# Metabolic targeting of cancer cells via the methylglyoxal detoxification systems

> **NIH NIH SC2** · CALIFORNIA STATE UNIVERSITY NORTHRIDGE · 2020 · $121,600

## Abstract

PROJECT SUMMARY/ABSTRACT
The rapid proliferation of cancer cells is often fueled by a significant elevation in glucose
consumption. A consequence of sustained elevation in glycolytic flux is the generation of
reactive carbonyl species such as methylglyoxal (MG). MG can form advanced glycation end-
products (AGEs) with amino acids, nucleic acids and lipids. The DNA AGE is of particular
interest because it serves as a molecular link between dysregulated glucose metabolism and
genome instability. In order to prevent the formation of AGEs, cells deploy the glutathione-
dependent Glyoxalase 1/2 (Glo1/2) pathway. Glo1 is over-expressed in breast and prostate
tumors and has been correlated with poor prognosis. Separately, BRCA1/2 defective breast,
ovarian and metastatic prostate cancers are being treated effectively in the clinic with inhibitors
of poly(ADP-ribose) polymerase (PARP). Here, we propose to investigate the inhibition of Glo1
using a glutathione analogue, S-p-bromobenzyl glutathione cyclopentyl diester [p-
BrBzGSH(Cp)2]. A novel stable isotope dilution liquid chromatography tandem mass
spectrometry (SID-LC/MS/MS) method will be used to quantify the DNA AGE, CEdG in Glo1
inhibitor treated cancer cells. Our long-term goal is to see if we can leverage Glo1 to target
aggressive glycolytic tumors that lack targeted therapy. We propose that effective inhibition of
MG detoxification pathways via Glo1 or aldo-keto reductase (AKR) inhibition will lead to the
formation of CEdG and downstream mutations and single strand breaks and potentiate cell
death. (Aim 1) To determine the biological effects of Glo1 inhibition in breast, prostate, ovarian,
and pancreatic cancer cells. (Aim 2) To interrogate the synergy of Glo1 inhibition with the
inhibition of DNA repair pathways. Progress towards these Specific Aims will contribute
towards establishing a strategy of pairing a novel metabolic target with a PARP inhibitor to
selectively kill glycolytic cancer cells with diminished DNA repair capacity. We do anticipate
that there may be compensatory responses to Glo1 inhibition, we are aware of the aldo-keto
reductase superfamily of NADPH-dependent oxido-reductases that may detoxify MG in the
absence of Glo1 activity. We are also aware of the potential over-expression of the glutathione
biosynthesis pathway that may respond in the event of effective Glo1 inhibition. This proposal
will work towards illuminating a potential novel strategy for targeting glycolytic tumors for
which there are no targeted therapy such as triple negative breast cancer and metastatic
castration-resistant prostate cancer.

## Key facts

- **NIH application ID:** 9864079
- **Project number:** 5SC2GM130471-02
- **Recipient organization:** CALIFORNIA STATE UNIVERSITY NORTHRIDGE
- **Principal Investigator:** Daniel Tamae
- **Activity code:** SC2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $121,600
- **Award type:** 5
- **Project period:** 2019-02-05 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9864079

## Citation

> US National Institutes of Health, RePORTER application 9864079, Metabolic targeting of cancer cells via the methylglyoxal detoxification systems (5SC2GM130471-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9864079. Licensed CC0.

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