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Light microscopy (LM) and scanning electron microscopy (SEM) demonstrating changes in multiple myeloma cell morphology in the presence of 0, 50, and 100 μM 3‐bromopyruvate (3BP) after 2 hr of incubation (Niedźwiecka et al., 2016)
Source publication
3‐bromopyruvate (3BP) is a small, highly reactive molecule formed by bromination of pyruvate. In the year 2000 the antitumor properties of 3BP were discovered. Studies using animal models proved its high efficacy for anti‐cancer therapy with no apparent side effects. This was also found to be the case in a limited number of cancer patients treated...
Citations
... 9,10 The efficacy of 3BP in anticancer therapy has been demonstrated through animal models, exhibiting no apparent side effects. 11 Nevertheless, due to its alkylating properties, free 3BP is unstable and controversial when delivered systemically, which has impeded its clinical development and use as a drug for cancer treatment. 12 Thus, there is a clear need to develop a new 3BP formulation with systemic delivery capability. ...
Cell membrane-camouflaged nanoparticles possess inherent advantages derived from their membrane structure and surface antigens, including prolonged circulation in the bloodstream, specific cell recognition and targeting capabilities, and potential for immunotherapy. Herein, we introduce a cell membrane biomimetic nanodrug platform termed MPB-3BP@CM NPs. Comprising microporous Prussian blue nanoparticles (MPB NPs) serving as both a photothermal sensitizer and carrier for 3-bromopyruvate (3BP), these nanoparticles are cloaked in a genetically programmable cell membrane displaying variants of signal regulatory protein α (SIRPα) with enhanced affinity to CD47. As a result, MPB-3BP@CM NPs inherit the characteristics of the original cell membrane, exhibiting an extended circulation time in the bloodstream and effectively targeting CD47 on the cytomembrane of colorectal cancer (CRC) cells. Notably, blocking CD47 with MPB-3BP@CM NPs enhances the phagocytosis of CRC cells by macrophages. Additionally, 3BP, an inhibitor of hexokinase II (HK 2 ), suppresses glycolysis, leading to a reduction in adenosine triphosphate (ATP) levels and lactate production. Besides, it promotes the polarization of tumor-associated macrophages (TAMs) towards an anti-tumor M1 phenotype. Furthermore, integration with MPB NPs-mediated photothermal therapy (PTT) enhances the therapeutic efficacy against tumors. These advantages make MPB-3BP@CM NPs an attractive platform for the future development of innovative therapeutic approaches for CRC. Concurrently, it introduces a universal approach for engineering disease-tailored cell membranes for tumor therapy.
... For these cancer cells, the TCA cycle is used mainly to provide anaplerotic carbon necessary for major energy requirements and for building biomass in rapidly dividing cells. L-Glutamine is a major source of this anaplerotic carbon via its conversion to α-ketoglutarate, while, at the same time, the nitrogen is used for DNA synthesis (e.g., [102][103][104][105][106][107][108][109]). As noted above, this process is commonly referred to as "glutamine addiction". ...
Many cancers utilize l-glutamine as a major energy source. Often cited in the literature as “l-glutamine addiction”, this well-characterized pathway involves hydrolysis of l-glutamine by a glutaminase to l-glutamate, followed by oxidative deamination, or transamination, to α-ketoglutarate, which enters the tricarboxylic acid cycle. However, mammalian tissues/cancers possess a rarely mentioned, alternative pathway (the glutaminase II pathway): l-glutamine is transaminated to α-ketoglutaramate (KGM), followed by ω-amidase (ωA)-catalyzed hydrolysis of KGM to α-ketoglutarate. The name glutaminase II may be confused with the glutaminase 2 (GLS2) isozyme. Thus, we recently renamed the glutaminase II pathway the “glutamine transaminase—ω-amidase (GTωA)” pathway. Herein, we summarize the metabolic importance of the GTωA pathway, including its role in closing the methionine salvage pathway, and as a source of anaplerotic α-ketoglutarate. An advantage of the GTωA pathway is that there is no net change in redox status, permitting α-ketoglutarate production during hypoxia, diminishing cellular energy demands. We suggest that the ability to coordinate control of both pathways bestows a metabolic advantage to cancer cells. Finally, we discuss possible benefits of GTωA pathway inhibitors, not only as aids to studying the normal biological roles of the pathway but also as possible useful anticancer agents.
