Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP

Ko, Young Hee; Smith, Barbara L.; Wang, Yuchuan; Pomper, Martin G.; Rini, David; Torbenson, Michael; Hullihen, Joanne; Pedersen, Peter L.

doi:10.1016/j.bbrc.2004.09.047

Cited by 327 publications

(261 citation statements)

References 10 publications

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“…Recent studies showed that 3-bromopyruvic acid (BrPA), a structural analog of pyruvate/lactate, can potently inhibit HK and deplete ATP 36 at concentrations of 30-300 mM. We found that even 25 mM of BrPA had a profound effect on proliferation and survival, with DKI/p110* and DKI/E40K cells exhibiting twice the sensitivity compared to WT cells (Figure 5c, left 2 panels).…”

Section: Csf-1-stimulated Mitogenesis Is Dependent On Glycolysismentioning

confidence: 76%

Colony-stimulating factor-1 requires PI3-kinase-mediated metabolism for proliferation and survival in myeloid cells

Lee

States

2006

Cell Death Differ

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Colony-stimulating factor-1 (CSF-1) is essential for macrophage growth, differentiation and survival. Myeloid cells expressing a CSF-1 receptor mutant (DKI) show markedly impaired CSF-1-mediated proliferation and survival, accompanied by absent signal transducers and activators of transcription 3 (Stat3) phosphorylation and reduced PI3-kinase/Akt activity. Restoring phosphatidylinositol 3-kinase (PI3-kinase) but not Stat3 signals reverses the mitogenic defect. CSF-1-induced proliferation and survival are sensitive to glycolytic inhibitors, 2-deoxyglucose and 3-bromopyruvate. Consistent with a critical role for PI3-kinase-regulated glycolysis, DKI cells reconstituted with active PI3-kinase or Akt are hypersensitive to these inhibitors. CSF-1 upregulates hexokinase II (HKII) expression through PI3-kinase, and PI3-kinase transcriptionally activates the HKII promoter. Moreover, HKII overexpression partially restores mitogenicity. In contrast, Bcl-x L expression does not enhance long-term proliferation, although short-term cell death is suppressed in a glycolysis-independent manner. This study identifies robust PI3-kinase activation as essential for optimal CSF-1-mediated mitogenesis in myeloid cells, in part through regulation of HKII and support of glycolysis.

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Section: Csf-1-stimulated Mitogenesis Is Dependent On Glycolysismentioning

confidence: 76%

Colony-stimulating factor-1 requires PI3-kinase-mediated metabolism for proliferation and survival in myeloid cells

Lee

States

2006

Cell Death Differ

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“…Later YHK would lead a team of investigators in an effort to test 3BP's capacity to cure rats bearing large solid tumors. Significantly and surprisingly, all the treated animals were cured, i.e., all tumors were eradicated (Ko et al 2004). Moreover, eradication occurred quickly (<1 month).…”

Section: Introductionmentioning

confidence: 79%

A translational study “case report” on the small molecule “energy blocker” 3-bromopyruvate (3BP) as a potent anticancer agent: from bench side to bedside

Ko¹,

Verhoeven

Lee

et al. 2012

J Bioenerg Biomembr

138

107

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The small alkylating molecule, 3-bromopyruvate (3BP), is a potent and specific anticancer agent. 3BP is different in its action from most currently available chemo-drugs. Thus, 3BP targets cancer cells' energy metabolism, both its high glycolysis ("Warburg Effect") and mitochondrial oxidative phosphorylation. This inhibits/ blocks total energy production leading to a depletion of energy reserves. Moreover, 3BP as an "Energy Blocker", is very rapid in killing such cells. This is in sharp contrast to most commonly used anticancer agents that usually take longer to show a noticeable effect. In addition, 3BP at its effective concentrations that kill cancer cells has little or no effect on normal cells. Therefore, 3BP can be considered a member, perhaps one of the first, of a new class of anticancer agents. Following 3BP's discovery as a novel anticancer agent in vitro in the Year 2000 (Published in Ko et al. Can Lett 173:83-91, 2001), and also as a highly effective and rapid anticancer agent in vivo shortly thereafter (Ko et al. Biochem Biophys Res Commun 324:269-275, 2004), its efficacy as a potent anticancer agent in humans was demonstrated. Here, based on translational research, we report results of a case study in a young adult cancer patient with fibrolamellar hepatocellular carcinoma. Thus, a bench side discovery in the

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“…An association between hexokinase and mitochondria influences apoptosis regulation 93 , and compounds isolated from plants that disrupt this association are toxic to cancer cells in culture 94 . HK is also a target of 3--bromopyruvate, a compound shown to be toxic to cancer cells 91,95 . However, 3--bromopyruvate is also toxic to some cancer cells at concentrations that are too low to inhibit HK and it has been argued that the combined inhibition of multiple metabolic enzymes accounts for the toxic effects of this compound on cancer cells 96 .…”

Section: --Deoxyglucose (2dg) Is An Inhibitor Of Glucose Metabolism mentioning

confidence: 99%

Targeting cancer metabolism: a therapeutic window opens

Heiden

2011

Nat Rev Drug Discov

1,248

1,064

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PrefaceGenetic driver events in cancer activate signaling pathways that alter cell metabolism. Clinical evidence has linked metabolism with cancer outcomes.Together, this has raised interest in targeting metabolic enzymes for cancer therapy, but also concerns that these therapies would have unacceptable effects on normal cells. However, some of the first cancer therapies target the specific metabolic needs of cancer cells and remain effective agents used in the clinic today. Research to understand how changes in cell metabolism promote tumor growth has accelerated in recent years. This has refocused efforts on targeting metabolic dependencies of cancer cells, an approach with the potential to have a major impact on patient care.

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Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP

Cited by 327 publications

References 10 publications

Colony-stimulating factor-1 requires PI3-kinase-mediated metabolism for proliferation and survival in myeloid cells

Colony-stimulating factor-1 requires PI3-kinase-mediated metabolism for proliferation and survival in myeloid cells

A translational study “case report” on the small molecule “energy blocker” 3-bromopyruvate (3BP) as a potent anticancer agent: from bench side to bedside

Targeting cancer metabolism: a therapeutic window opens

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