Specificity of the anti-glycolytic activity of 3-bromopyruvate confirmed by FDG uptake in a rat model of breast cancer

Buijs, Manon; Vossen, Josephina A.; Geschwind, Jean François H.; Ishimori, Takayoshi; Engles, James; Acha-Ngwodo, Obele; Wahl, Richard L.; Vali, Mustafa

doi:10.1007/s10637-008-9145-0

Cited by 30 publications

(17 citation statements)

References 22 publications

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“…3-Bromopyruvate (3-Br-PA) was reported to deplete cancer cells of ATP and to have antitumor effects against hepatocellular carcinoma in rats (43) without damage to normal tissues. Similar reports described activity against breast carcinoma in rats (44). 3-Br-PA is an alkylating agent that has a structural similarity to lactate (43).…”

Section: Starvation Of Cancer Cellssupporting

confidence: 74%

Metabolic Approaches to Treatment of Melanoma

Hersey

Watts

Zhang

et al. 2009

Clinical Cancer Research

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Purpose: Lactate dehydrogenase (LDH) levels in blood of patients with melanoma have proven to be an accurate predictor of prognosis and response to some treatments. Exclusion of patients with high LDH levels from many trials of new treatments has created a need for treatments aimed at patients with high LDH levels. This article reviews the metabolic basis for the association of LDH with prognosis and the treatment initiatives that may be successful in this patient group. Experimental Design: Review of current literature on the topic. The growth rates and sites of spread of metastatic melanoma vary widely between patients. In some instances, the disease shows indolent growth rates and limited spread to skin, lymph nodes, or lungs. In other patients, the disease has rapid growth rates and early spread to multiple sites, including internal organs. Several studies have identified lactate dehydrogenase (LDH) levels as the most reliable marker of the more rapidly growing highly metastatic forms of the disease (1, 2). LDH levels also identify melanoma that are resistant to certain forms of treatment (3) and is widely used by sponsors to exclude patients with unfavorable prognosis from clinical trials of new agents. Data from the Genasense study (3) suggest that approximately one third of patients are excluded from trials if a cutoff of >1.2 upper limit of normal is taken as an entry criteria.LDH is coded for by two genes, LDH-A (M-muscle type) and LDH-B (H-heart type), which code for two polypeptide chains that form five isoenzymes depending on the combinations of the two chains. LDH-5 is composed of four M subunits, whereas LDH-1 is composed of four H subunits (4). LDH-5 is the most efficient isotype in catalyzing conversion of pyruvate to lactate (5). LDH-5 expression is readily detected in histologic sections of melanoma and was shown to be a strong correlate of prognosis in primary melanoma. It was not an independent predictor and correlated with the other prognostic determinants of thickness and mitotic rate. Increased levels of LDH within the cell are believed to be due largely to upregulation by the transcription factor hypoxiainducible factor 1α (HIF-1α). The latter is normally degraded by the E3 ligase von Hippel-Lindau protein under normal oxygen levels but not under hypoxic conditions, leading to posttranslational increases in HIF-1α (6). Hypoxia also activates the endoplasmic reticulum (ER) stress response, which indirectly upregulates mRNA for HIF-1α (7) through the transcription factor XBP-1 and Akt activation (8); however, this needs to be confirmed. Hypoglycemia and other factors resulting from the demands of the malignant process also contribute to ER stress and the resultant unfolded protein response (9-11).One of the consequences of ER stress is a change in metabolism of the cell due to activation of HIF-1α and activation of the Akt pathway. These changes are believed to result in reduced mitochondrial-dependent oxidation of glucose by cancer cells referred to as the Warburg effect (12). As ...

