3-bromopyruvate

[Rich66]

Curr Pharm Biotechnol. 2010 Aug;11(5):510-7.
3-bromopyruvate: a new targeted antiglycolytic agent and a promise for cancer therapy.

Ganapathy-Kanniappan S, Vali M, Kunjithapatham R, Buijs M, Syed LH, Rao PP, Ota S, Kwak BK, Loffroy R, Geschwind JF.

LINK

Source

Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Abstract

The pyruvate analog, 3-bromopyruvate, is an alkylating agent and a potent inhibitor of glycolysis. This antiglycolytic property of 3-bromopyruvate has recently been exploited to target cancer cells, as most tumors depend on glycolysis for their energy requirements. The anticancer effect of 3-bromopyruvate is achieved by depleting intracellular energy (ATP) resulting in tumor cell death. In this review, we will discuss the principal mechanism of action and primary targets of 3-bromopyruvate, and report the impressive antitumor effects of 3-bromopyruvate in multiple animal tumor models. We describe that the primary mechanism of 3-bromopyruvate is via preferential alkylation of GAPDH and that 3-bromopyruvate mediated cell death is linked to generation of free radicals. Research in our laboratory also revealed that 3-bromopyruvate induces endoplasmic reticulum stress, inhibits global protein synthesis further contributing to cancer cell death. Therefore, these and other studies reveal the tremendous potential of 3-bromopyruvate as an anticancer agent.

PMID:

20420565

[PubMed - indexed for MEDLINE]

J Bioenerg Biomembr. 2007 Feb;39(1):1-12.
The cancer cell's "power plants" as promising therapeutic targets: an overview.

Pedersen PL.
Source

Department of Biological Chemistry, Johns Hopkins University, School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205-2185, USA. ppederse@jhmi.edu


LINK


Abstract

This introductory article to the review series entitled "The Cancer Cell's Power Plants as Promising Therapeutic Targets" is written while more than 20 million people suffer from cancer. It summarizes strategies to destroy or prevent cancers by targeting their energy production factories, i.e., "power plants." All nucleated animal/human cells have two types of power plants, i.e., systems that make the "high energy" compound ATP from ADP and P( i ). One type is "glycolysis," the other the "mitochondria." In contrast to most normal cells where the mitochondria are the major ATP producers (>90%) in fueling growth, human cancers detected via Positron Emission Tomography (PET) rely on both types of power plants. In such cancers, glycolysis may contribute nearly half the ATP even in the presence of oxygen ("Warburg effect"). Based solely on cell energetics, this presents a challenge to identify curative agents that destroy only cancer cells as they must destroy both of their power plants causing "necrotic cell death" and leave normal cells alone. One such agent, 3-bromopyruvate (3-BrPA), a lactic acid analog, has been shown to inhibit both glycolytic and mitochondrial ATP production in rapidly growing cancers (Ko et al., Cancer Letts., 173, 83-91, 2001), leave normal cells alone, and eradicate advanced cancers (19 of 19) in a rodent model (Ko et al., Biochem. Biophys. Res. Commun., 324, 269-275, 2004). A second approach is to induce only cancer cells to undergo "apoptotic cell death." Here, mitochondria release cell death inducing factors (e.g., cytochrome c). In a third approach, cancer cells are induced to die by both apoptotic and necrotic events. In summary, much effort is being focused on identifying agents that induce "necrotic," "apoptotic" or apoptotic plus necrotic cell death only in cancer cells. Regardless how death is inflicted, every cancer cell must die, be it fast or slow.

PMID:

17404823

[PubMed - indexed for MEDLINE]

Biochem Biophys Res Commun. 2004 Nov 5;324(1):269-75.
Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP.

Ko YH, Smith BL, Wang Y, Pomper MG, Rini DA, Torbenson MS, Hullihen J, Pedersen PL.
The Russell H. Morgan Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2185, USA. yko@jhmi.edu
A common feature of many advanced cancers is their enhanced capacity to metabolize glucose to lactic acid. In a challenging study designed to assess whether such cancers can be debilitated, we seeded hepatocellular carcinoma cells expressing the highly glycolytic phenotype into two different locations of young rats. Advanced cancers (2-3cm) developed and were treated with the alkylating agent 3-bromopyruvate, a lactate/pyruvate analog shown here to selectively deplete ATP and induce cell death. In all 19 treated animals advanced cancers were eradicated without apparent toxicity or recurrence. These findings attest to the feasibility of completely destroying advanced, highly glycolytic cancers.

PMID: 15465013 [PubMed - indexed for MEDLINE]




Mol Oncol. 2008 Jun;2(1):94-101. Epub 2008 Jan 13.
3-Bromopyruvate as inhibitor of tumour cell energy metabolism and chemopotentiator of platinum drugs.

Ihrlund LS, Hernlund E, Khan O, Shoshan MC.
Department of Oncology-Pathology, Cancer Centre Karolinska, Karolinska Institute, S-171 76 Stockholm, Sweden.
Tumour cells depend on aerobic glycolysis for adenosine triphosphate (ATP) production, making energy metabolism an interesting therapeutic target. 3-Bromopyruvate (BP) has been shown by others to inhibit hexokinase and eradicate mouse hepatocarcinomas. We report that similar to the glycolysis inhibitor 2-deoxyglucose (DG), BP rapidly decreased cellular ATP within hours, but unlike DG, BP concomitantly induced mitochondrial depolarization without affecting levels of reducing equivalents. Over 24h, and at equitoxic doses, DG reduced glucose consumption more than did BP. The observed BP-induced loss of ATP is therefore largely due to mitochondrial effects. Cell death induced over 24h by BP, but not DG, was blocked by N-acetylcysteine, indicating involvement of reactive oxygen species. BP-induced cytotoxicity was independent of p53. When combined with cisplatin or oxaliplatin, BP led to massive cell death. The anti-proliferative effects of low-dose platinum were strikingly potentiated also in resistant p53-deficient cells. Together with the reported lack of toxicity, this indicates the potential of BP as a clinical chemopotentiating agent.

