1.Cancer cell metabolism: implications for therapeutic targets.
Miran JANG ; Sung Soo KIM ; Jinhwa LEE
Experimental & Molecular Medicine 2013;45(10):e45-
Cancer cell metabolism is characterized by an enhanced uptake and utilization of glucose, a phenomenon known as the Warburg effect. The persistent activation of aerobic glycolysis in cancer cells can be linked to activation of oncogenes or loss of tumor suppressors, thereby fundamentally advancing cancer progression. In this respect, inhibition of glycolytic capacity may contribute to an anticancer effect on malignant cells. Understanding the mechanisms of aerobic glycolysis may present a new basis for cancer treatment. Accordingly, interrupting lactate fermentation and/or other cancer-promoting metabolic sites may provide a promising strategy to halt tumor development. In this review, we will discuss dysregulated and reprogrammed cancer metabolism followed by clinical relevance of the metabolic enzymes, such as hexokinase, phosphofructokinase, pyruvate kinase M2, lactate dehydrogenase, pyruvate dehydrogenase kinase and glutaminase. The proper intervention of these metabolic sites may provide a therapeutic advantage that can help overcome resistance to chemotherapy or radiotherapy.
Animals
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Antineoplastic Agents/*pharmacology/therapeutic use
;
Carcinogenesis/drug effects/metabolism
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Glycolysis/*drug effects
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Humans
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Neoplasms/drug therapy/*metabolism
2.Effect of 3-bromopyruvate on mitochondrial membrane potential and apoptosis of human breast carcinoma SK-BR-3 cells.
Yuanyuan ZHANG ; Zhe LIU ; Qianwen ZHANG ; Zhenhua CHAO ; Pei ZHANG ; Fei XIA ; Chenchen JIANG ; Hao LIU ; Zhiwen JIANG
Journal of Southern Medical University 2013;33(9):1304-1307
OBJECTIVETo study the effect of glycolysis inhibitor 3-bromopyruvate (3-BrPA) in inducing apoptosis of human breast carcinoma cells SK-BR-3 and the possible mechanism.
METHODSMTT assay was used to detect the growth inhibition induced by 3-BrPA in breast cancer cells SK-BR-3. The apoptotic cells were detected by flow cytometry with propidium iodide (PI). ATP levels in the cells were detected by ATP assay kit, and DHE fluorescent probe technique was used to determine superoxide anion levels; the mitochondrial membrane potential was assessed using JC-1 staining assay.
RESULTSMTT assay showed that the proliferation of SK-BR-3 cells was inhibited by 3-BrPA in a time- and concentration-dependent manner. Exposure to 80, 160, and 320 µmol·L(-1) 3-BrPA for 24 h resulted in cell apoptosis rates of 6.7%, 22.3%, and 79.6%, respectively, and the intracellular ATP levels of SK-BR-3 cells treated with 80, 160, 320 µmol·L(-1) 3-BrPA for 5 h were 87.7%, 60.6%, and 23.7% of the control levels. 3-BrPA at 160 µmol·L(-1) increased reactive oxygen levels and lowered mitochondrial membrane potential of SK-BR-3 cells.
CONCLUSION3-BrPA can inhibit cell proliferation, reduce the mitochondrial membrane potential and induce apoptosis in SK-BR-3 cells, the mechanism of which may involve a reduced ATP level by inhibiting glycolysis and increasing the reactive oxygen level in the cells.
Apoptosis ; drug effects ; Cell Line, Tumor ; Female ; Glycolysis ; Humans ; Membrane Potential, Mitochondrial ; drug effects ; Pyruvates ; pharmacology ; Reactive Oxygen Species ; metabolism
3.High dose vitamin C inhibits proliferation of breast cancer cells through reducing glycolysis and protein synthesis.
Qingmei WANG ; Qianzi XU ; Anyi WEI ; Shishuo CHEN ; Chong ZHANG ; Linghui ZENG
Journal of Zhejiang University. Medical sciences 2019;48(3):296-302
OBJECTIVE:
To investigate the effects of high dose vitamin C (VC) on proliferation of breast cancer cells and to explore its mechanisms.
METHODS:
Human breast cancer cells Bcap37 and MDA-MB-453 were treated with VC at low dose (0.01 mmol/L), medium dose (0.10 mmol/L) and high dose (2.00 mmol/L). Cell proliferation was determined with CCK-8 assay, protein expression was evaluated by Western blot, and the secretion of lactic acid in tumor cells was detected by colorimetric method. Bcap37 cells were inoculated in nude mice, and tumor baring nude mice were intraperitoneally injected with high VC(4 g/kg, VC group, =5)or normal saline (control group, =5) for 24 d. Tumor weight and body weight were calculated.