... Aerobic glycolysis, also known as the Warburg effect, has been widely documented as the main energy source in most cancer cells [36]. In this study, 3BP disrupted the energy supply by inhibiting glycolysis, which can affect a series of biological events, as ATP is required for numerous biological processes, such as DNA replication and transcription [37]. ATP levels of 4T1 cells after different treatments were measured quantitatively. ...
Background
Radiotherapy (RT) is one of the most mainstream cancer therapeutic modalities. However, due to the lack of specificity of the radiation adopted, both normal and cancerous cells are destroyed indiscriminately. This highlights the crucial need to improve radiosensitization. This study aims to address this issue by constructing a multifunctional nanospheres that can sensitize multiple aspects of radiotherapy.
Results
Nanospheres containing high atomic element Bi can effectively absorb ionizing radiation and can be used as radiosensitizers. Cell viability after Bi2S3 + X-ray treatment was half that of X-ray treatment alone. On the other hand, exposed 3-bromopyruvate (3BP) could reduce the overactive oxygen (O2) metabolism of tumor cells and alleviate tumor hypoxia, thereby promoting radiation-induced DNA damage. The combination index (CI) of 3BP and Bi2S3-based RT in Bi2S3-3BP + X-ray was determined to be 0.46 with the fraction affected (fa) was 0.5 via Chou-Talalay’s isobolographic method, which indicated synergistic effect of 3BP and Bi2S3-based RT after integration into Bi2S3-3BP + X-ray. Under the combined effect of 3BP and RT, autophagy was over-activated through starvation-induced and redox homeostasis dysregulation pathways, which in turn exhibited pro-death effects. In addition, the prepared nanospheres possess strong X-ray attenuation and high near-infrared (NIR) optical absorption, thus eliminating the need for additional functional components and could serve as bimodal contrast agents for computed tomography/photoacoustic (CT/PA) imaging.
Conclusions
The rational design of multifunctional nanospheres with the unique properties provided a novel strategy to achieving high therapeutic efficacy in RT. This was accomplished through simultaneous activation of multiple sensitization pathways by increasing ionizing radiation, reducing tumor oxygen consumption, inducing pro-death autophagy, and providing multiple-imaging guidance/monitoring.
... The clonogenic survival data have shown that 3-BP drug was quite effective in kill-that Panc-2 cells over express hexokinase II and its N-terminal domain interacts and binds with VDAC-1, an outer mitochondrial membrane protein and regulates glycolysis and ATP transport across mitochondrial membrane. Their interaction also suppresses apoptosis by interacting with BCL2L1 ( Figure 3) [26]. We observed that HK-II expression was almost completely abolished after treatment with 40 µM of 3-BP (Figure 2A), and there was no change in expression level of VDAC-1 protein (Figure 2A). ...
Pancreatic cancer (PC) is the fourth-most-deadly cancer in the United States with a 5-year survival rate of only 8%. The majority of patients with locally advanced pancreatic cancer undergo chemotherapy and/or radiation therapy (RT). However, current treatments are inadequate and novel strategies are desperately required. 3-Bromopyruvate (3-BP) is a promising anticancer drug against pancreatic cancer. It exerts potent anticancer effects by inhibiting hexokinase II enzyme (HK2) of the glycolytic pathway in cancer cells while not affecting the normal cells. 3-BP killed 95% of Panc-2 cells at 15 μM concentration and severely inhibited ATP production by disrupting the interaction between HK2 and mitochondrial Voltage Dependent Anion Channel-1 (VDAC1) protein. Electron mi-croscopy data revealed that 3-BP severely damaged mitochondrial membrane in cancer cells. We further examined therapeutic effect of 3-BP in syngeneic mouse pancreatic cancer model by treating animals with 10, 15 and 20 mg/kg dose. 3-BP at 15 & 20 mg/kg dose level significantly reduced tumor growth by approximately 75-80% in C57BL/6 female mice. Immunohistochemistry data showed complete inhibition of hexokinase II (HK2) and TGFβ, in animals treated with 3-BP drug. We also observed enhanced expression of active caspase-3 in tumor tissues exhibited apoptotic death. Flow Cytometry analysis showed significant inhibition in MDSC (CD11b) population in treated tumor which may have allowed infiltration of CD8+ T cells and inhibited tumor growth. Notably, metabolomic data also revealed severe inhibition in glycolysis, NADP, ATP and lactic acid production in cancer cells treated with 40 μM 3-BP. Importantly, we also observed inhibition in lactic acid production responsible for tumor aggression. These results provide new evidence that 3-BP severely inhibit glucose metabolism in cancer cells by blocking hexo-kinase II, and disrupting mitochondria by suppressing BCL2L1 in pancreatic cancer.
