Application of the antitussive agents oxelaidin and butamirate as anti-glioma agents

Sook-Ja Lee,Jee-Young Lee,Chaehwa Park,Seon-Yong Yeom

doi:10.1038/s41598-021-89238-9

Abstract

Glioblastoma (GBM) is an aggressive brain tumor with a strong tendency of relapse and resistance to chemotherapy, but we currently lack non-toxic agents that effectively treat GBM. In this study, high-throughput screening of FDA-approved drugs was performed to identify safe and effective molecules and test their effect on GBM cell lines, LN229, U87 and T98G. Cough suppressants, oxelaidin and butamirate inhibited GBM growth. A Ras family GTPase, Ras-related associated with diabetes (RRAD), contributes to activation of STAT3, which is essential for survival and growth of many cancer types. Interestingly, oxelaidin and butamirate did not affect proliferation in RRAD negative GBM cells. Docking simulation analyses revealed selective interactions between oxelaidin and RRAD. The mechanism by which butamirate and oxelaidin inhibits GBM cell growth involves the suppression of STAT3 transcriptional activity, leading to down-regulation of cyclin D1 and survivin. In addition, components of RRAD-associated signaling cascades, including p-EGFR, p-Akt, and p-STAT3, were inhibited upon oxelaidin treatment. Intraperitoneal administration of oxelaidin or butamirate markedly suppressed tumor growth in a glioblastoma xenograft mouse model without significant adverse effects. Our collective findings indicate that oxelaidin and butamirate exert anti-tumor effects in glioblastoma, supporting its utility as a novel therapeutic candidate for glioblastoma.

Highlights

Glioblastoma (GBM) is an aggressive brain tumor with a strong tendency of relapse and resistance to chemotherapy, but we currently lack non-toxic agents that effectively treat GBM
Database revealed a correlation between upregulation of Ras-related associated with diabetes (RRAD) in epidermal growth factor receptor (EGFR)-expressing glioma patients and poorer prognosis[10]. These findings suggest that expression of RRAD is critical for malignant progression of human glioma, supporting the theory that targeting RRAD may prolong the survival of RRAD-overexpressing glioblastoma patients
Owing to the nonspecific cytotoxicity (MI/topoisomerase inhibitors (TI)) and well-known efficacy (AH) against cancers, we focused on the antitussive agent, oxelaidin, which remained unknown for its anti-cancer activity (Fig. 1B)

Summary

Introduction

Glioblastoma (GBM) is an aggressive brain tumor with a strong tendency of relapse and resistance to chemotherapy, but we currently lack non-toxic agents that effectively treat GBM. A Ras family GTPase, Ras-related associated with diabetes (RRAD), contributes to activation of STAT3, which is essential for survival and growth of many cancer types. The mechanism by which butamirate and oxelaidin inhibits GBM cell growth involves the suppression of STAT3 transcriptional activity, leading to down-regulation of cyclin D1 and survivin. Components of RRAD-associated signaling cascades, including p-EGFR, p-Akt, and p-STAT3, were inhibited upon oxelaidin treatment. EGFR vIII and RRAD expression in glioblastoma tissue is associated with poor prognosis and correlated with activation of the EGFR/ STAT3 pathway along with resistance of cancer cells to cytotoxic d rugs. To identify RRAD inhibitors, we used a cell-based assay with a high RRAD-expressing glioblastoma cell line for screening ~ 2000 clinical compounds as a drug repositioning strategy. Owing to the nonspecific cytotoxicity (MI/TI) and efficacy (AH) against cancers, we focused on the antitussive agent, oxelaidin, which remained skku.edu

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