PMID: 19383331 [PubMed - indexed for MEDLINE]



J Hepatobiliary Pancreat Sci. 2010 Jul;17(4):405-6. Epub 2009 Nov 5.
Interventional oncology: new options for interstitial treatments and intravascular approaches: targeting tumor metabolism via a loco-regional approach: a new therapy against liver cancer.

Liapi E, Geschwind JF. jfg@jhmi.edu
Source

Division of Cardiovascular and Interventional Radiology, The Russell H Morgan Department of Radiology and Radiological Sciences, The Johns Hopkins Hospital, Baltimore, MD 21287, USA.


FREE TEXT


Abstract

Recent research in tumor metabolism has uncovered cancer-cell-specific pathways that cancer cells depend on for energy production. 3-Bromopyruvate (3-BrPA), a specific alkylating agent and potent ATP inhibitor, has been shown both in vitro and in vivo to disrupt some of these cancer-specific metabolic pathways, thereby leading to the demise of the cancer cells through apoptosis. 3-BrPA has been successfully tested in animal models of liver cancer. For optimal results, 3-BrPA can be delivered intra-arterially, with minimal toxicity to the surrounding hepatic parenchyma. In the era of development of drugs with lower toxicity for the treatment of liver cancer, inhibition of cancer metabolism with 3-BrPA appears to be a very attractive potent novel therapeutic option.

PMID:

19890602

[PubMed - indexed for MEDLINE]

PMCID: PMC3063000

3-BrPA has proven to be quite effective at killing tumors in various animal models. An initial study conducted in a rabbit model of liver cancer showed that 3-BrPA acted as an irreversible inhibitor of metabolic enzyme(s) associated with cancer glycolysis [6, 8].

In this study, direct intra-arterial infusion of 3-BrPA showed complete tumor destruction, without affecting the surrounding normal liver parenchyma. This is an important finding, in view of the fact that most liver cancers arise in the background of underlying liver disease (cirrhosis) and that liver failure is a major risk of treatment-related morbidity and mortality [10]. Furthermore, this method of delivery of 3-BrPA showed a significant survival benefit when compared to other established intra-arterial treatments in the rabbit Vx-2 model of liver cancer [11]. In addition, FDG–PET imaging has proven quite useful in determining adequate delivery of the drug to the target tumor, in assessing tumor response after therapy with 3-BrPa and in detecting possible tumor recurrence.3-BrPa is now being tested in human cancer cell lines transplanted in animals (xenografts). The results have so far matched those demonstrated in the Vx-2 rabbit model. In the era of development of less toxic drugs for treatment of liver cancer, inhibition of cancer metabolism is an appealing therapeutic option. This brand new anticancer approach is extremely promising and perfectly suited for catheter-based delivery. Clinical trials should be under way within 1 year.

Semin Cancer Biol. 2009 Feb;19(1):17-24. Epub 2008 Dec 3.
Hexokinase-2 bound to mitochondria: cancer's stygian link to the "Warburg Effect" and a pivotal target for effective therapy.

Mathupala SP, Ko YH, Pedersen PL.
Department of Neurological Surgery and Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, United States.
The most common metabolic hallmark of malignant tumors, i.e., the "Warburg effect" is their propensity to metabolize glucose to lactic acid at a high rate even in the presence of oxygen. The pivotal player in this frequent cancer phenotype is mitochondrial-bound hexokinase [Bustamante E, Pedersen PL. High aerobic glycolysis of rat hepatoma cells in culture: role of mitochondrial hexokinase. Proc Natl Acad Sci USA 1977;74(9):3735-9; Bustamante E, Morris HP, Pedersen PL. Energy metabolism of tumor cells. Requirement for a form of hexokinase with a propensity for mitochondrial binding. J Biol Chem 1981;256(16):8699-704]. Now, in clinics worldwide this prominent phenotype forms the basis of one of the most common detection systems for cancer, i.e., positron emission tomography (PET). Significantly, HK-2 is the major bound hexokinase isoform expressed in cancers that exhibit a "Warburg effect". This includes most cancers that metastasize and kill their human host. By stationing itself on the outer mitochondrial membrane, HK-2 also helps immortalize cancer cells, escapes product inhibition and gains preferential access to newly synthesized ATP for phosphorylating glucose. The latter event traps this essential nutrient inside the tumor cells as glucose-6-P, some of which is funneled off to serve as carbon precursors to help promote the production of new cancer cells while much is converted to lactic acid that exits the cells. The resultant acidity likely wards off an immune response while preparing surrounding tissues for invasion. With the re-emergence and acceptance of both the "Warburg effect" as a prominent phenotype of most clinical cancers, and "metabolic targeting" as a rational therapeutic strategy, a number of laboratories are focusing on metabolite entry or exit steps. One remarkable success story [Ko YH, Smith BL, Wang Y, Pomper MG, Rini DA, Torbenson MS, et al. Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP. Biochem Biophys Res Commun 2004;324(1):269-75] is the use of the small molecule 3-bromopyruvate (3-BP) that selectively enters and destroys the cells of large tumors in animals by targeting both HK-2 and the mitochondrial ATP synthasome. This leads to very rapid ATP depletion and tumor destruction without harm to the animals. This review focuses on the multiple roles played by HK-2 in cancer and its potential as a metabolic target for complete cancer destruction.

PMID: 19101634 [PubMed - indexed for MEDLINE]





Invest New Drugs. 2009 Apr;27(2):120-3. Epub 2008 Jun 14.
Specificity of the anti-glycolytic activity of 3-bromopyruvate confirmed by FDG uptake in a rat model of breast cancer.

