Literature References Showing Benefit and Efficacy of 3-Bromopyruvate:

  1. “The pyruvate analogue 3-bromopyruvate (3-BP) is an electrophilic alkylator that is considered a promising anticancer drug because it has been shown to kill cancer cells efficiently while having little toxic effect on nontumor cells.”
    J Neurosci Res. 2014 Sep 4. doi: 10.1002/jnr.23474. [Epub ahead of print]
  2. “The pyruvate mimetic 3-bromopyruvate (3-BP) is generally presented as an inhibitor of glycolysis and has shown remarkable efficacy in not only preventing tumor growth, but even eradicating existent tumors in animal studies.”
    Journal of Bioenergetics and Biomembranes February 2012, Volume 44, Issue 1, pp 7-15. 02 Feb 2012
  3. “This led to the discovery in an experiment conceived, designed, and conducted by Young Ko that the small molecule 3-bromopyruvate (3bp), the subject of this mini-review series, is an incredibly powerful and swift acting anticancer agent. Significantly, in subsequent experiments with rodents (19 animals with advanced cancer) Ko led a project in which 3bp was shown in a short treatment period to eradicate all (100%).
    Suffice it to say in this bottom line, “3BP, a small molecule, results in a remarkable therapeutic effect when it comes to treating cancers exhibiting a “Warburg effect”. This includes most cancer types.”
    J Bioenerg Biomembr. 2012 Feb;44(1):1-6. doi: 10.1007/s10863-012-9425-4. PMID: 22382780
  4. “We describe the principal mechanisms of action and the main targets of 3-bromopyruvate, an alkylating agent with impressive antitumor effects in several models of animal tumors. Moreover, we discuss the chemo-potentiating strategies that would make unparalleled the putative therapeutic efficacy of its use in clinical settings.”
    J of Bioenergetics and Biomemb Feb 2012, Vol 44, Issue 1, pp 17-29. 12 Feb 2012
  5. The small alkylating (attaching to a thiol/sulfur/sulfhydryl group) agent, 3-bromopyruvate (3bp), is a potent, targeted anticancer agent. 3bp does not act like most currently available chemotherapy drugs. Instead, 3bp specifically goes to a cancer cells’ energy metabolism, specifically its high aerobic glycolysis. It inhibits energy production leading to a loss of energy within the cancer cell. 3bp does this so effectively that it is very rapid in killing cancer cells. This is in sharp contrast to most commonly used anticancer agents which work on the DNA of rapidly dividing cells. In addition, 3bp at concentrations that kill cancer cells has little or no effect on normal cells. Thus, 3bp can be considered part of a new class of anticancer agents that works on the metabolism of cancer cells.
    Journal of Bioenergetics and Biomembranes February 2012, Volume 44, Issue 1, pp 163-170, 11 Feb 2012.
  6. “Glycolytic phenotype in cancer cells maintains a high non-toxic oxidative stress in cancer cells and may be responsible for their malignant behavior. Through HK II, glycolysis fuels the energetic arm of malignancy, the mitotic arm of malignancy (DNA synthesis through HMP shunt pathway) and the metastatic arm of malignancy (hyaluronan synthesis through uronic acid pathway) in addition to the role of phosphohexose isomerase (autocrine motility factor). All those critical three arms start with the substrate G6P that is a direct product of HK II. 3-bromopyruvate (3BP, inhibitor of HK II) may prove as a promising anticancer and antimetastatic agent based on antagonizing the Warburg effect and disturbing the malignant behavior in cancer cells.”
    Med Hypotheses. 2013 Nov;81(5):866-70. doi: 10.1016/j.mehy.2013.08.024. Epub 2013 Sep 3
  7. “Contrary to predictions, 3BP interferes with glycolysis and oxidative phosphorylation in cancer cells without side effects in normal tissues. The mitochondrial hexokinase II has been claimed as the main target.”
    J Biochem Cell Biol. 2014 Sep;54:266-71. doi: 10.1016/j.biocel.2014.05.013. Epub 2014 May 16.
  8. “The pyruvate mimetic 3-bromopyruvate (3-BP) is generally presented as an inhibitor of glycolysis and has shown remarkable efficacy in not only preventing tumor growth, but even eradicating existant tumors in animal studies. We here review reported molecular targets of 3-BP and suggest that the very range of possible targets, which pertain to the altered energy metabolism of tumor cells, contributes both to the efficacy and the tumor specificity of the drug. Its in vivo efficacy is suggested to be due to a combination of glycolytic and mitochondrial targets, as well as to secondary effects affecting the tumor microenvironment.”
  9. “Pyruvate can be transported into or secreted from the cells by the specific H1-monocarboxylate cotransporter (Poole and Halestrap, 1993; Garcia et al., 1994). It could thus act as both intracellular and extracellular H2O2 scavengers. The present study was undertaken to determine whether pyruvate and other a -ketoacids can indeed protect neurons against H2O2. Cultured striatal neurons from mouse embryos were exposed to either exogenous H2O2 or to H2O2 intracellularly formed as a result of the use of menadione (2-methyl-1,4-naphthoquinone), a quinone that generates intracellular O2z2 and H2O2, through a redox cycling process (Thor et al., 1982; Doroshow, 1986). We demonstrate that pyruvate protects neurons against both exogenous and endogenously produced H2O2.”
    The Journal of Neuroscience, December 1, 1997, 17(23):9060–9067
  10. 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.”
    Oncogene (2006) 25, 4777–4786. doi:10.1038/sj.onc.1209603
  11. “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.”
  12. “Treatment with 3-bromopyruvate increased immunohistochemical staining for cleaved caspase-3, suggesting that the lung tumor inhibitory effects of 3-bromopyruvate were through induction of apoptosis. 3-Bromopyruvate also dissociated hexokinase II from mitochondria, reduced hexokinase activity and blocked energy metabolism in cancer cells, finally triggered cancer cell death and induced apoptosis through caspase-3, and poly (ADP) ribose polymerase in a human lung cancer cell line.”

