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

doi:10.1016/j.bbrc.2004.09.047

Biochemical and Biophysical Research Communications

Volume 324, Issue 1, 5 November 2004, Pages 269-275

https://doi.org/10.1016/j.bbrc.2004.09.047 Get rights and content

Abstract

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 (2–3 cm) 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.

Section snippets

Materials and methods

Cell source, passage, culture, and viability or ATP content ±3-BrPA. A highly glycolytic hepatocellular carcinoma (HCC) line “AS-30D” [7], [8] was used and maintained (Fig. 1A) in female Sprague–Dawley rats (Charles River). For culture, cells (∼1 × 10⁶) were seeded on a six-well plate in 2 ml RPMI 1640 medium (Invitrogen) containing 10% fetal bovine serum plus 1× antibiotic–antimycotic mixture (Invitrogen) at 37 °C for 3 h in a CO₂ incubator. Hepatocytes (∼ 1.5 × 10⁶) were fresh from Cambrex. Cell

The chemical agent 3-BrPA depletes ATP stores and inhibits HCC cell viability

For therapy, we selected the alkylating agent 3-BrPA [13]. This was based on the hypothesis that because of its structural similarity to lactate (Fig. 1B), the reactive 3-BrPA may enter cancer cells on the same transporter that exports lactate and then induce ATP depletion. Although earlier work [14], [15] showed that 3-BrPA inhibits in vitro the cell’s two ATP producing systems, glycolysis and mitochondria, and has antitumor activity, the most critical support for the above hypothesis is

Acknowledgments

Drs. Paul Talalay and Donald Coffey are acknowledged for valuable discussions and James Fox and David Blum for technical assistance. Y.H.K. is grateful also to Ilona McClintick and Dr. Ann Morrill for encouragement.

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^☆: This work was supported by start-up funds to Y.H.K. from the Department of Radiology, by NIH Grants CA 10951 and CA 80118 to P.L.P. and Grant CA92871 to M.G.P.

^☆☆: Abbreviations: 3-BrPA, 3-bromopyruvic acid; HCC, hepatocellular carcinoma; PET, positron emission tomography; FDG, ¹⁸F-2-deoxyglucose.

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Biochemical and Biophysical Research Communications

Abstract

Section snippets

Materials and methods

The chemical agent 3-BrPA depletes ATP stores and inhibits HCC cell viability

Acknowledgments

References (15)

Focus on hepatocellular carcinoma

Cancer Cell

Mitochondrial bound type II hexokinase: a key player in the growth and survival of many cancers and an ideal prospect for therapeutic intervention

Biochim. Biophys. Acta

Hexokinase II and VEGF expression in liver tumors: correlation with hypoxia-inducible factor 1 alpha and its significance

J. Hepatol.

Alkylation of isocitrate lyase from Escherichia coli by 3-bromopyruvate

Arch. Biochem. Biophys.

Glucose catabolism in the rabbit VX2 tumor model for liver cancer: characterization and targeting hexokinase

Cancer Lett.

The Metabolism of Tumors

Tumor mitochondria and the bioenergetics of cancer cells

Prog. Exp. Tumor Res.

Cited by (321)

Targeting the Warburg effect: A revisited perspective from molecular mechanisms to traditional and innovative therapeutic strategies in cancer

Targeting metabolic reprogramming in hepatocellular carcinoma to overcome therapeutic resistance: A comprehensive review

Small-molecule redox modulators with anticancer activity: A comprehensive mechanistic update

Oxygen-economizing liposomes for synergistic photodynamic and starvation therapy

Translating a radiolabeled imaging agent to the clinic

Network biology and artificial intelligence drive the understanding of the multidrug resistance phenotype in cancer

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

Abstract

Section snippets

Materials and methods

The chemical agent 3-BrPA depletes ATP stores and inhibits HCC cell viability

Acknowledgments

Cancer Cell

Biochim. Biophys. Acta

J. Hepatol.

Arch. Biochem. Biophys.

Cancer Lett.

The Metabolism of Tumors

Tumor mitochondria and the bioenergetics of cancer cells

Prog. Exp. Tumor Res.