Buijs M, Vossen JA, Geschwind JF, Ishimori T, Engles JM, Acha-Ngwodo O, Wahl RL, Vali M.
Russell H. Morgan Department of Radiology, and Radiological Sciences, Division of Vascular and Interventional Radiology, 600 North Wolfe Street, Blalock 545, Baltimore, MD 21287, USA.
PURPOSE: To evaluate the anti-glycolytic effects of 3-BrPA on rats bearing RMT mammary tumors, by determining FDG uptake after intravenous administration of the therapeutic dose. MATERIALS AND METHODS: Sixteen rats bearing RMT tumors were treated either with 15 mM 3-BrPA in 2.5 ml of PBS or with 2.5 ml of PBS. After treatment, all rats received FDG and were sacrificed 1 h later. Results: 3-BrPA treatment significantly decreased FDG uptake in tumors by 77% (p = 0.002). FDG uptake did not significantly decrease in normal tissues after treatment. CONCLUSION: Our study showed that 3-BrPA exhibits a strong anti-glycolytic effect on RMT cells implanted in rats.





Science. 2009 Sep 18;325(5947):1555-9. Epub 2009 Aug 6.
Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells.

Yun J, Rago C, Cheong I, Pagliarini R, Angenendt P, Rajagopalan H, Schmidt K, Willson JK, Markowitz S, Zhou S, Diaz LA Jr, Velculescu VE, Lengauer C, Kinzler KW, Vogelstein B, Papadopoulos N.
Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
Tumor progression is driven by genetic mutations, but little is known about the environmental conditions that select for these mutations. Studying the transcriptomes of paired colorectal cancer cell lines that differed only in the mutational status of their KRAS or BRAF genes, we found that GLUT1, encoding glucose transporter-1, was one of three genes consistently up-regulated in cells with KRAS or BRAF mutations. The mutant cells exhibited enhanced glucose uptake and glycolysis and survived in low-glucose conditions, phenotypes that all required GLUT1 expression. In contrast, when cells with wild-type KRAS alleles were subjected to a low-glucose environment, very few cells survived. Most surviving cells expressed high levels of GLUT1, and 4% of these survivors had acquired KRAS mutations not present in their parents. The glycolysis inhibitor 3-bromopyruvate preferentially suppressed the growth of cells with KRAS or BRAF mutations. Together, these data suggest that glucose deprivation can drive the acquisition of KRAS pathway mutations in human tumors.

PMID: 19661383 [PubMed - indexed for MEDLINE]





Cancer. 2009 Oct 15;115(20):4655-66.
Transport by SLC5A8 with subsequent inhibition of histone deacetylase 1 (HDAC1) and HDAC3 underlies the antitumor activity of 3-bromopyruvate.

Thangaraju M, Karunakaran SK, Itagaki S, Gopal E, Elangovan S, Prasad PD, Ganapathy V.
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia 30912, USA. mthangaraju@mcg.edu
BACKGROUND: 3-bromopyruvate is an alkylating agent with antitumor activity. It is currently believed that blockade of adenosine triphosphate production from glycolysis and mitochondria is the primary mechanism responsible for this antitumor effect. The current studies uncovered a new and novel mechanism for the antitumor activity of 3-bromopyruvate. METHODS: The transport of 3-bromopyruvate by sodium-coupled monocarboxylate transporter SMCT1 (SLC5A8), a tumor suppressor and a sodium (Na+)-coupled, electrogenic transporter for short-chain monocarboxylates, was studied using a mammalian cell expression and the Xenopus laevis oocyte expression systems. The effect of 3-bromopyruvate on histone deacetylases (HDACs) was monitored using the lysate of the human breast cancer cell line MCF7 and human recombinant HDAC isoforms as the enzyme sources. Cell viability was monitored by fluorescence-activated cell-sorting analysis and colony-formation assay. The acetylation status of histone H4 was evaluated by Western blot analysis. RESULTS: 3-Bromopyruvate is a transportable substrate for SLC5A8, and that transport process is Na+-coupled and electrogenic. MCF7 cells did not express SLC5A8 and were not affected by 3-bromopyruvate. However, when transfected with SLC5A8 or treated with inhibitors of DNA methylation, these cells underwent apoptosis in the presence of 3-bromopyruvate. This cell death was associated with the inhibition of HDAC1/HDAC3. Studies with different isoforms of human recombinant HDACs identified HDAC1 and HDAC3 as the targets for 3-bromopyruvate. CONCLUSIONS: 3-Bromopyruvate was transported into cells actively through the tumor suppressor SLC5A8, and the process was energized by an electrochemical Na+ gradient. Ectopic expression of the transporter in MCF7 cells led to apoptosis, and the mechanism involved the inhibition of HDAC1/HDAC3. Copyright (c) 2009 American Cancer Society.

PMID: 19637353 [PubMed - in process]






Oncogene. 2006 Aug 7;25(34):4777-86.
Hexokinase II: cancer's double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria.

Mathupala SP, Ko YH, Pedersen PL.
Department of Neurological Surgery and Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.
A key hallmark of many cancers, particularly the most aggressive, is the capacity to metabolize glucose at an elevated rate, a phenotype detected clinically using positron emission tomography (PET). This phenotype provides cancer cells, including those that participate in metastasis, a distinct competitive edge over normal cells. Specifically, after rapid entry of glucose into cancer cells on the glucose transporter, the highly glycolytic phenotype is supported by hexokinase (primarily HK II) that is overexpressed and bound to the outer mitochondrial membrane via the porin-like protein voltage-dependent anion channel (VDAC). This protein and the adenine nucleotide transporter move ATP, newly synthesized by the inner membrane located ATP synthase, to active sites on HK II. The abundant amounts of HK II bind both the ATP and the incoming glucose producing the product glucose-6-phosphate, also at an elevated rate. This critical metabolite then serves both as a biosynthetic precursor to support cell proliferation and as a precursor for lactic acid, the latter exiting cancer cells causing an unfavorable environment for normal cells. Although helping facilitate this chemical warfare, HK II via its mitochondrial location also suppresses the death of cancer cells, thus increasing their possibility for metastasis and the ultimate death of the human host. For these reasons, targeting this key enzyme is currently being investigated in several laboratories in a strategy to develop novel therapies that may turn the tide on the continuing struggle to find effective cures for cancer. One such candidate is 3-bromopyruvate that has been shown recently to eradicate advanced stage, PET positive hepatocellular carcinomas in an animal model without apparent harm to the animals.

