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Coronal MR scans of immunodeficient rat orthotopic glioblastoma models treated with ACCA. Representative coronal MR scans of one of the six animals that survived beyond experimental end points is shown. Gadolinium contrast – enhanced images are shown at the cannulation point. (A) Day 1, immediately after implantation of tumor in the CPu region; the needle tract is indicated by arrow. (B – D) Images of the same coronal position at day 14 (day of osmotic pump implantation and cannulation of the tumor for CED of ACCA), day 56 (42 days after CED of ACCA and 14 days after exhaustion of ACCA in the osmotic pumps), and day 120 (106 days after CED of ACCA and 78 days after exhaustion of ACCA in the osmotic pump). Representative images of an animal that survived to day 120 are shown. (E) Tumor growth at day 20 in a representative animal that did not receive saline or ACCA through CED.
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Glioblastoma multiforme (GBM) are the most malignant among brain tumors. They are frequently refractory to chemotherapy and radiotherapy with mean patient survival of approximately 6 months, despite surgical intervention. The highly glycolytic nature of glioblastomas describes their propensity to metabolize glucose to lactic acid at an elevated rat...
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... the test animals, three survived 212% longer than control animals that were treated with saline. MRI of the other three test animals indicated complete necrosis of tumor, and all three animals survived beyond the experimental end points (3 months after tumor implantation) with no recurrence of the tumor after ACCA was exhausted in the osmotic pumps (Figure 4, A-D). Thus, in this cohort, a 50% tumor- free survival rate was observed. ...
Citations
... It has also been shown that the secretion and accumulation of lactate within the tumor microenvironment are important for effectively modulating the activation and antigen expression of dendritic cells [69]. Consistently, therapeutic targeting of the lactate transporter gene, MCT, results in the inhibition of tumor growth and invasion [70]. ...
Metabolic reprogramming is a defining hallmark of cancer metastasis, warranting thorough exploration. The tumor-promoting function of the "Warburg Effect", marked by escalated glycolysis and restrained mitochondrial activity, is widely acknowledged. Yet, the functional significance of mitochondria-mediated oxidative phosphorylation (OXPHOS) during metastasis remains controversial. Circulating tumor cells (CTCs) are considered metastatic precursors that detach from primary or secondary sites and harbor the potential to seed distant metastases through hematogenous dissemination. A comprehensive metabolic characterization of CTCs faces formidable obstacles, including the isolation of these rare cells from billions of blood cells, coupled with the complexities of ex vivo-culturing of CTC lines or the establishment of CTC-derived xenograft models (CDX). This review summarized the role of the "Warburg Effect" in both tumorigenesis and CTC-mediated metastasis. Intriguingly, bioinformatic analysis of single-CTC transcriptomic studies unveils a potential OXPHOS dominance over Glycolysis signature genes across several important cancer types. From these observations, we postulate a potential "Anti-Warburg Effect" (AWE) in CTCs—a metabolic shift bridging primary tumors and metastases. The observed AWE could be clinically important as they are significantly correlated with therapeutic response in melanoma and prostate patients. Thus, unraveling dynamic metabolic regulations within CTC populations might reveal an additional layer of regulatory complexities of cancer metastasis, providing an avenue for innovative anti-metastasis therapies.
... Lonidamine is a derivative of indazole-3-carboxylic acid, which was shown to inhibit aerobic glycolysis in cancer cells, in part through targeting the lactate transport machinery and LDH activity (19)(20)(21). LTIs have been shown to have therapeutic benefits in cancer treatment (22)(23)(24)(25). Several studies have demonstrated their ability to inhibit lactate efflux from cancer cells (26)(27)(28), lactate production, cell migration and invasion (29). ...
... For example, oxamate has been variously described as a general LDH inhibitor (38), a specific LDH-A inhibitor (13,39), and a specific LDH-C inhibitor (32) with the absence of testing its specificity of the various isoforms in these studies. Also, other studies (18,(22)(23)(24)(25) have grouped these inhibitors into two different categories: LDH enzyme inhibitors (oxamate and GNE-140) and LTIs (quercetin and lonidamine). In the current study, experimental evidence was provided suggesting that all of these inhibitors have direct inhibitory effects on intracellular LDH enzymatic activities without necessarily affecting the lactate transport machinery in ERand ER + breast cancer cell lines. ...
... Another way to reduce extracellular lactate levels is through targeting lactate transporters or monocarboxylate transporters (MCTs), which have been investigated as potential therapeutic targets for cancer treatment (22)(23)(24)(25). Various MCT inhibitors have been shown to inhibit lactate efflux from cancer cells. ...