RESULTS:
experiments demonstrated that high dose VC significantly inhibited cell proliferation in Bcap37 and MDA-MB-453 cells (all <0.01); the expressions of Glut1 and mTOR signaling pathway-related proteins were decreased (all <0.05); and the secretion of lactic acid was also markedly reduced (all <0.05). experiment showed that the tumor weight was decreased in mice treated with high-dose VC as compared with control group (<0.05), but no difference in body weights between two groups was observed.
CONCLUSIONS
High dose VC may inhibit proliferation of breast cancer cells both and through reducing glycolysis and protein synthesis.
Animals
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Ascorbic Acid
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pharmacology
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Breast Neoplasms
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drug therapy
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Cell Line, Tumor
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Cell Proliferation
;
drug effects
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Glycolysis
;
drug effects
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Humans
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Mice
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Mice, Nude
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Protein Biosynthesis
;
drug effects
4.Effectiveness of Sodium Fluoride as a Glycolysis Inhibitor on Blood Glucose Measurement: Comparison of Blood Glucose using Specimens from the Korea National Health and Nutrition Examination Survey.
Yong Wha LEE ; Young Joo CHA ; Seok Lae CHAE ; Junghan SONG ; Yeo Min YUN ; Hae Il PARK ; Moon Woo SEONG ; Dong Hee WHANG ; Hyun Soo KIM ; Jeong Ho KIM ; Bong Suk LEE ; Yoo Sung HWANG
The Korean Journal of Laboratory Medicine 2009;29(6):524-528
BACKGROUND: Accurate measurement of blood glucose concentrations is essential for defining diabetes, and the minimization of ex vivo glycolysis has been recommended. Recent guidelines advocate two kinds of methods for sample collection and processing: either the sodium fluoride (NaF) method or immediate refrigeration using a serum separation tube (SST). We investigated the difference between the two methods in measuring subsequent glucose concentrations using blood specimens from participants recruited for the fourth Korean National Health and Nutrition Examination Survey. METHODS: Paired venous blood samples were collected in an SST and a NaF tube from 1,103 men and women. SST serum was separated within 30 min, including standing for 15 min, and then refrigerated. The NaF samples were refrigerated, but not separated until immediately before analysis. We compared the blood glucose concentrations between the SST (SST glucose) and NaF (NaF glucose) methods. RESULTS: The mean SST glucose was significantly higher than NaF glucose (99.0 mg/dL vs 96.5 mg/dL, P<0.05). NaF glucose showed a negative mean bias of 2.6 mg/dL vs SST glucose but showed high correlation (R=0.9899). There was no significant correlation between the bias of blood glucose concentrations by two methods and the storage time of NaF glucose. CONCLUSIONS: The negative bias associated with the use of NaF tubes may significantly affect the prevalence of diabetes. Serum separation and refrigeration within 30 min after venous sampling is recommended over NaF method, not only to minimize the preanalytical impact on detecting diabetes but also to reduce sample volume and number of tubes.
Blood Glucose/*analysis
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Blood Specimen Collection/*methods
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Diabetes Mellitus/diagnosis
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Female
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Glycolysis/*drug effects
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Humans
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Male
;
Nutrition Surveys
;
Republic of Korea
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Sodium Fluoride/*pharmacology
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Specimen Handling
5.Influences of trans-trans farnesol, a membrane-targeting sesquiterpenoid, on Streptococcus mutans physiology and survival within mixed-species oral biofilms.