PMID: 16892090 [PubMed - indexed for MEDLINE]






(The FASEB Journal. 2007;21:890.6)
© 2007 FASEB

890.6

Effects of the Anti-Tumor Agent 3-Bromopyruvate (3BrPA) on Glycolytic Energy Metabolism

R. Brooks Robey¹, Richard Hong², Lihui Zhong¹, Lanfei Feng² and Hongmei Zhang^{1 1} Dartmouth/WRJVAMC, 215 N Main St, White River Jct, VT, 05009,
² UIC/JBVAMC, 820 S Wood St, Chicago, IL, 60612

ABSTRACT
BACKGROUND & METHODS: 3BrPA has been reported to eradicate liver cancer in animals without associated systemic toxicity. The molecular basis of this effect is incompletedly characterized but has been attributed to selective hexokinase (HK) inhibition and ATP depletion. We therefore examined 3BrPA and other alkylating agents - 3-fluoropyruvate (3FPA), iodoacetate (IAA), and iodoacetamide (IAM) - for the ability to alter glycolytic HK and GAPDH activities, lactate accumulation, ATP content, and cell viability in non-transformed renal epithelial cells.
RESULTS: 3BrPA inhibited HK activity in cell-free lysates in a concentration-dependent manner, an effect that was less potently mimicked by IAA (IC₅₀ 8 vs 0.7 mM), but not by pyruvate, 3FPA, or IAM. Monothioglycerol had no effect on basal activity but markedly decreased sensitivity to 3BrPA and IAA inhibition. 3BrPA was also non-competitive with Glc and ATP. When examined in intact cells, 3BrPA and IAA reduced ATP content and lactate accumulation at µM concentrations that were orders of magnitude lower than those required for HK inhibition in vitro. Cytotoxic LDH release was only observed following profound ATP depletion but was uniformly higher for IAA. Interestingly, 3BrPA inhibited GAPDH more potently than its classic antagonist IAA in cell-free lysates (IC₅₀ 2.5 vs 150 µM).
CONCLUSIONS: 3BrPA inhibits HK activity, presumably via selective alkylation of sulfhydryl groups important for enzymatic function but not involved in Glc or ATP binding. However, 3BrPA glycolytic inhibitory potency correlates better with GAPDH inhibition than with HK inhibition in non-tumor epithelial cells. IAA - but not 3FPA or IAM - can mimic these effects, albeit with greater relative ATP depletion and cytotoxicity that suggest actions additional to those shared with 3BrPA.

[Rich66]

Found these links in a forum:

http://www.oncolink.org/resources/ar...th=11&id=11258
"Dr. Young Ko has shown already that several human breast cancer cell lines are killed by 3-BrPA, and in future studies she will examine the effect of 3-BrPA on advanced breast cancers growing in an animal model," Dr. Pedersen said. "She will be examining also the effect of 3-BrPA on aggressive metastatic cancers."
Biochem Biophys Res Commun 2004;324:268-274.

http://www.law.com/jsp/article.jsp?id=1124787912428
http://www.cancerforums.net/about2092.html
http://www.ncbi.nlm.nih.gov/pubmed/15465013


here is an important addition to the discussion:
http://scienceblogs.com/terrasig/200...ting_anoth.php

And here's Lani's post relating P53:
http://her2support.org/vbulletin/sho...ght=hexokinase

[Rich66]

PATENT: Ok...2002 filing, 2009 publication???? At least suggestion the researcher lives..maybe. Anyone live in Pikesville, Maryland?


http://www.freepatentsonline.com/7547673.html
Title:
Therapeutics for cancer using 3-bromopyruvate and other selective inhibitors of ATP production

United States Patent 7547673

Abstract:
The present invention relates to methods of treating a cancerous tumor using selective inhibitors of ATP production. The present invention also relates to pharmaceutical preparations comprising such inhibitors and methods for administering them intraarterially directly to a tumor, as well as methods for identifying compositions that selectively inhibitor ATP production for use in the invention.

Inventors:
Ko, Young He (Pikesville, MD, US)
Geschwind, Jean-francois H. (Potomac, MD, US)
Pedersen, Peter L. (Columbia, MD, US)


Application Number:
10/243550

Publication Date:
06/16/2009

Filing Date:
09/13/2002

View Patent Images:
Download PDF 7547673 PDF help

Export Citation:
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Assignee:
The Johns Hopkins University (Baltimore, MD, US)


Primary Class:
514/34

Other Classes:
514/1, 514/171, 514/557

International Classes:
A61K38/16; A61K38/21

Field of Search:
604/510, 514/563, 514/1, 514/562, 514/922, 514/893, 604/508, 604/507, 514/908, 514/274, 514/557, 514/440

US Patent References:

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Primary Examiner:
Marschel, Ardin

Assistant Examiner:
Vakili, Zohreh

Attorney, Agent or Firm:
Russell, Esq. Hathaway P.
Foley Hoag LLP


Parent Case Data:
RELATED APPLICATIONS

This application claims the benefit of priority under 35 U.S.C. § 119(e) to Provisional Application Ser. No. 60/318,710, filed Sep. 13, 2001, the content of which is incorporated by reference in its entirety herein.