Lactate dehydrogenase (LDH) is being increasingly recognized as a major factor in the progression of breast cancer. It was previously shown that short interfering RNA‑mediated knockdown of either LDH‑A or ‑B isoform resulted in inhibition of cell motility due to reduced lactate levels in the extracellular environment. The aim of the present study was to determine the use of pharmacological LDH inhibitors to reduce aggressive behavior of breast cancer cells. The effect of LDH inhibitors was investigated in both estrogen receptor (ER)+ and ER‑ breast cancer cell lines and in normal breast epithelial cells. Cell proliferation, motility and invasion were measured using MTT, wound healing and cultrex assays, respectively. Changes in several key mediators of mitogenic signaling important in breast cancer cells were determined using western blotting. Treatment with various inhibitors reported to block LDH activity resulted in significant reduction in extracellular lactate level, cell proliferation, motility and invasion. This was associated with changes in the levels of vimentin, E‑cadherin, p38 MAPK, ERK1/2 and AKT. A couple of these inhibitors such as quercetin and lonidamine showed preferential inhibition of cancer cell proliferation compared with normal epithelial cell inhibition. These data extend initial findings, further underlining the importance of lactate as a major factor in breast cancer progression and indicate the practical use of various commercially available LDH inhibitors as promising therapeutic agents to oppose the processes leading to cancer progression.
... However, studies have shown that MCT4 can compensate for its lactic acid transporter function when MCT1 is inhibited, which may be a mechanism for resistance to AZD3965. 75 a-Cyano-4-hydroxycinnamate (CHC) 76 and BAY-8002 have also been developed as effective MCT1 inhibitors, but BAY-8002 has a higher (6-fold) selectivity for MCT1 over CHC and no off-target effects. 77 However, of the many MCT1 inhibitors, only AZD3965 was enrolled in a clinical trial (NCT01791595), but it was stopped early. ...
Lactic acid is one of the most abundant products of cellular metabolism and has historically been considered a cell-damaging metabolic product. However, as research has deepened, the beneficial effects of lactic acid on tumor cells and the tumor microenvironment have received increasing attention from the oncology community. Lactic acid can not only provide tumor cells with energy but also act as a messenger molecule that promotes tumor growth and progression and protects tumor cells from immune cells and killing by radiation and chemotherapy. Thus, the inhibition of tumor cell lactic acid metabolism has emerged as a novel antitumor treatment strategy that can also effectively enhance the efficacy of conventional antitumor therapies. In this review, we classify the currently available therapies targeting lactic acid metabolism and examine their prospects for clinical application.
... 47 Colen et al used CHC to inhibit lactate efflux in glioblastoma tumors, affecting tumor invasion and proliferation capacity. 173 CHC also inhibits MCT in the mitochondrial membrane, which reduces the flow of pyruvate to mitochondria and inhibits cell proliferation. 174,175 Other studies have shown that CHC affects DNA repair by inhibiting MCT to limit lactate flux. ...
In recent years, the abnormal glucose metabolism of tumor cells has attracted increasing attention. Abnormal glucose metabolism is closely related to the occurrence and development of tumors. Monocarboxylate transporters (MCTs) transport the sugar metabolites lactic acid and pyruvate, which affect glucose metabolism and tumor progression in a variety of ways. Thus, research has recently focused on MCTs and their potential functions in cancer. The MCT superfamily consists of 14 members. MCT1 and MCT4 play a crucial role in the maintenance of intracellular pH in tumor cells by transporting monocarboxylic acids (such as lactate, pyruvate and butyrate). MCT1 and MCT4 are highly expressed in a variety of tumor cells and are involved the proliferation, invasion and migration of tumor cells, which are closely related to the prognosis of cancer. Because of their important functions in tumor cells, MCT1 and MCT4 have become potential targets for cancer treatment. In this review, we focus on the structure, function and regulation of MCT1 and MCT4 and discuss the developed inhibitors of MCT1 and MCT4 to provide more comprehensive information that might aid in the development of strategies targeting MCTs in cancer.
... It has been established that rapidly dividing cells undergo metabolic adaptation without mitochondrial function defects [7]. For example, the inhibition of lactate efflux adversely affects the glioma invasion, indicating that accelerated lactate efflux is required for invasive abilities in tumor cells [8]. In addition to the invasive phenotype, glycolytic metabolism can regulate and delay programmed cell death [9]. ...
Multiple metabolic pathways are utilized to maintain cellular homeostasis. Given the evidence that altered cell metabolism significantly contributes to glioma biology, the current research efforts aim to improve our understanding of metabolic rewiring between glioma’s complex genotype and tissue context. In addition, extensive molecular profiling has revealed activated oncogenes and inactivated tumor suppressors that directly or indirectly impact the cellular metabolism that is associated with the pathogenesis of gliomas. The mutation status of isocitrate dehydrogenases (IDHs) is one of the most important prognostic factors in adult-type diffuse gliomas. This review presents an overview of the metabolic alterations in IDH-mutant gliomas and IDH-wildtype glioblastoma (GBM). A particular focus is placed on targeting metabolic vulnerabilities to identify new therapeutic strategies for glioma.
