Search Results (34)

Butyrate, a short-chain fatty acid produced by the fermentation of soluble dietary fiber by gut bacteria, also functions as a histone deacetylase inhibitor known to induce apoptosis and promote differentiation in colon tumor cells. During tumorigenesis, cancer cells undergo metabolic reprogramming to meet energetic and biosynthetic demands, increasing glycolytic metabolism and reducing oxidative metabolism—a phenomenon known as the Warburg effect. This study aimed to evaluate the impact of butyrate on the aggressiveness-related metabolic phenotype of three colon cancer cell lines (LS1034, C2BBe1, and WiDr). Butyrate’s effects were assessed through fluorine-18 fluorodeoxyglucose ([¹⁸F]FDG) uptake, flow cytometry analysis of cytoplasmic and membrane expression of glucose transporters (GLUT1, GLUT3, GLUT5, and GLUT12), lactate production, and analysis of Krebs cycle turnover and glycolysis–Krebs cycle coupling using nuclear magnetic resonance isotopomer profiling. [¹⁸F]FDG uptake decreased in C2BBe1 and WiDr cells, whereas an opposite response was observed in LS1034 cells, which also exhibited reduced GLUT5 expression. These uptake patterns were consistent with lactate production measurements, and an enhancement of oxidative metabolism was detected in C2BBe1 and WiDr cells. Although butyrate was consumed by all three cell lines, its metabolic handling appeared to differ in LS1034 cells, possibly reflecting cytotoxic stress and/or distinct metabolic regulation mechanisms. Overall, these findings indicate that butyrate exerts cell-line-dependent metabolic effects in colorectal cancer cells. In C2BBe1 and WiDr cells, butyrate exposure was broadly consistent with the attenuation of glycolytic/Warburg-associated features, whereas LS1034 cells displayed a divergent response and were interpreted separately. These data support further investigation of butyrate as a modulator of colorectal cancer cell metabolism, while highlighting the heterogeneity of metabolic responses across tumor models. Full article

Lactic acid accumulates in the tumour microenvironment (TME) at concentrations reaching up to 40 mM. Initially, lactic acid was considered merely a metabolic by-product of aerobic glycolysis, a phenomenon commonly referred to as the Warburg effect and observed in the majority of tumours. Recent evidence, however, has demonstrated that lactic acid is not merely a waste product; rather, it plays a pivotal role in tumour biology. High plasma lactic acid levels correlate with increased metastatic potential and lower survival rates. Elevated lactic acid levels in the TME have been shown to suppress antitumour immune responses, facilitate both metastasis and cellular senescence, and might modulate gene expression through novel epigenetic mechanisms such as histone lactylation. This review aims to summarize current knowledge on the multifaceted impact of elevated lactic acid in the TME on tumour progression and biology. Full article

The Warburg effect, a unique glycolytic phenomenon in cancer cells, presents a promising target for developing selective anticancer agents. Previously, BH10, a hit compound disrupting glycolytic metabolism, was identified via phenotypic screening, with Kelch-like ECH-associated protein 1 (Keap1) proposed as a potential target. To enhance its potency and selectivity, a library of BH10-derived salt compounds was synthesized. Among these, 7b exhibited nanomolar anticancer activity (IC₅₀ = 22.97 nM) and a high selectivity ratio (IC₅₀ of non-cancerous cells/IC₅₀ of cancer cells = 41.43). Molecular docking revealed that all naphthoimidazole salt analogues (7a–f) bind to Keap1 via carbonyl-mediated interactions, with variations in hydrogen-bonding residues (e.g., VAL606, ILE559). Full article

Neoplastic cells are characterized by metabolic reprogramming, known as the Warburg effect, in which glucose metabolism is predominantly directed toward aerobic glycolysis, with reduced mitochondrial oxidative phosphorylation and increased lactate production even in the presence of oxygen. This phenomenon provides cancer cells with a proliferative advantage, allowing them to rapidly produce energy (in the form of ATP) and generate metabolic intermediates necessary for the biosynthesis of macromolecules essential for cell growth. It is important to understand the role of ion channels in the tumor context since they participate in various physiological processes and in the regulation of the tumor microenvironment. These changes may contribute to the development and transformation of cancer cells, as well as affect the communication between cells and the surrounding microenvironment, including impaired or altered expression and functionality of ion channels. Therefore, the aim of this review is to elucidate the impact of the tumor microenvironment on the electrical properties of the cellular membranes in several cancers as a possible therapeutic target. Full article