Claims:
We claim:

1. A method of treating primary or secondary liver cancer in a subject comprising administering to a subject having a primary or secondary liver tumor an effective amount of a 3-halopyruvate or a salt thereof delivered by transcatheter hepatic intraarterial injection into the liver.

2. The method of claim 1, wherein the 3-halopyruvate is 3-bromopyruvate.

3. A method of treating primary or secondary liver cancer in a subject comprising administering to a subject having a primary or secondary liver tumor a therapeutically effective amount of a 3-halopyruvate or a salt thereof and fluorouracil delivered by transcatheter hepatic intraarterial injection into the liver.

4. The method of claim 1, wherein the 3-halopyruvate or salt thereof is provided in a sustained-release formulation.

5. The method of claim 3, wherein the 3-halopyruvate is 3-bromopyruvate.

6. A method of treating primary or secondary liver cancer in a subject comprising administering to a subject having a primary or secondary liver tumor delivered by transcatheter hepatic intraarterial injection into the liver an effective amount of a compound represented by formula: wherein, independently of each occurrence: X represents a halide; R₁ represents OR, H, N(R″)2, C1-C6 alkyl, C6-C12 aryl, C1-C6 heteroalkyl, or C6-C12 heteroaryl; R″ represents H, C1-C6 alkyl, or C6-C12 aryl; R represents H, alkali metal, C1-C6 alkyl, C6-C12 aryl or C(O)R′; and R′ represents H, C1-C20 alkyl or C6-C12 aryl, or a salt thereof.

7. The method of claim 6, wherein the halide is bromide.

8. A method of treating primary or secondary liver cancer in a subject comprising administering to a subject having a primary or secondary liver tumor delivered by transcatheter hepatic intraarterial injection into the liver an effective amount of a compound represented by formula: wherein, independently of each occurrence: X represents a halide; R₁ represents OR, H, N(R″)2, C1-C6 alkyl, C6-C12 aryl, C1-C6 heteroalkyl, or C6-C12 heteroaryl; R″ represents H, C1-C6 alkyl, or C6-C12 aryl; R represents H, alkali metal, C1-C6 alkyl, C6-C12 aryl or C(O)R′; and R′ represents H, C1-C20 alkyl or C6-C12 aryl, or a salt thereof and administering fluorouracil to said subject.

9. The method of claim 8, wherein the halide is bromide.

10. A method of treating a liver tumor that has metastasized within the liver of a subject an effective amount of a 3-halopyruvate or a salt thereof delivered by transcatheter hepatic intraarterial injection into the liver.

11. The method of claim 10, wherein the 3-halopyruvate is 3-bromopyruvate.

12. The method of claim 1, wherein the 3-halopyruvate is administered directly to the blood supply of the tumor without embolization of the tumor.

13. The method of claim 1, consisting of administering to a subject having a liver tumor an effective amount of a 3-halopyruvate or a salt thereof delivered by transcatheter hepatic intraarterial injection into the liver.



Description:
GOVERNMENT SUPPORT

The subject invention was made in part with support from the U.S. Government under a grant (CA 80118) from the National Institutes of Health. Accordingly, the U.S. Government has certain rights in this invention.
BACKGROUND OF THE INVENTION

One of the most common, profound, and intriguing phenotypes of highly malignant tumors, known for more than six decades, is their ability to metabolize glucose at high rates to synthesize high levels of ATP. Under aerobic conditions more than half of the ATP produced in such tumor cells is derived via glycolysis, in sharp contrast to normal cells, where this value is usually less than 10% and oxidative phosphorylation is the predominant method for ATP generation. Under hypoxic (low oxygen tension) conditions, frequently present within tumors, the already high glycolytic rate may double, allowing the tumor cells to thrive while neighboring normal cells become growth deficient. This is a characteristic of both animal and human tumors including those derived from brain, breast, colon, liver, lung, and stomach. In each, a close correlation exists among the degree of de-differentiation, growth rate, and glucose metabolism, where the most de-differentiated tumors exhibit the fastest growth and the highest glycolytic rate. In fact, this unique phenotype is used clinically worldwide in Positron Emission Tomography (PET) to detect tumors, assess their degree of malignancy, and in some, cases even predict survival time.
Despite the commonality of the high glycolytic phenotype and its widespread use clinically as a diagnostic tool, it has not been exploited as a major target for arresting or slowing the growth of cancer cells because the underlying molecular basis of the high glycolytic phenotype is not completely characterized. It had long been suspected to involve some type of mitochondrial glycolytic interaction. Recent experiments have demonstrated a requirement for an overexpressed mitochondrially bound form of hexokinase, now identified as Type II hexokinase.
Liver cancer, in particular hepatocellular carcinoma (hepatoma), is one of the most common fatal cancers in the world and soon may reach epidemic levels due to increased incidences of virally-induced hepatitis. Among its numerous victims are not only those with primary tumors that develop directly in the liver but those with secondary tumors that frequently arise in this critical metabolic organ as a result of metastasis from other tissues, e.g., the colon. Unfortunately, traditional treatment options are limited by poor response rates, severe toxicities, and high recurrence rates resulting in a mean survival time of about 6 months. Hepatomas are known to exhibit a high glucose catabolic rate, and where examined carefully, to contain elevated levels of hexokinase bound to their mitochondria. Moreover, in the AS-30D hepatoma, the most extensively studied tumor in this class, it has been shown also that the gene for hexokinase is amplified and that the mRNA levels are markedly elevated. Therapeutic methods directed at inhibition of metabolic activity in hepatoma are limited by the fact that a potent agent directed at any of the metabolic enzymes such as hexokinase in the tumor will also target the patient's metabolic enzymes, resulting in severe toxicity. Thus, less potent, but very specific agents such as antisense molecules, have been used to inhibit tumor metabolic activity.
In recent years, the VX2 tumor, an epidermoid rabbit tumor induced by the Shope papilloma virus, has shown promise as a model system for studying hepatoma. The VX2 tumor grows well when implanted in the rabbit's liver, where it takes on growth properties and a vascularization system similar to many human liver tumors. Thus, it is possible via the method known as transcatheter chemoembolization to deliver anticancer agents directly to the implanted tumor via the hepatic artery. In addition, it has been shown that when delivery is made using certain oils the mixture preferentially localizes in the tumor rather than in the surrounding liver tissue. This is important as it may allow for the targeting of exceptionally potent cancer killing agents directly to the tumor for brief periods of time thus minimizing damage to the surrounding liver tissue and toxicity to the host. The energy metabolism of the VX2 tumor requires further characterization in order to determine to what extent it mimics a rapidly growing hepatoma (e.g. exhibits a high glycolytic phenotype, expresses mitochondrially bound hexokinase, etc.).
SUMMARY OF THE INVENTION