... In contrast to traditional or standard pharmacological cancer treatment methods, novel approaches such as combined therapy are highly requested. An effective and promising anti-cancer drug against many different types of tumor cells is 3-bromopyruvate (3BP) [1]. Recent studies have revealed that 3BP's anticancer activity may be mediated by several molecular mechanisms including reduction of global protein synthesis [2,3], histone deacetylases activity [4], endoplasmic reticulum and oxidative stress [2,5], induction of apoptosis or necroptosis [6], upregulation of gene expression of some pro-apoptotic proteins [7] as well as modulation of autophagy and cardiolipin degradation [8]. ...
Cancer is one of the leading causes of death in the modern world. Nowadays, most often treatment methods used in clinical oncology are drug therapies applied as monotherapy or combined therapy. Additionally, recent studies focus on developing approaches with the use of a drug in combination with other factors, not only chemical, to improve the probability and magnitude of therapeutic responses and reduce the possibility of chemoresistance. Such a promising factor seems to be an electromagnetic field (EMF) application. Here, we tested the effect of continuous or pulsed EMF on human cancer cells of different origin treated or not with 3-bromopyruvate, a small and powerful alkylating agent with a broad spectrum of anticancer activities. We provide strong evidence suggesting that ELF-EMF potentiates the anti-cancer activity of 3BP in human cancer cells through inhibition of TNFα secretion leading to irreversible p21/p27-dependent G2/M cell cycle arrest and finally cancer cell death. Our findings suggest a novel approach combining pharmacotherapy with ELF-EMF. In conclusion, electromagnetic field seems to be a potential modulator of anti-cancer efficacy of 3BP while combined therapy offers off-target activity. These features contribute to the development of innovative therapeutic strategies for cancer treatment.
... Regarding the anti-proliferative effect observed here, it indicates that L. amazonensis can internalize 3-BrPA, which could be active intracellularly. Indeed, it has been shown that the sensitivity of cells to 3-BrPA depends not only on the rate of 3-BrPA uptake but also on the activity/expression level of glycolytic and/or mitochondrial oxidative phosphorylation enzymes (such as hexokinase, GAPDH and, succinate dehydrogenase, among others), as well as the pH of the microenvironment (Fan et al., 2019;Ko et al., 2019). At neutral pH or in alkaline condition, 3-BrPA is converted to 3-bromoxypyruvate, followed by a decrease in its half-life, which contributes to minimal toxicity for normal tissues. ...
... Despite extensive studies of the effects of 3-BrPA on different tumor cells (Ko et al., 2019), there is no record in the scientific literature about the effect of 3-BrPA on L. amazonensis species. Since glycolysis is a central pathway in carbon metabolism and accounts for part of the ATP produced in Leishmania parasites, compounds able to inhibit glycolytic enzymes have the potential to act as effective anti-Leishmania agents. ...