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Section: Starvation Of Cancer Cellssupporting

confidence: 74%

Metabolic Approaches to Treatment of Melanoma

Hersey

Watts

Zhang

et al. 2009

Clinical Cancer Research

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“…The results from the current study establish that a low, non-cytotoxic dose of 3-BrPA is sufficient to induce metabolic perturbation in order to elevate the surface expression level of MICA/B. 3-BrPA has been shown to promote antitumor effects in many solid malignancies including liver, 30,31 breast, 32 pancreas, 33 brain 34 and colon cancers. 35 However, at the dose tested in this study, no cytotoxicity or antitumor effects "per se" have been reported.…”

Section: Discussionsupporting

confidence: 59%

Metabolic perturbation sensitizes human breast cancer to NK cell-mediated cytotoxicity by increasing the expression of MHC class I chain-related A/B

Geschwind

Karthikeyan

et al. 2015

OncoImmunology

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Cleavage or shedding of the surface antigen, MHC class I chain-related (MIC) protein (A/B) has been known to be one of the mechanisms by which tumor cells escape host immune surveillance. Thus, any strategy to augment the surface expression of MICA/B could facilitate anticancer immune response. Here, we demonstrate that metabolic perturbation by the glycolytic inhibitor, 3-bromopyruvate (3-BrPA) augments the surface expression of MICA/B in human breast cancer cell lines, MDA-MB-231 and T47D. Data from in vitro studies show that a non-toxic, low-dose of 3-BrPA is sufficient to perturb energy metabolism, as evident by the activation of p-AMPK, p-AKT and p-PI3K. Further, 3-BrPAtreatment also elevated the levels of MICA/B in human breast cancer cell lines. Significantly, 3-BrPA-dependent increase in MICA/B levels also enhanced the sensitivity of cancer cells to natural killer (NK-92MI)-mediated cytotoxicity. In vivo, 3-BrPA-pretreated cells demonstrated greater sensitivity to NK-92MI therapy than their respective controls. The antitumor effect was confirmed by a reduction in tumor size and decreased tumor viability as observed by bioluminescence imaging. Histological examination and TUNEL staining demonstrated that NK-92MI administration promoted apoptosis in 3-BrPA-pretreated cells. Taken together, our data show that targeting energy metabolism could be a novel strategy to enhance the effectiveness of anticancer immunotherapeutics.

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“…The effects on HK, GAPDH, SDH and vacuolar H + ATPase mentioned above were observed in rat liver mitochondria and in normal rat thymocytes (Dell'Antone 2009); it was indeed proposed that above 20-30 μM, 3-BP may lead to severe toxic side effects (Dell'Antone 2006). Direct effects on highly ATPdependent spermatozoa have been reported (Jones et al 1996;Kumar et al 2008), and on similarly ATP-dependent kidney proximal tubule cells (Jones et al 1996); these findings are in line with effects on mitochondria and with increased uptake of FDG in liver and kidney (Vali et al 2008;Buijs et al 2009). Clearly, more investigation of 3-BP effects on normal cells is warranted.…”

Section: Tumor Specificity In Vivo Studies and Toxicitymentioning

confidence: 72%

3-bromopyruvate: Targets and outcomes

Shoshan

2012

J Bioenerg Biomembr

130

100

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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. The cytotoxicity of 3-BP is less due to pyruvate mimicry than to alkylation of, e.g., key thiols. Alkylation of DNA/RNA has not been reported. More research is warranted to better understand the pharmacokinetics of 3-BP, and its potential toxic effects to normal cells, in particular those that are highly ATP-/mitochondrion-dependent.

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Specificity of the anti-glycolytic activity of 3-bromopyruvate confirmed by FDG uptake in a rat model of breast cancer

Abstract: Our study showed that 3-BrPA exhibits a strong anti-glycolytic effect on RMT cells implanted in rats.

Cited by 30 publications

References 22 publications

Metabolic Approaches to Treatment of Melanoma

Metabolic Approaches to Treatment of Melanoma

Metabolic perturbation sensitizes human breast cancer to NK cell-mediated cytotoxicity by increasing the expression of MHC class I chain-related A/B

3-bromopyruvate: Targets and outcomes

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