The present invention provides in part therapeutic compositions comprising and methods of treating cancer using 3-bromopyruvate and other selective inhibitors of ATP production.
In a preferred embodiment, the invention further provides inhibitors of ATP production represented in general formula:
X—CH2—CO—COOH,


Related delivery formulation patent:
http://www.freshpatents.com/Composit...0070203074.php

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http://www.encognitive.com/node/1738


Giving Cancer an Energy Blackout

Tagged:

• Cancer

In the 1920s, the German researcher Dr. Otto Warburg discovered that cancer cells rely heavily on a process known as glycolysis to produce energy.
Dr. Warburg, a Nobel Prize winner, also found that cancer cells did this even when there was sufficient oxygen available for a far more efficient, oxygen-dependent energy-production process used by many normal cells, called oxidative phosphorylation. The paradox came to be known as the "Warburg effect."
Dr. Warburg believed that this "aerobic glycolysis" was at the root of cancer development, but his theory never caught on.
Over the last decade, however, there has been a resurgence of interest in learning more about cancer cell metabolism - how cancer cells produce energy and use it to grow and divide.
Cancer cell metabolism hasn't traditionally been "considered as part of the cancer problem," says Dr. Craig Thompson, scientific director at the Abramson Family Cancer Research Institute. But the renewed interest in it, he believes, "gives us a number of new avenues to investigate to see whether it can be exploited for therapeutic benefit."
And Dr. Thompson isn't the only one. A growing cadre of researchers is now delving deep into cancer cells' energy-production machinery, with the hope of finding effective ways to short-circuit it.
Tumor cells' glucose problem
The renewed focus on energy production and Warburg's discoveries from 80 years ago is an ideal case in point.
"More and more, multiple groups are looking at the molecular mechanisms behind the Warburg effect, because it's consistently observed in tumor cells," says Dr. Peng Huang, an associate professor of molecular pathology at the University of Texas M.D. Anderson Cancer Center. "Certainly, in both cell culture and animal models, we see the cancer cells' increased dependence on glycolysis."
Both glycolysis and oxidative phosphorylation begin with the ingestion of glucose by a cell. The difference resides in how the cell transforms that raw material into energy - in the form of a complex molecule called ATP - and the efficiency with which it does it. Oxidative phosphorylation can produce as much as 18 times more ATP per molecule of glucose than glycolysis.
This inefficiency leads tumor cells that are reliant on glycolysis to take up a tremendous amount of glucose. This reliance forms the basis for the now widespread use of PET scans that involve the glucose analog FDG for the detection of a number of different cancer types.
Researchers like Drs. Huang and Thompson believe tumor cells' addiction to glycolysis might represent a bona fide Achilles heel: Disrupt glycolysis and tumor cells won't be able to produce enough energy to survive. Data from laboratory and animal model studies support this belief.
But the question remains: Why do tumor cells rely on a less efficient energy-production process when they don't have to?
"It's still a matter of debate," says Dr. Huang.
Several theories have been proposed to explain this. One suggests that genetic mutations have damaged the tumor cells' mitochondria, where oxidative phosphorylation takes place, so the cell switches to an alternative energy-production pathway. Another argues that it's an adaptation that gives the cell a survival advantage once a tumor becomes larger and oxygen - but not necessarily glucose - becomes far less abundant.
Dr. Thompson admits that it's complicated and requires more intensive study.
"We need to look more closely at issues like which signaling pathways tumor cells are using when they just want to survive for the day, or if they want to engage in growth and proliferation," he says.
Mucking up the machinery
Efforts to exploit this potential tumor cell weakness are moving ahead full steam, with glycolytic inhibitors already in human clinical trials or headed in that direction.
One company, Threshold Pharmaceuticals, has based its entire therapeutic enterprise on what they call "metabolic targeting." Two of its products are currently in clinical trials, including 2DG, a glucose analog being investigated in combination with docetaxel in a phase I trial.
Because tumor cells are so hungry for glucose - particularly those that are in hypoxic regions of a tumor and are more likely to be resistant to standard chemotherapy agents - 2DG is readily taken up by tumor cells, says the scientist who developed it, Dr. Ted Lampidis.
Once inside, explains Dr. Lampidis, a professor of cell biology at the University of Miami Sylvester Cancer Center, the agent competes with regular glucose to be synthesized into ATP. However, because of the slight difference in 2DG's makeup compared with glucose, that synthesis never happens, starving the cell of energy.
"We've made tremendous progress from developing the concept of 2DG to getting it into the clinic," he says. "I see now that there's a real possibility it's going to work."
The phase I trial is almost complete and plans are under way to launch a phase II trial.
Another agent, 3-BrPA, completely eradicated large, highly glycolytic tumors in one animal model and markedly shrank similar tumors in another model. The agent's target, explains Dr. Peter Pedersen, a professor of biological chemistry at the Johns Hopkins University School of Medicine - who along with Dr. Young Ko, is moving it through preclinical studies - is an enzyme called hexokinase that is bound to the surface of mitochondria but plays a key role in both glycolysis and oxidative phosphorylation. Dr. Ko, who discovered the agent's potent anticancer activity, calls 3-BrPA a "total energy blocker."
Most recently, they've been investigating 3-BrPA's effect on different cancer cell lines.
"Once inside [the tumor cell], it's like a Trojan horse," Dr. Pedersen explains. "You see dissipation of ATP very quickly. But if you do the same thing to a hepatocyte [an important and abundant liver cell], for example, it hardly has any effect."
A number of companies have approached Dr. Petersen's lab about taking 3-BrPA into clinical trials.
By Carmen Phillips