The following are articles showing that 3-bromopyruvate as a pyruvate analog will cross the BBB.

  1. “To prove the functional significance of monocarboxylic acid transporter, MCT1 at the blood-brain barrier (BBB) for the passage of both endogenous and exogenous monocarboxylic acids into the central nervous system.”
  2. “Lactic acid and other monocarboxylates are important metabolic products and energy substrates of brain metabolism in mammalians, and their movement across the BBB is regulated by specific uptake and efflux transporters. The carrier-mediated transport system for these drugs is presumably common to short-chain fatty acids such as acetate.”
  3. “Earlier in vivo studies suggested the presence of a monocarboxylate transport (MCT) system at the BBB as demonstrated by stereospecific and saturable transport of lactate and pyruvate across the BBB.
    These observations demonstrate that MCT1 is responsible for monocarboxylate transport at the BBB. MCT1 is likely to transport relatively small molecules having a monocarboxylate moiety and with a molecular weight of up to ∼200.”
  4. “Monocarboxylic acids, including lactate, pyruvate, and ketones play an important role in energy metabolism within the body. Monocarboxylates such as pyruvate, lactate, and ketone bodies (i.e acetoacetate and β-hydroxybutyarate) can be utilized by neurons, in the absence of glucose, to generate a substantial amount of energy for the brain.”
  5. “The BBB lactate carrier, which also transports other monocarboxylic acids (pyruvate, and the ketone bodies, acetoacetate, and β-hydroxybutryyrate), was identified as the monocarboxylic acid transporter type 1 or MCT1.”

Results for 3bp in conjunction with chemotherapy:

  1. “3-Bromopyruvate treatment led to marked decreases in the IC50 which is a measure of the effectiveness of a substance in inhibiting a specific biological or biochemical function.values of selected chemotherapeutic drugs [e.g., doxorubicin (283 folds), paclitaxel (85 folds), daunorubicin (201 folds), and epirubicin (171 folds)] in MCF-7/ADR cells. 3-Bromopyruvate was found also to potentiate significantly the antitumor activity of epirubicin against MCF-7/ADR xenografts. The intracellular level of ATP decreased 44%, 46% in the presence of 12.5.25 µM 3-Bromopyruvate, whereas the accumulation of rhodamine 123 and epirubicin (two typical P-glycoprotein substrates) in cells was significantly increased.”
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