Jae-Gyu JEON ; Santosh PANDIT ; Jin XIAO ; Stacy GREGOIRE ; Megan L FALSETTA ; Marlise I KLEIN ; Hyun KOO
International Journal of Oral Science 2011;3(2):98-106
Trans-trans farnesol (tt-farnesol) is a bioactive sesquiterpene alcohol commonly found in propolis (a beehive product) and citrus fruits, which disrupts the ability of Streptococcus mutans (S. mutans) to form virulent biofilms. In this study, we investigated whether tt-farnesol affects cell-membrane function, acid production and/or acid tolerance by planktonic cells and biofilms of S. mutans UA159. Furthermore, the influence of the agent on S. mutans gene expression and ability to form biofilms in the presence of other oral bacteria (Streptococcus oralis (S. oralis) 35037 and Actinomyces naeslundii (A. naeslundii) 12104) was also examined. In general, tt-farnesol (1 mmol x L(-1)) significantly increased the membrane proton permeability and reduced glycolytic activity of S. mutans in the planktonic state and in biofilms (P < 0.05). Moreover, topical applications of 1 mmol x L(-1) tt-farnesol twice daily (1 min exposure/treatment) reduced biomass accumulation and prevented ecological shifts towards S. mutans dominance within mixed-species biofilms after introduction of 1% sucrose. S. oralis (a non-cariogenic organism) became the major species after treatments with tt-farnesol, whereas vehicle-treated biofilms contained mostly S. mutans (>90% of total bacterial population). However, the agent did not affect significantly the expression of S. mutans genes involved in acidogenicity, acid tolerance or polysaccharide synthesis in the treated biofilms. Our data indicate that tt-farnesol may affect the competitiveness of S. mutans in a mixed-species environment by primarily disrupting the membrane function and physiology of this bacterium. This naturally occurring terpenoid could be a potentially useful adjunctive agent to the current anti-biofilm/anti-caries chemotherapeutic strategies.
Actinomyces
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physiology
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Biofilms
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drug effects
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Cell Membrane Permeability
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drug effects
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Colony Count, Microbial
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Durapatite
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Farnesol
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pharmacology
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Gene Expression Regulation, Bacterial
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drug effects
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Glycolysis
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Humans
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Hydrogen-Ion Concentration
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Microbial Viability
;
drug effects
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Plankton
;
drug effects
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Saliva
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microbiology
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Streptococcus mutans
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drug effects
;
genetics
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physiology
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Streptococcus oralis
;
physiology
6.The influence of microtubule intervention drugs on glycolytic key enzymes in myocardial cells after hypoxia.
Miao TENG ; Yue-Sheng HUANG ; Yong-Ming DANG ; Ya-Dong FANG ; Qiong ZHANG
Chinese Journal of Burns 2008;24(2):102-106
OBJECTIVETo investigate the influence of microtubule intervention drugs on glycolytic key enzymes in myocardial cells after hypoxia.
METHODSThe primary passage of cultured myocardial cells from neonatal rats were divided into A group (with hypoxia), B group (with hypoxia and administration of l0 micromol/L colchicine), C group (with hypoxia and administration of 5 micromol/L taxol), D group (with hypoxia and administration of 10 micromol/L taxol), E group (with hypoxia and administration of 15 micromol/L taxol). The morphology of microtubule was observed with laser scanning microscope (LSM). The cell vitality was assayed by cell counting kit (CCK). The activities of hexokinase (HK), pyruvate kinase (PK), phosphofructokinase (PFK) and lactate dehydrogenase (LDH) were assayed with colorimetry.
RESULTSIn group B and E, the microtubule structure was damaged heavily, and the cell vitality was decreased significantly [The cell vitality was (89.99 +/- 3.47)% in B group and (84.56 +/- 6.61)% in E group, respectively, at 1.0 post hypoxia hour (PHH), and hoth values were obviously lower than that in A group (97.44 +/- 1.76)%, P < 0.01]. The HK, PK and PFK activities decreased obviously. The activities of HK, PK and PFK in group C were similar to those of the A group. Compared with that in other groups, the degree of damage of microtubule structure in D group was milden. The activities of HK, PK and PFK in D group during 0.5 - 6.0 PHH were significantly higher than those in A group. The activity of LDH in each group was increased after hypoxia.
CONCLUSIONProper concentration of microtubule-stabilizing drugs can alleviate the damages to microtubule structure, and enhance the activity of glycolytic key enzymes of myocardial cells at early stage of hypoxia.
Animals ; Cell Hypoxia ; Cells, Cultured ; Glycolysis ; drug effects ; Hexokinase ; metabolism ; L-Lactate Dehydrogenase ; metabolism ; Microtubules ; drug effects ; metabolism ; Myocytes, Cardiac ; enzymology ; metabolism ; Phosphofructokinase-1 ; metabolism ; Pyruvate Kinase ; metabolism ; Rats ; Rats, Sprague-Dawley
7.Metabolic alterations in cancer cells and therapeutic implications.
Naima HAMMOUDI ; Kausar Begam Riaz AHMED ; Celia GARCIA-PRIETO ; Peng HUANG
Chinese Journal of Cancer 2011;30(8):508-525
Cancer metabolism has emerged as an important area of research in recent years. Elucidation of the metabolic differences between cancer and normal cells and the underlying mechanisms will not only advance our understanding of fundamental cancer cell biology but also provide an important basis for the development of new therapeutic strategies and novel compounds to selectively eliminate cancer cells by targeting their unique metabolism. This article reviews several important metabolic alterations in cancer cells, with an emphasis on increased aerobic glycolysis (the Warburg effect) and glutamine addiction, and discusses the mechanisms that may contribute to such metabolic changes. In addition, metabolic alterations in cancer stem cells, mitochondrial metabolism and its influence on drug sensitivity, and potential therapeutic strategies and agents that target cancer metabolism are also discussed.