We revisit the seminal model of glycolysis first proposed by Sel’kov more than fifty years ago. We investigate the onset of instabilities in biological systems described by the Sel’kov model in order to determine the conditions of the model parameters that lead to bifurcations. We analyze the glycolysis reaction under the circumstances when the diffusivity of both ATP and ADP reactants are taken into account. We estimate the critical value of the model’s single compact dimensionless parameter, which is responsible for the onset of reaction instability and the system’s symmetry breaking. It appears that it leads to spatial inhomogeneities of reactants, leading to the formation of standing waves instead of a homogeneous distribution of ATP molecules. The consequences of this model and its results are discussed in the context of the Warburg effect, which signifies a transition from oxidative phosphorylation to glycolysis that is correlated with the initiation and progression of cancer. Our analysis may lead to the selection of therapeutic interventions in order to prevent the symmetry-breaking phenomenon described in our work. Full article

This review article investigates the relationship between mitochondrial dysfunction and cancer progression, emphasizing the metabolic shifts that promote tumor growth. Mitochondria are crucial for cellular energy production, but they also play a significant role in cancer progression by promoting glycolysis even under oxygen-rich conditions, a phenomenon known as the Warburg effect. This metabolic reprogramming enables cancer cells to maintain an alkaline internal pH and an acidic external environment, which are critical for their proliferation and survival in hypoxic conditions. The article also explores the acidic tumor microenvironment (TME), a consequence of intensive glycolytic activity and proton production by cancer cells. This acidic milieu enhances the invasiveness and metastatic potential of cancer cells and contributes to increased resistance to chemotherapy. Alkalization therapy, which involves neutralizing this acidity through dietary modifications and the administration of alkalizing agents such as sodium bicarbonate, is highlighted as an effective strategy to counteract these adverse conditions and impede cancer progression. Integrating insights from science-based medicine, the review evaluates the effectiveness of alkalization therapy across various cancer types through clinical assessments. Science-based medicine, which utilizes inductive reasoning from observed clinical outcomes, lends support to the hypothesis of metabolic reprogramming in cancer treatment. By addressing both metabolic and environmental disruptions, this review suggests that considering cancer as primarily a metabolic disorder could lead to more targeted and effective treatment strategies, potentially improving outcomes for patients with advanced-stage cancers. Full article

A major hallmark of cancer is the reprogramming of cellular metabolism from oxidative phosphorylation (OXPHOS) to glycolysis, a phenomenon known as the Warburg effect. To sustain high rates of glycolysis, cancer cells overexpress GLUT transporters and glycolytic enzymes, allowing for the enhanced uptake and consumption of glucose. The Warburg effect may be exploited in the treatment of cancer; certain epimers and derivatives of glucose can enter cancer cells and inhibit glycolytic enzymes, stunting metabolism and causing cell death. These include common dietary monosaccharides (ᴅ-mannose, ᴅ-galactose, ᴅ-glucosamine, ʟ-fucose), as well as some rare monosaccharides (xylitol, ᴅ-allose, ʟ-sorbose, ʟ-rhamnose). This article reviews the literature on these sugars in in vitro and in vivo models of cancer, discussing their mechanisms of cytotoxicity. In addition to this, the anticancer potential of some synthetically modified monosaccharides, such as 2-deoxy-ᴅ-glucose and its acetylated and halogenated derivatives, is reviewed. Further, this article reviews how certain monosaccharides can be used in combination with anticancer drugs to potentiate conventional chemotherapies and to help overcome chemoresistance. Finally, the limitations of administering two separate agents, a sugar and a chemotherapeutic drug, are discussed. The potential of the glycoconjugation of classical or repurposed chemotherapy drugs as a solution to these limitations is reviewed. Full article

Cancer cells metabolize a large fraction of glucose to lactate, even under a sufficient oxygen supply. This phenomenon—the “Warburg Effect”—is often regarded as not yet understood. Cancer cells change gene expression to increase the uptake and utilization of glucose for biosynthesis pathways and glycolysis, but they do not adequately up-regulate the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS). Thereby, an increased glycolytic flux causes an increased production of cytosolic NADH. However, since the corresponding gene expression changes are not neatly fine-tuned in the cancer cells, cytosolic NAD⁺ must often be regenerated by loading excess electrons onto pyruvate and secreting the resulting lactate, even under sufficient oxygen supply. Interestingly, the Michaelis constants (K_M values) of the enzymes at the pyruvate junction are sufficient to explain the priorities for pyruvate utilization in cancer cells: 1. mitochondrial OXPHOS for efficient ATP production, 2. electrons that exceed OXPHOS capacity need to be disposed of and secreted as lactate, and 3. biosynthesis reactions for cancer cell growth. In other words, a number of cytosolic electrons need to take the “emergency exit” from the cell by lactate secretion to maintain the cytosolic redox balance. Full article