... Additionally, the enzyme LDH is an attractive pharmacological target because it is among the potential biomarkers for predicting patients' prognoses in COVID-19 (Kermali et al., 2020;Martinez Mesa et al., 2021). Increases in lactate production have beneficial effects on many processes, such as angiogenesis (Végran et al., 2011;De Saedeleer et al., 2012), invasiveness (Colen et al., 2011;Izumi et al., 2011), commensalism, inflammation (Colegio et al., 2014), and redox homeostasis (Doherty and Cleveland, 2013;Keddie et al., 2020). Furthermore, a metabolic symbiosis is established between glycolytic cancer cells that quickly generate lactate from glucose and oxidative cancer cells that prefer lactate-effective fuel source instead of glucose, which is called lactate metabolism (Sonveaux et al., 2008;Chiarugi et al., 2012). ...
Lactate dehydrogenase (LDH, EC 1.1.1.27) is one of the vital glycolytic conditions, especially during anaerobic conditions. It is a significant diagnostic, prognostic, and monitoring biomarker parameter. A 950-bp DNA fragment containing the gene (LDH) encoding LDH was amplified from Bacillus cereus NRC1. The deduced amino acid sequence reveals that B. cereus LDH (Bc-LDH) is highly homologous to the LDHs of Bacillus organisms. All LDH enzymes have a significant degree of conservation in their active site and several additional domains with unidentified functions. The gene for LDH, which catalyzes lactate synthesis, was cloned, sequenced (accession number: LC706200.1), and expressed in Escherichia coli BL21 (DE3). In this investigation, Bc-LDH was purified to homogeneity with a specific activity of 22.7 units/mg protein and a molecular weight of 35 kDa. It works optimally at pH 8.0. The purified enzyme was inhibited by FeCl2, CuCl2, ZnCl2, and NiCl, whereas CoCl2 was found to boost the activity of Bc-LDH. The molecular docking of the 3D model of the Bc-LDH structure with a natural inhibitor, mangiferin, demonstrated excellent LDH inhibition, with a free binding energy of −10.2 kcal/mol. Moreover, mangiferin is a potent Bc-LDH inhibitor that inhibits Bc-LDH competitively and has one binding site with a Ki value of 0.075 mM. The LDH-mangiferin interaction exhibits a low RMSF value (>1.5 Å), indicating a stable contact at the residues. This study will pave the way for more studies to improve the understanding of mangiferin, which could be considered an intriguing candidate for creating novel and improved LDH inhibitors.
... Stiripentol, an agonist of GABA A R, approved for the treatment of seizures associated with Dravet syndrome [177], showed selective cytotoxic and anti-migratory activity in GBM cells and additive or synergistic effects with TMZ [178]. Interestingly, stiripentol decreases GBM invasion and growth in xenografted mice [179], likely via lactate dehydrogenase (LDH) block, an enzyme involved in both neuron hyperpolarization [180] and highly glycolytic metabolism of GBM cells, which catalyzes lactate production and correlates with high proliferation and invasion [181]. ...
Glioblastoma (GBM) is characterized by fast-growing cells, genetic and phenotypic heterogeneity, and radio-chemo-therapy resistance, contributing to its dismal prognosis. Various medical comorbidities are associated with the natural history of GBM. The most disabling and greatly affecting patients’ quality of life are neurodegeneration, cognitive impairment, and GBM-related epilepsy (GRE). Hallmarks of GBM include molecular intrinsic mediators and pathways, but emerging evidence supports the key role of non-malignant cells within the tumor microenvironment in GBM aggressive behavior. In this context, hyper-excitability of neurons, mediated by glutamatergic and GABAergic imbalance, contributing to GBM growth strengthens the cancer-nervous system crosstalk. Pathogenic mechanisms, clinical features, and pharmacological management of GRE with antiepileptic drugs (AEDs) and their interactions are poorly explored, yet it is a potentially promising field of research in cancer neuroscience. The present review summarizes emerging cooperative mechanisms in oncogenesis and epileptogenesis, focusing on the neuron-to-glioma interface. The main effects and efficacy of selected AEDs used in the management of GRE are discussed in this paper, as well as their potential beneficial activity as antitumor treatment. Overall, although still many unclear processes overlapping in GBM growth and seizure onset need to be elucidated, this review focuses on the intriguing targeting of GBM-neuron mutual interactions to improve the outcome of the so challenging to treat GBM.
... Gliomas are highly glycolytic tumors that convert glucose to lactic acid in high amounts to generate ATP and maintain macromolecule synthesis. Thus, in order to survive its own waste product, gliomas e ux lactic acid out of their cells through transmembrane transporters into the tumor microenvironment and drain it through tumor vessels to reduce microenvironment acidi cation and maintain physiological pH 17,18 . Lactic acid is known to cause an increased vascular permeability through compromising the integrity of the EC monolayer by loosening their cell-cell adhesion, which subsequently induces the disassembly of the VW components 16 . ...