NOBEL PRIZE WINNER SAYS CELLULAR ADAPTATION CAUSES CANCER

According to Nobel Prize Winner Otto Warburg, a normal cell deprived of 4 nutrients causes the cell to become a cancer cell by irreversibly changing the cell into a simpler form like yeast cells, which grows out of control like yeast.
In 1931 Dr. Otto Warburg was awarded the Nobel Prize in medicine for determining the role of a group of enzymes involved in aerobic (with oxygen) respiration of healthy cells. During his research he found that when a normal body cell switches from aerobic respiration to anaerobic (without oxygen) respiration the cell becomes a form of simpler cells, called cancer, similar to yeast. Like yeast and mold, cancer grows out of control.
(Respiration is the cellular process of extracting energy from the bonds of molecules of food. Aerobic respiration is highly efficient and provides plenty of energy to sustain complex life (animals). Anaerobic respiration is much less efficient and provides only enough energy to support simple life, like fungi, yeast, many forms of bacteria.)
Warburg believed what causes a cell to switch to anaerobic respiration is a cell being starved of iron and 3 B-vitamins, and also that the change to anaerobic respiration is irreversible. To this day scientists haven’t claimed he was wrong.
In presenting the Nobel Prize to Warburg, hopes were very high, “The medical world expects great things from your experiments on cancer and other tumours and experiments which seem already to be sufficiently far advanced to be able to furnish an explanation for at least one cause of the destructive and unlimited growth of these tumours. “
Nobel Prize Presentation to Warburg
Warburg’s Nobel Lecture (.pdf)
Otto Warburg: Nobel Prize in Physiology
“The Prime Cause And Prevention Of Cancer”
In June of 1966 Warburg wrote The Prime Cause and Prevention of Cancer which included this paragraph,
“To prevent cancer it is therefore proposed first to keep the speed of the blood stream so high that the venous blood still contains sufficient oxygen; second, to keep high the concentration of hemoglobin in the blood; third, to add always to the food, even of healthy people, the active groups of the respiratory enzymes; and to increase the doses of these groups, if a precancerous state has already developed. If at the same time exogenous carcinogens are excluded rigorously, then much of the endogenous cancer may be prevented today.”
In August of the same year, Warburg revised The Prime Cause and Prevention of Cancer which includes the names of the “active groups of the respiratory enzymes” he wrote of in his orginal.
“ Cancer, above all other diseases, has countless secondary causes. But, even for cancer, there is only one prime cause. The prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by fermentation of sugar [anaerobic respiration].
All normal body cells meet their energy needs by respiration of oxygen, whereas cancer cells meet their energy needs in great part by fermentation. All normal body cells are thus obligate aerobes, whereas all cancer cells are partial anaerobes. From the standpoint of the physics and chemistry of life this difference between normal and cancer cells is so great that one can scarcely picture a greater difference. Oxygen gas, the donor of energy in plants and animals is dethroned in the cancer cells and replaced by an energy yielding reaction of the lowest living forms, namely, a fermentation of glucose.
Of what use is it to know the prime cause of cancer? Here is an example. In Scandinavian countries there occurs a cancer of throat and esophagus whose precursor is the so-called Plummer-Vinson syndrome. This syndrome can be healed when one adds to the diet the active groups of respiratory enzymes, for example: iron salts, riboflavin, pantothenic acid, and nicotinamide. When one can heal the precursor of a cancer, one can prevent this cancer. According to Ernest Wynder of the Sloan-Kettering Institute for Cancer Research in New York, the time has come when one can exterminate this kind of cancer with the help of the active groups of the respiratory enzymes.
It is of interest in this connection that with the help of one of these active groups of the respiratory enzymes, namely nicotinamide, tuberculosis can be healed quite as well as with streptomycin, but without the side effects of the latter. Since the sulfonamides and antibiotics, this discovery made in 1945 is the most important event in the field of chemotherapy generally, and encourages, in association with the experiences in Scandinavia, efforts to prevent cancer by dietary addition of large amounts of the active groups of the respiratory enzymes. “

[Rich66]

http://www.nature.com/nature/journal...ture06734.html


Nature 452, 230-233 (13 March 2008) | doi:10.1038/nature06734; Received 18 October 2007; Accepted 19 January 2008
The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth

Heather R. Christofk¹, Matthew G. Vander Heiden^1,2, Marian H. Harris³, Arvind Ramanathan⁴, Robert E. Gerszten^4,5,6, Ru Wei⁴, Mark D. Fleming³, Stuart L. Schreiber^4,7 & Lewis C. Cantley^1,8

1. Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
2. Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA
3. Department of Pathology, Children's Hospital, Boston, Massachusetts 02115, USA
4. Chemical Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA
5. Cardiology Division and Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, Massachusetts 02129, USA
6. Donald W. Reynolds Cardiovascular Clinical Research Center on Atherosclerosis, Harvard Medical School, Boston, Massachusetts 02115, USA
7. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA
8. Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA

Correspondence to: Lewis C. Cantley^1,8 Correspondence and requests for materials should be addressed to L.C.C. (Email: lcantley@hms.harvard.edu).