In recent years, researchers have often encountered the significance of the aberrant metabolism of tumor cells in the pathogenesis of malignant neoplasms. This phenomenon, known as the Warburg effect, provides a number of advantages in the survival of neoplastic cells, and its application is considered a potential strategy in the search for antitumor agents. With the aim of developing a promising platform for designing antitumor therapeutics, we synthesized a library of conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones. To gain insight into the determinants of the biological activity of the prepared compounds, we showed that the conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones, which are cytotoxic agents, demonstrate selective activity toward a number of tumor cell lines with glycolysis-inhibiting ability. Moreover, the results of molecular and in silico screening allowed us to identify these compounds as potential inhibitors of the pyruvate kinase M2 oncoprotein, which is the rate-determining enzyme of glycolysis. Thus, the results of our work indicate that the synthesized conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones can be considered a promising platform for designing selective cytotoxic agents against the glycolysis process, which opens new possibilities for researchers involved in the search for antitumor therapeutics among compounds containing piperidone platforms. Full article

Cancer cells adeptly manipulate their metabolic processes to evade immune detection, a phenomenon intensifying the complexity of cancer progression and therapy. This review delves into the critical role of cancer cell metabolism in the immune-editing landscape, highlighting how metabolic reprogramming facilitates tumor cells to thrive despite immune surveillance pressures. We explore the dynamic interactions within the tumor microenvironment (TME), where cancer cells not only accelerate their glucose and amino acid metabolism but also induce an immunosuppressive state that hampers effective immune response. Recent findings underscore the metabolic competition between tumor and immune cells, particularly focusing on how this interaction influences the efficacy of emerging immunotherapies. By integrating cutting-edge research on the metabolic pathways of cancer cells, such as the Warburg effect and glutamine addiction, we shed light on potential therapeutic targets. The review proposes that disrupting these metabolic pathways could enhance the response to immunotherapy, offering a dual-pronged strategy to combat tumor growth and immune evasion. Full article

Dysregulated metabolic dynamics are evident in both cancer and diabetes, with metabolic alterations representing a facet of the myriad changes observed in these conditions. This review delves into the commonalities in metabolism between cancer and type 2 diabetes (T2D), focusing specifically on the contrasting roles of oxidative phosphorylation (OXPHOS) and glycolysis as primary energy-generating pathways within cells. Building on earlier research, we explore how a shift towards one pathway over the other serves as a foundational aspect in the development of cancer and T2D. Unlike previous reviews, we posit that this shift may occur in seemingly opposing yet complementary directions, akin to the Yin and Yang concept. These metabolic fluctuations reveal an intricate network of underlying defective signaling pathways, orchestrating the pathogenesis and progression of each disease. The Warburg phenomenon, characterized by the prevalence of aerobic glycolysis over minimal to no OXPHOS, emerges as the predominant metabolic phenotype in cancer. Conversely, in T2D, the prevailing metabolic paradigm has traditionally been perceived in terms of discrete irregularities rather than an OXPHOS-to-glycolysis shift. Throughout T2D pathogenesis, OXPHOS remains consistently heightened due to chronic hyperglycemia or hyperinsulinemia. In advanced insulin resistance and T2D, the metabolic landscape becomes more complex, featuring differential tissue-specific alterations that affect OXPHOS. Recent findings suggest that addressing the metabolic imbalance in both cancer and diabetes could offer an effective treatment strategy. Numerous pharmaceutical and nutritional modalities exhibiting therapeutic effects in both conditions ultimately modulate the OXPHOS–glycolysis axis. Noteworthy nutritional adjuncts, such as alpha-lipoic acid, flavonoids, and glutamine, demonstrate the ability to reprogram metabolism, exerting anti-tumor and anti-diabetic effects. Similarly, pharmacological agents like metformin exhibit therapeutic efficacy in both T2D and cancer. This review discusses the molecular mechanisms underlying these metabolic shifts and explores promising therapeutic strategies aimed at reversing the metabolic imbalance in both disease scenarios. Full article