Gliomas are the most prevalent type of malignant brain tumors with a very dismal prognosis. Angiogenesis in glioma has recently gotten more attention and its molecular aspects have been published; however, these were not complemented with ultrastructural evidence. Our ultrastructural examination of glioma vessels reveals several unique and critical features related to their mechanisms of progression and metastasis strategy. The detailed ultrastructural survey of 18 IDH1 -wildtype glioblastomas (GBM) and 12 IDH1 -mutant High-grade gliomas indicated that tumor vessels of both types had undergone deformities such as the thickening of the vessel wall (VW) and proliferation of the basement membrane, contour distortions, abnormal and discontinuous basal lamina, tumor cells’ invasion and colonization of VW, disappearance of endothelial cells (ECs), pericytes, and smooth muscle cells, as well as the formation of a continuous ring of tumor cells attached to the luminal side of VW in numerous cases. The latter feature is a clear sign of vascular mimicry (VM) that was previously suggested in gliomas but never shown by TEM. Additionally, the vascular invasion was carried out by a large number of tumor cells and was accompanied by the accumulation of tumor lipids in the vessels’ lumina and VWs; these two features are distinct for gliomas and may alter the course of the clinical presentation and overall prognosis. This raises the issue of how to specifically target tumor cells involved in vascular invasion in order to optimize prognosis and overcome these mechanisms employed by the tumor cells.
... Moreover, several studies have shown that LDHA activity and lactate secretion promote invasion and metastasis (Goetze et al, 2011;Rizwan et al, 2013). Lactate has also been linked to in vitro migration of GB cells (Baumann et al, 2009;Colen et al, 2011;Seliger et al, 2013). LDHA has indeed been found at GB invasive borders of antiangiogenic-treated tumors (Fack et al, 2015). ...
Lactate is a central metabolite in brain physiology but also contributes to tumor development. Glioblastoma (GB) is the most common and malignant primary brain tumor in adults, recognized by angiogenic and invasive growth, in addition to its altered metabolism. We show herein that lactate fuels GB anaplerosis by replenishing the tricarboxylic acid (TCA) cycle in absence of glucose. Lactate dehydrogenases (LDHA and LDHB), which we found spatially expressed in GB tissues, catalyze the interconversion of pyruvate and lactate. However, ablation of both LDH isoforms, but not only one, led to a reduction in tumor growth and an increase in mouse survival. Comparative transcriptomics and metabolomics revealed metabolic rewiring involving high oxidative phosphorylation (OXPHOS) in the LDHA/B KO group which sensitized tumors to cranial irradiation, thus improving mouse survival. When mice were treated with the antiepileptic drug stiripentol, which targets LDH activity, tumor growth decreased. Our findings unveil the complex metabolic network in which both LDHA and LDHB are integrated and show that the combined inhibition of LDHA and LDHB strongly sensitizes GB to therapy.
... Phenolic acids can also be involved in the inhibition of MCT activity. Alpha-cyano-4-hydroxycinnamic acid, a derivative of cinnamic acid, is a competitive inhibitor of lactate transport and has been linked to the inhibition of MCT activity in several tumor models [403][404][405][406][407]. However, further studies are needed to better understand the mechanisms by which propolis affects glycolytic metabolism; in particular, if its effects are mediated by the inhibition of lactate transport via MCTs. ...
In recent years, interest in natural products such as alternative sources of pharmaceuticals for numerous chronic diseases, including tumors, has been renewed. Propolis, a natural product collected by honeybees, and polyphenolic/flavonoid propolis-related components modulate all steps of the cancer progression process. Anticancer activity of propolis and its compounds relies on various mechanisms: cell-cycle arrest and attenuation of cancer cells proliferation, reduction in the number of cancer stem cells, induction of apoptosis, modulation of oncogene signaling pathways, inhibition of matrix metalloproteinases, prevention of metastasis, anti-angiogenesis, anti-inflammatory effects accompanied by the modulation of the tumor microenvironment (by modifying macrophage activation and polarization), epigenetic regulation, antiviral and bactericidal activities, modulation of gut microbiota, and attenuation of chemotherapy-induced deleterious side effects. Ingredients from propolis also ”sensitize“ cancer cells to chemotherapeutic agents, likely by blocking the activation of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). In this review, we summarize the current knowledge related to the the effects of flavonoids and other polyphenolic compounds from propolis on tumor growth and metastasizing ability, and discuss possible molecular and cellular mechanisms involved in the modulation of inflammatory pathways and cellular processes that affect survival, proliferation, invasion, angiogenesis, and metastasis of the tumor.