Antineoplastic Agents
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therapeutic use
;
Drug Resistance, Neoplasm
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Genes, Tumor Suppressor
;
physiology
;
Glutamine
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metabolism
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Glycolysis
;
drug effects
;
physiology
;
Humans
;
Mitochondria
;
genetics
;
metabolism
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Mutation
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Neoplasms
;
drug therapy
;
metabolism
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pathology
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Neoplastic Stem Cells
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metabolism
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Oncogenes
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physiology
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Oxidative Phosphorylation
8.miR-181c inhibits glycolysis by targeting hexokinase 2 in cancer-associated fibroblasts.
Haibing LAN ; Liang LUO ; Xiefei QI ; Yuanqi GONG ; Yu CHEN
Journal of Southern Medical University 2015;35(11):1619-1623
OBJECTIVETo investigate the role of miR-181c in glycolysis of cancer-associated fibroblasts (CAFs) and explore the mechanism.
METHODSHuman lung CAFs and normal fibroblasts (NFs), isolated from fresh human lung adenocarcinoma tissue specimens by primary culture of tissue explants, were transfected with a miR -181c mimics, a miR-181c inhibitor, a siRNA siRNA-HK2 or the vector HK2-vector via Lipofectamine(TM) 2000. Quantitative real-time PCR was used to analyze the changes in miR-125b expression in the transfected cells; hexokinase-2 (HK2) protein expression in the cells was detected using Western blotting, and the cellular glucose uptake was assessed with 2-NBDG. Lactate production in the cells was examined and expression of HK2 mRNA was detected with dual luciferase reporter gene assay.
RESULTSNo obvious difference was found in the cell morphology between CAFs and NFs. Compared with the NFs, the CAFs showed obviously increased glucose uptake, lactate production and HK2 protein expression with decreased expressions of the miR-181 family (P<0.05). Transfection with the miR-181 inhibito- rsignificantly increased glucose uptake, lactate production and HK2 protein expression in the NFs. In CAFs, transfection with the miR-181 mimics caused significantly lowered glucose uptake, lactate production and HK2 protein expression of. Knockdown of endogenous HK2 by siRNA abolished miR-181 mimics-mediated decrease of glucose uptake and lactate production in CAFs, while transfection with miR-181 mimics suppressed HK2 overexpression-induced enhancement of glucose uptake and lactate production in NFs.
CONCLUSIONTransfection with miR-181 mimics can suppress glycolysis in CAFs by inhibiting HK2 expression.
4-Chloro-7-nitrobenzofurazan ; analogs & derivatives ; Adenocarcinoma ; pathology ; Deoxyglucose ; analogs & derivatives ; Fibroblasts ; drug effects ; Glycolysis ; Hexokinase ; antagonists & inhibitors ; Humans ; Lung Neoplasms ; pathology ; MicroRNAs ; pharmacology ; RNA, Messenger ; RNA, Small Interfering ; Real-Time Polymerase Chain Reaction ; Transfection ; Tumor Cells, Cultured
9.Aerobic glycolysis in colon cancer is repressed by naringin via the HIF1Α pathway.
Guangtao PAN ; Ping ZHANG ; Aiying CHEN ; Yu DENG ; Zhen ZHANG ; Han LU ; Aoxun ZHU ; Cong ZHOU ; Yanran WU ; Sen LI
Journal of Zhejiang University. Science. B 2023;24(3):221-231
Metabolic reprogramming is a common phenomenon in cancer, with aerobic glycolysis being one of its important characteristics. Hypoxia-inducible factor-1α (HIF1Α) is thought to play an important role in aerobic glycolysis. Meanwhile, naringin is a natural flavanone glycoside derived from grapefruits and many other citrus fruits. In this work, we identified glycolytic genes related to HIF1Α by analyzing the colon cancer database. The analysis of extracellular acidification rate and cell function verified the regulatory effects of HIF1Α overexpression on glycolysis, and the proliferation and migration of colon cancer cells. Moreover, naringin was used as an inhibitor of colon cancer cells to illustrate its effect on HIF1Α function. The results showed that the HIF1Α and enolase 2 (ENO2) levels in colon cancer tissues were highly correlated, and their high expression indicated a poor prognosis for colon cancer patients. Mechanistically, HIF1Α directly binds to the DNA promoter region and upregulates the transcription of ENO2; ectopic expression of ENO2 increased aerobic glycolysis in colon cancer cells. Most importantly, we found that the appropriate concentration of naringin inhibited the transcriptional activity of HIF1Α, which in turn decreased aerobic glycolysis in colon cancer cells. Generally, naringin reduces glycolysis in colon cancer cells by reducing the transcriptional activity of HIF1Α and the proliferation and invasion of colon cancer cells. This study helps to elucidate the relationship between colon cancer progression and glucose metabolism, and demonstrates the efficacy of naringin in the treatment of colon cancer.