The majority of glucose in tumor cells is converted to lactate despite the presence of sufficient oxygen and functional mitochondria, a phenomenon known as the “Warburg effect” or “aerobic glycolysis”. Aerobic glycolysis supplies large amounts of ATP, raw material for macromolecule synthesis, and also lactate, thereby contributing to cancer progression and immunosuppression. Increased aerobic glycolysis has been identified as a key hallmark of cancer. Circular RNAs (circRNAs) are a type of endogenous single-stranded RNAs characterized by covalently circular structures. Accumulating evidence suggests that circRNAs influence the glycolytic phenotype of various cancers. In gastrointestinal (GI) cancers, circRNAs are related to glucose metabolism by regulating specific glycolysis-associated enzymes and transporters as well as some pivotal signaling pathways. Here, we provide a comprehensive review of glucose-metabolism-associated circRNAs in GI cancers. Furthermore, we also discuss the potential clinical prospects of glycolysis-associated circRNAs as diagnostic and prognostic biomarkers and therapeutic targets in GI cancers. Full article

Cancer cells undergo metabolic reprogramming and switch to a ‘glycolysis-dominant’ metabolic profile to promote their survival and meet their requirements for energy and macromolecules. This phenomenon, also known as the ‘Warburg effect,’ provides a survival advantage to the cancer cells and make the tumor environment more pro-cancerous. Additionally, the increased glycolytic dependence also promotes chemo/radio resistance. A similar switch to a glycolytic metabolic profile is also shown by the immune cells in the tumor microenvironment, inducing a competition between the cancer cells and the tumor-infiltrating cells over nutrients. Several recent studies have shown that targeting the enhanced glycolysis in cancer cells is a promising strategy to make them more susceptible to treatment with other conventional treatment modalities, including chemotherapy, radiotherapy, hormonal therapy, immunotherapy, and photodynamic therapy. Although several targeting strategies have been developed and several of them are in different stages of pre-clinical and clinical evaluation, there is still a lack of effective strategies to specifically target cancer cell glycolysis to improve treatment efficacy. Herein, we have reviewed our current understanding of the role of metabolic reprogramming in cancer cells and how targeting this phenomenon could be a potential strategy to improve the efficacy of conventional cancer therapy. Full article

Back to beginnings. A century ago, Otto Warburg published that aerobic glycolysis and the respiratory impairment of cells were the prime cause of cancer, a phenomenon that since then has been known as “the Warburg effect”. In his early studies, Warburg looked at the effects of hydrogen ions (H⁺), on glycolysis in anaerobic conditions, as well as of bicarbonate and glucose. He found that gassing with CO₂ led to the acidification of the solutions, resulting in decreased rates of glycolysis. It appears that Warburg first interpreted the role of pH on glycolysis as a secondary phenomenon, a side effect that was there just to compensate for the effect of bicarbonate. However, later on, while talking about glycolysis in a seminar at the Rockefeller Foundation, he said: “Special attention should be drawn to the remarkable influence of the bicarbonate…”. Departing from the very beginnings of this metabolic cancer research in the 1920s, our perspective advances an analytic as well as the synthetic approach to the new “pH-related paradigm of cancer”, while at the same time addressing the most fundamental and recent changing concepts in cancer metabolic etiology and its potential therapeutic implications. Full article

Cancer cells drive the glycolytic process towards the fermentation of pyruvate into lactate even in the presence of oxygen and functioning mitochondria, a phenomenon known as the “Warburg effect”. Although not energetically efficient, glycolysis allows the cancer cell to synthesize the metabolites needed for cell duplication. Autophagy, a macromolecular degradation process, limits cell mass accumulation and opposes to cell proliferation as well as to cell migration. Cancer cells corrupt cancer-associated fibroblasts to release pro-inflammatory cytokines, which in turn promote glycolysis and support the metastatic dissemination of cancer cells. In mimicking in vitro this condition, we show that IL-6 promotes ovarian cancer cell migration only in the presence of glycolysis. The nutraceutical resveratrol (RV) counteracts glucose uptake and metabolism, reduces the production of reactive oxygen species consequent to excessive glycolysis, rescues the mitochondrial functional activity, and stimulates autophagy. Consistently, the lack of glucose as well as its metabolically inert analogue 2-deoxy-D-glucose (2-DG), which inhibits hexokinase 2 (HK2), trigger autophagy through mTOR inhibition, and prevents IL-6-induced cell migration. Of clinical relevance, bioinformatic analysis of The Cancer Genome Atlas dataset revealed that ovarian cancer patients bearing mutated TP53 with low expression of glycolytic markers and IL-6 receptor, together with markers of active autophagy, display a longer overall survival and are more responsive to platinum therapy. Taken together, our findings demonstrate that RV can counteract IL-6-promoted ovarian cancer progression by rescuing glycolysis-mediated inhibition of autophagy and support the view that targeting Warburg metabolism can be an effective strategy to limit the risk for cancer metastasis. Full article