also related to breast cancer prognosis. Triple negative breast cancer (TNBC), which is a high-grade breast cancer, is especially dependent on glucose metabolism. Breast cancer also harbors various stromal cells such as cancer-associated fibroblasts and immune cells as tumor microenvironment, and there exists a metabolic interaction between these stromal cells and breast cancer cells as explained by the reverse Warburg effect. Breast cancer is heterogeneous, and, consequently, its metabolic status is also diverse, which is especially affected by the molecular subtype, progression stage, and metastatic site. In this review, we will focus on glucose metabolism and glucose transporters in breast cancer, and we will additionally discuss their potential applications as cancer imaging tracers and treatment targets.
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Ramzy, Asmaa, Sara ElSafy, Hisham A. Elshoky, Aya Soliman, Rana A. Youness, Samar Mansour, and Aya Sebak. "Drugless nanoparticles tune-up an array of intertwined pathways contributing to immune checkpoint signaling and metabolic reprogramming in triple-negative breast cancer." Biomedical Materials, December 2, 2022. http://dx.doi.org/10.1088/1748-605x/aca85d.
Повний текст джерелаАнотація:
Abstract Background and Purpose Metabolic reprogramming “Warburg effect” and immune checkpoint signaling are immunosuppressive hallmarks of Triple-Negative Breast Cancer (TNBC) contributing to the limited clinical applicability of immunotherapy. Biomaterials arise as novel tools for immunomodulation of the tumor microenvironment (TME) that can be used alongside conventional immunotherapeutics. Chitosan and lecithin are examples of versatile biomaterials with interesting immunomodulatory properties. In this study, we aimed at investigation of the role of carefully designed hybrid nanoparticles (NPs) on common mediators of both PD-L1 expression and glycolytic metabolism. Materials and Methods Hybrid lecithin-chitosan NPs were prepared and characterized. Their intracellular concentration, localization and effect on the viability of MDA-MB-231 cells were assessed. Glycolytic metabolism was quantified by measuring glucose consumption, ATP generation, lactate production and extracellular acidification. Nitric oxide (NO) production was quantified using Greiss reagent. Gene expression of iNOS, PI3K, Akt, mTOR, HIF-1α and PD-L1 was quantified by reverse transcription and q-RT-PCR. Results Chitosan, lecithin and the NPs-formulated forms have been shown to influence the “Warburg effect” and immune checkpoint signaling of TNBC cells differently. The composition of the hybrid systems dictated their subcellular localization and hence the positive or negative impact on the immunosuppressive characteristics of TNBC cells. Conclusions Carefully engineered hybrid lecithin-chitosan NPs could convert the immune-suppressive microenvironment of TNBC to an immune-active microenvironment via reduction of PD-L1 expression and reversal of the Warburg effect.
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Wu, Fanglong, Shimeng Wang, Qingxiang Zeng, Junjiang Liu, Jin Yang, Jingtian Mu, Hongdang Xu та ін. "TGF-βRII regulates glucose metabolism in oral cancer-associated fibroblasts via promoting PKM2 nuclear translocation". Cell Death Discovery 8, № 1 (10 січня 2022). http://dx.doi.org/10.1038/s41420-021-00804-6.
Повний текст джерелаАнотація:
AbstractCancer-associated fibroblasts (CAFs) are highly heterogeneous and differentiated stromal cells that promote tumor progression via remodeling of extracellular matrix, maintenance of stemness, angiogenesis, and modulation of tumor metabolism. Aerobic glycolysis is characterized by an increased uptake of glucose for conversion into lactate under sufficient oxygen conditions, and this metabolic process occurs at the site of energy exchange between CAFs and cancer cells. As a hallmark of cancer, metabolic reprogramming of CAFs is defined as reverse Warburg effect (RWE), characterized by increased lactate, glutamine, and pyruvate, etc. derived from aerobic glycolysis. Given that the TGF-β signal cascade plays a critical role in RWE mainly through metabolic reprogramming related proteins including pyruvate kinase muscle isozyme 2 (PKM2), however, the role of nuclear PKM2 in modifying glycolysis remains largely unknown. In this study, using a series of in vitro and in vivo experiments, we provide evidence that TGF-βRII overexpression suppresses glucose metabolism in CAFs by attenuating PKM2 nuclear translocation, thereby inhibiting oral cancer tumor growth. This study highlights a novel pathway that explains the role of TGF-βRII in CAFs glucose metabolism and suggests that targeting TGF-βRII in CAFs might represent a therapeutic approach for oral cancer.
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Barbato, Alessandro, Grazia Scandura, Fabrizio Puglisi, Daniela Cambria, Enrico La Spina, Giuseppe Alberto Palumbo, Giacomo Lazzarino, et al. "Mitochondrial Bioenergetics at the Onset of Drug Resistance in Hematological Malignancies: An Overview." Frontiers in Oncology 10 (December 21, 2020). http://dx.doi.org/10.3389/fonc.2020.604143.
Повний текст джерелаАнотація:
The combined derangements in mitochondria network, function and dynamics can affect metabolism and ATP production, redox homeostasis and apoptosis triggering, contributing to cancer development in many different complex ways. In hematological malignancies, there is a strong relationship between cellular metabolism, mitochondrial bioenergetics, interconnections with supportive microenvironment and drug resistance. Lymphoma and chronic lymphocytic leukemia cells, e.g., adapt to intrinsic oxidative stress by increasing mitochondrial biogenesis. In other hematological disorders such as myeloma, on the contrary, bioenergetics changes, associated to increased mitochondrial fitness, derive from the adaptive response to drug-induced stress. In the bone marrow niche, a reverse Warburg effect has been recently described, consisting in metabolic changes occurring in stromal cells in the attempt to metabolically support adjacent cancer cells. Moreover, a physiological dynamic, based on mitochondria transfer, between tumor cells and their supporting stromal microenvironment has been described to sustain oxidative stress associated to proteostasis maintenance in multiple myeloma and leukemia. Increased mitochondrial biogenesis of tumor cells associated to acquisition of new mitochondria transferred by mesenchymal stromal cells results in augmented ATP production through increased oxidative phosphorylation (OX-PHOS), higher drug resistance, and resurgence after treatment. Accordingly, targeting mitochondrial biogenesis, electron transfer, mitochondrial DNA replication, or mitochondrial fatty acid transport increases therapy efficacy. In this review, we summarize selected examples of the mitochondrial derangements in hematological malignancies, which provide metabolic adaptation and apoptosis resistance, also supported by the crosstalk with tumor microenvironment. This field promises a rational design to improve target-therapy including the metabolic phenotype.