Glycolysis
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Colonic Neoplasms/metabolism*
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit/metabolism*
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Phosphopyruvate Hydratase/metabolism*
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Flavanones/pharmacology*
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Cell Line, Tumor
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Databases, Genetic
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Cell Proliferation/drug effects*
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Transfection
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Warburg Effect, Oncologic
10.Safety and outcome of treatment of metastatic melanoma using 3-bromopyruvate: a concise literature review and case study.
Salah Mohamed El SAYED ; Walaa Gamal MOHAMED ; Minnat-Allah Hassan SEDDIK ; Al-Shimaa Ahmed AHMED ; Asmaa Gamal MAHMOUD ; Wael Hassan AMER ; Manal Mohamed Helmy NABO ; Ahmed Roshdi HAMED ; Nagwa Sayed AHMED ; Ali Abdel-Rahman ABD-ALLAH
Chinese Journal of Cancer 2014;33(7):356-364
3-Bromopyruvate (3BP) is a new, promising anticancer alkylating agent with several notable functions. In addition to inhibiting key glycolysis enzymes including hexokinase II and lactate dehydrogenase (LDH), 3BP also selectively inhibits mitochondrial oxidative phosphorylation, angiogenesis, and energy production in cancer cells. Moreover, 3BP induces hydrogen peroxide generation in cancer cells (oxidative stress effect) and competes with the LDH substrates pyruvate and lactate. There is only one published human clinical study showing that 3BP was effective in treating fibrolamellar hepatocellular carcinoma. LDH is a good measure for tumor evaluation and predicts the outcome of treatment better than the presence of a residual tumor mass. According to the Warburg effect, LDH is responsible for lactate synthesis, which facilitates cancer cell survival, progression, aggressiveness, metastasis, and angiogenesis. Lactate produced through LDH activity fuels aerobic cell populations inside tumors via metabolic symbiosis. In melanoma, the most deadly skin cancer, 3BP induced necrotic cell death in sensitive cells, whereas high glutathione (GSH) content made other melanoma cells resistant to 3BP. Concurrent use of a GSH depletor with 3BP killed resistant melanoma cells. Survival of melanoma patients was inversely associated with high serum LDH levels, which was reported to be highly predictive of melanoma treatment in randomized clinical trials. Here, we report a 28-year-old man presented with stage IV metastatic melanoma affecting the back, left pleura, and lung. The disease caused total destruction of the left lung and a high serum LDH level (4,283 U/L). After ethics committee approval and written patient consent, the patient received 3BP intravenous infusions (1-2.2 mg/kg), but the anticancer effect was minimal as indicated by a high serum LDH level. This may have been due to high tumor GSH content. On combining oral paracetamol, which depletes tumor GSH, with 3BP treatment, serum LDH level dropped maximally. Although a slow intravenous infusion of 3BP appeared to have minimal cytotoxicity, its anticancer efficacy via this delivery method was low. This was possibly due to high tumor GSH content, which was increased after concurrent use of the GSH depletor paracetamol. If the anticancer effectiveness of 3BP is less than expected, the combination with paracetamol may be needed to sensitize cancer cells to 3BP-induced effects.
Acetaminophen
;
therapeutic use
;
Adult
;
Carcinoma, Hepatocellular
;
Disease Progression
;
Drug Therapy, Combination
;
Enzyme Inhibitors
;
Glutathione
;
Glycolysis
;
Hexokinase
;
Humans
;
L-Lactate Dehydrogenase
;
Lactic Acid
;
Lung Neoplasms
;
secondary
;
Male
;
Melanoma
;
drug therapy
;
Necrosis
;
Neovascularization, Pathologic
;
Pleural Neoplasms
;
secondary
;
Prognosis
;
Pyruvates
;
adverse effects
;
therapeutic use
;
Treatment Outcome