The compound 3-bromopyruvate (3-BrPA) is well-known and studies from several researchers have demonstrated its involvement in tumorigenesis. It is an analogue of pyruvic acid that inhibits ATP synthesis by inhibiting enzymes from the glycolytic pathway and oxidative phosphorylation. In this work, we investigated the effect of 3-BrPA on energy metabolism of L. amazonensis. In order to verify the effect of 3-BrPA on L. amazonensis glycolysis, we measured the activity level of three glycolytic enzymes located at different points of the pathway: (i) glucose kinases, step 1, (ii) glyceraldehyde 3-phosphate dehydrogenase (GAPDH), step 6, and (iii) enolase, step 9. 3-BrPA, in a dose-dependent manner, significantly reduced the activity levels of all the enzymes. In addition, 3-BrPA treatment led to a reduction in the levels of phosphofruto-1-kinase (PFK) protein, suggesting that the mode of action of 3-BrPA involves the downregulation of some glycolytic enzymes. Measurement of ATP levels in promastigotes of L. amazonensis showed a significant reduction in ATP generation. The O2 consumption was also significantly inhibited in promastigotes, confirming the energy depletion effect of 3-BrPA. When 3-BrPA was added to the cells at the beginning of growth cycle, it significantly inhibited L. amazonensis proliferation in a dose-dependent manner. Furthermore, the ability to infect macrophages was reduced by approximately 50% when promastigotes were treated with 3-BrPA. Taken together, these studies corroborate with previous reports which suggest 3-BrPA as a potential drug against pathogenic microorganisms that are reliant on glucose catabolism for ATP supply.
... Full understanding of the mechanisms of potential drugs is extremely important in the conduct of therapy. 3-BP is a compound with the potential to be an effective anticancer drug that has already been characterized in many aspects ( Figure 8) [1,2,42,43]. It is known from previous studies that 3-BP affected several glycolytic and mitochondrial enzymes in the cell and shows strong activity against many cancers [4,[7][8][9]42]. ...
3-bromopuryvate (3-BP) is a compound with unique antitumor activity. It has a selective action against tumor cells that exhibit the Warburg effect. It has been proven that the action of 3-BP is pleiotropic: it acts on proteins, glycolytic enzymes, reduces the amount of ATP, induces the formation of ROS (reactive oxygen species), and induces nuclear DNA damage. Mitochondria are important organelles for the proper functioning of the cell. The production of cellular energy (ATP), the proper functioning of the respiratory chain, or participation in the production of amino acids are one of the many functions of mitochondria. Here, for the first time, we show on the yeast model that 3-BP acts in the eukaryotic cell also by influence on mitochondria and that agents inhibiting mitochondrial function can potentially be used in cancer therapy with 3-BP. We show that cells with functional mitochondria are more resistant to 3-BP than rho0 cells. Using an MTT assay (a colorimetric assay for assessing cell metabolic activity), we demonstrated that 3-BP decreased mitochondrial activity in yeast in a dose-dependent manner. 3-BP induces mitochondrial-dependent ROS generation which results in ∆sod2, ∆por1, or ∆gpx1 mutant sensitivity to 3-BP. Probably due to ROS mtDNA lesions rise during 3-BP treatment. Our findings may have a significant impact on the therapy with 3-BP.
... In addition, 3-BrPA 1 inhibited the glycolytic rate by directly inhibiting hexokinase in the liver model of rabbit VX2 tumors. The toxic and side effects of 3-BrPA 1 are dosedependent: low doses of 3-BrPA 1 can effectively kill tumor cells and the tumor-bearing animal models have rarely obvious systemic toxicity, while high doses of 3-BrPA 1 are strong toxicity to the liver and gastrointestinal system [48][49][50]. In the other hand, 3-BrPA 1 is also an alkylating agent, its cytotoxic action may be induced by other molecular mechanisms [51]. ...
Tumor cells mainly provide necessary energy and substances for rapid cell growth through aerobic perglycolysis rather than oxidative phosphorylation. This phenomenon is called the “Warburg effect”. The mechanism of glycolysis in tumor cells is more complicated, which is caused by the comprehensive regulation of multiple factors. Abnormal enzyme metabolism is one of the main influencing factors and inhibiting the three main rate-limiting enzymes in glycolysis is thought to be important strategies for cancer treatment. Therefore, numerous inhibitors of glycolysis rate-limiting enzyme have been developed in recent years, such as the latest HKII inhibitor and PKM2 inhibitor Pachymic acid (PA) and N-(4-(3-(3-(methylamino)-3-oxopropyl)-5-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-1-yl)phenyl)propiolamide. The review focuses on source, structure-activity relationship, bioecological activity and mechanism of the three main rate-limiting enzymes inhibitors, and hopes to guide the future research on the design and synthesis of rate-limiting enzyme inhibitors.
