EXTH-10: A novel small molecule therapy sensitizes high-grade glioma to temozolomide chemotherapy

Affiliations

Aurora Neuroscience Innovation Institute

Abstract

INTRODUCTION: Despite best medical therapy, high-grade glioma (HGG) has a poor prognosis, creating an urgent need for better therapies. The DNA-alkylating agent temozolomide (TMZ) is the standard HGG chemotherapy. However, TMZ benefits only a subset of patients, mainly because O-6-methylguanine-DNA methyltransferase (MGMT) repairs the TMZ-induced DNA damages, establishing TMZ resistance in many HGGs. Recent reports suggest peroxiredoxin (PRDX4) is an intriguing therapeutic target. PRDX4 decreases reactive oxygen species (ROS), decreases endoplasmic reticulum (ER) stress, and activates MGMT through STAT3. We have previously shown that these multiple oncostimulatory effects are mitigated by the safe, naturally occurring compound piperlongumine (PL), a specific inhibitor of PRDX4. We thus hypothesized that inactivation of PRDX4 by piperlongumine can sensitize HGGs to TMZ chemotherapy.

METHODS: We treated several MGMT expressing and non-expressing HGG cell lines with various doses of PL and TMZ. We then assessed cell proliferation and related molecular changes. We also tested in vivo efficacy of PL plus TMZ in an orthotopic mouse model of HGG.

RESULTS: Piperlongumine pretreatment sensitized TMZ-resistant HGG cells to TMZ in vitro, resulting in significantly increased HGG cell death. The underlying mechanism of the synergistic effect may include STAT3 inactivation. Finally, piperlongumine plus TMZ treatment prolonged the survival of orthotopic mouse model of HGGs.

CONCLUSION: Piperlongumine is a safe, natural compound with minimal toxicity to normal cells. Moreover, piperlongumine crosses the blood brain barrier. Therefore, utilizing piperlongumine to sensitize TMZ-resistant HGGs should be considered as a putative HGG therapy. At the conclusion of this session, participants will be able to: Describe the mechanisms of action of PRDX4, describe the mechanism of action of piperlongumine, and review the effect of PL and TMZ on HGG cells in culture and in xenograft models.

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Abstract

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