Many tumour cells have elevated rates of glucose uptake but reduced rates of oxidative phosphorylation. This persistence of high lactate production by tumours in the presence of oxygen, known as aerobic glycolysis, was first noted by Otto Warburg more than 75 yr ago¹. How tumour cells establish this altered metabolic phenotype and whether it is essential for tumorigenesis is as yet unknown. Here we show that a single switch in a splice isoform of the glycolytic enzyme pyruvate kinase is necessary for the shift in cellular metabolism to aerobic glycolysis and that this promotes tumorigenesis. Tumour cells have been shown to express exclusively the embryonic M2 isoform of pyruvate kinase². Here we use short hairpin RNA to knockdown pyruvate kinase M2 expression in human cancer cell lines and replace it with pyruvate kinase M1. Switching pyruvate kinase expression to the M1 (adult) isoform leads to reversal of the Warburg effect, as judged by reduced lactate production and increased oxygen consumption, and this correlates with a reduced ability to form tumours in nude mouse xenografts. These results demonstrate that M2 expression is necessary for aerobic glycolysis and that this metabolic phenotype provides a selective growth advantage for tumour cells in vivo.

Oncogene. 2006 Aug 7;25(34):4777-86.
Hexokinase II: cancer's double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria.

Mathupala SP, Ko YH, Pedersen PL.
Department of Neurological Surgery and Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.
A key hallmark of many cancers, particularly the most aggressive, is the capacity to metabolize glucose at an elevated rate, a phenotype detected clinically using positron emission tomography (PET). This phenotype provides cancer cells, including those that participate in metastasis, a distinct competitive edge over normal cells. Specifically, after rapid entry of glucose into cancer cells on the glucose transporter, the highly glycolytic phenotype is supported by hexokinase (primarily HK II) that is overexpressed and bound to the outer mitochondrial membrane via the porin-like protein voltage-dependent anion channel (VDAC). This protein and the adenine nucleotide transporter move ATP, newly synthesized by the inner membrane located ATP synthase, to active sites on HK II. The abundant amounts of HK II bind both the ATP and the incoming glucose producing the product glucose-6-phosphate, also at an elevated rate. This critical metabolite then serves both as a biosynthetic precursor to support cell proliferation and as a precursor for lactic acid, the latter exiting cancer cells causing an unfavorable environment for normal cells. Although helping facilitate this chemical warfare, HK II via its mitochondrial location also suppresses the death of cancer cells, thus increasing their possibility for metastasis and the ultimate death of the human host. For these reasons, targeting this key enzyme is currently being investigated in several laboratories in a strategy to develop novel therapies that may turn the tide on the continuing struggle to find effective cures for cancer. One such candidate is 3-bromopyruvate that has been shown recently to eradicate advanced stage, PET positive hepatocellular carcinomas in an animal model without apparent harm to the animals.

PMID: 16892090 [PubMed - indexed for MEDLINE]

Cancers' sweet tooth may be weakness

http://www.physorg.com/news177769436.html
November 18th, 2009 in Medicine & Health / Cancer
The pedal-to-the-metal signals driving the growth of several types of cancer cells lead to a common switch governing the use of glucose, researchers at Winship Cancer Institute of Emory University have discovered.
Scientists who study cancer have known for decades that cancer cells tend to consume more glucose, or blood sugar, than healthy cells. This tendency is known as the "Warburg effect," honoring discoverer Otto Warburg, a German biochemist who won the 1931 Nobel Prize in Medicine. Now a Winship-led team has identified a way to possibly exploit cancer cells' taste for glucose.
The results were published this week in the journal Science Signaling.
Normally cells have two modes of burning glucose, comparable to sprinting and long-distance running: glycolysis, which doesn't require oxygen and doesn't consume all of the glucose molecule, and oxidative phosphorylation, which requires oxygen and is more thorough.
Cancer cells often outgrow their blood supply, leading to a lack of oxygen in a tumor, says Jing Chen, PhD, assistant professor of hematology and medical oncology at Emory University School of Medicine and Winship Cancer Institute. They also benefit from glycolysis because leftovers from the inefficient consumption of glucose can be used as building blocks for growing cells.
"Even if they have oxygen, cancer cells still prefer glycolysis," Chen says. "They depend on it to grow quickly."
Working with Chen, postdoctoral researcher Taro Hitosugi focused on the enzyme PKM2 (pyruvate kinase M2), which governs the use of glucose and controls whether cells make the switch between glycolysis and oxidative phosphorylation. PKM2 is found predominantly in fetal cells and in tumor cells.
In many types of cancer, mutations lead to over-activation of proteins called tyrosine kinases. Chen's team showed that tyrosine kinases turn off PKM2 in lung, breast, prostate and blood cancers. Introducing a form of PKM2 that is not sensitive to tyrosine kinases into cancer cells forces them to grow slower and be more dependent on oxygen, they found.
Because the active form of PKM2 consists of four protein molecules stuck together, having a tyrosine kinase flip the "off" switch on one molecule can dampen the activity for the others.
"People knew that tyrosine kinases might modify PKM2 for decades but they didn't think it mattered," Chen says. "We showed that such a modification is important and you even don't need that much modification of PKM2 to make a difference in the cells' metabolism."
PKM2 could be a good drug target, because both inhibiting it or activating it can slow down cancer cell growth. Biotechnology companies are already searching for ways to do so, Chen says.
More information: T. Hitosugi et al. Tyrosine phosphorylation inhibits PKM2 to promote the Wargurg effect and tumor growth. Sci. Signal. 2, ra73 (2009).
Source: Emory University (news : web) http://www.physorg.com/news177769436.html

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