... 3-BP is a small reactive molecule formed by bromination of pyruvate, which is one of the widely studied compounds due to its antitumor properties (5). A glycolysis inhibitor, 3-BP can inhibit cancer cell proliferation through energy metabolism interruption (6), primarily through inhibition of the glycolytic enzymes and those related with mitochondrial function, including hexokinase II (HK II) (7), pyruvate dehydrogenase (PDH) (6), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), lactate dehydrogenase (LDH), and by altering adenosine triphosphate (ATP) levels (8). ...
Up to 30% of breast cancer mortality is caused by cancer relapse despite primary clinical treatments due to distant metastases. Further research focusing on breast cancer mechanisms are needed for deeper understanding of disease prognosis. 3-bromopyruvate (3-BP), a glycolysis inhibitor, has been studied as one of the antitumor agents in recent years. In this report, we want to investigate the form of cell death induced by 3-BP and demonstrate the inhibitory effect of 3-BP on breast cancer cell proliferation and its mechanism in vivo and in vitro. We found that 3-BP could inhibit MDA-MB-231 and MCF-7 breast cancer cell proliferation, through energy metabolism inhibition. Further, necroptosis characters in MDA-MB-231 cells after 3-BP treatment were observed, which could be negatively regulated through Ppm1b by dephosphorylation of RIP3. In addition, 3-BP treatment in an MDA-MB-231 cell-transplanted mouse model showed a significant antitumor effect, which correlated with necroptosis-related protein Ppm1b. The findings demonstrate the potential for 3-BP in the treatment of breast cancer, providing impetus for further clinical studies.
... Although enhanced glycolysis is the main metabolic feature of cancer cells and the target of antiglycolytics, other targets related to energy metabolism may be considered in the approaches oriented to remodel metabolic pathways, such as the modulation of mitochondrial activities aimed to contrast drug resistance. The antiglycolytic 3-bromopyruvate (3BP) is a reactive non-specific drug that can act as a metabolic modifier by interfering with glycolysis and oxidative phosphorylation in cancer cells (Shoshan, 2012;Lis et al., 2016;Ko et al., 2019;Azevedo--Silva et al., 2016;Fan et al., 2019). The mitochondrial hexokinase-II is the main target since its activity is specifically blocked by the formation of a pyruvinyl adduct after reacting with 3BP at the surface of the outer mitochondrial membrane (Mathupala et al., 2009;Galina, 2014). ...
Metabolic reprogramming of tumour cells sustains cancer progression. Similar to other cancer cells, glioblastoma cells exhibit an increased glycolytic flow, which encourages the use of antiglycolytics as an effective complementary therapy. We used the antiglycolytic 3-bromopyruvate (3BP) as a metabolic modifier to treat U118 glioblastoma cells and investigated the toxic effects and the conditions to increase drug effectiveness at the lowest concentration. Cellular vitality was not affected by 3BP concentrations lower than 40 μM, although p-Akt dephosphorylation, p53 degradation, and ATP reduction occurred already at 30 μM 3BP. ROS generated in mitochondria were enhanced at 30 μM 3BP, possibly by unbalancing their generation and their disposal because of glutathione peroxidase inhibition. ROS triggered JNK and ERK phosphorylation, and cyt c release outside mitochondria, not accompanied by caspases-9 and -3 activation, probably due to 3BP-dependent alkylation of cysteine residues at caspase-9 catalytic site. To explore the possibility of sensitizing cells to 3BP treatment, we exploited 3BP effects on mitochondria by using 30 μM 3BP in association with antimycin A or menadione concentrations that in themselves exhibit poor toxicity. 3BP effect on cyt c release and cell vitality loss was potentiated due the greater oxidative stress induced by antimycin or menadione association with 3BP, supporting a preeminent role of mitochondrial ROS in 3BP toxicity. Indeed, the scavenger of mitochondrial superoxide MitoTEMPO counteracted 3BP-induced cyt c release and weakened the potentiating effect of 3BP/antimycin association. In conclusion, the biochemical mechanisms leading U118 glioblastoma cells to viability loss following 3BP treatment rely on mitochondrial ROS-dependent pathways. Their potentiation at low 3BP concentrations is consistent with the goal to minimize the toxic effect of the drug towards non-cancer cells.
