Bardoxolone-Methyl (CDDO-Me) Impairs Tumor Growth and Induces Radiosensitization of Oral Squamous Cell Carcinoma Cells.

Cornelius Hermann,Dirk Steinritz,Matthias Port,Simon Lang,Alexis Rump,Tanja Popp,Susanne Hafner,Stefan Eder

doi:10.3389/fphar.2020.607580

Abstract

Radiotherapy represents a common treatment strategy for patients suffering from oral squamous cell carcinoma (OSCC). However, application of radiotherapy is immanently limited by radio-sensitivity of normal tissue surrounding the tumor sites. In this study, we used normal human epithelial keratinocytes (NHEK) and OSCC cells (Cal-27) as models to investigate radio-modulating and anti-tumor effects of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9,-dien-28-oic acid methyl ester (CDDO-Me). Nanomolar CDDO-Me significantly reduced OSCC tumor xenograft-growth in-ovo applying the chick chorioallantoic membrane (CAM) assay. In the presence of CDDO-Me reactive oxygen species (ROS) were found to be reduced in NHEK when applying radiation doses of 8 Gy, whereas ROS levels in OSCC cells rose significantly even without radiation. In parallel, CDDO-Me was shown to enhance metabolic activity in malignant cells only as indicated by significant accumulation of reducing equivalents NADPH/NADH. Furthermore, antioxidative heme oxygenase-1 (HO-1) levels were only enhanced in NHEK and not in the OSCC cell line, as shown by immunoblotting. Clonogenic survival was left unchanged by CDDO-Me treatment in NHEK but revealed to be abolished almost completely in OSCC cells. Our results indicate anti-cancer and radio-sensitizing effects of CDDO-Me treatment in OSCC cells, whereas nanomolar CDDO-Me failed to provoke clear detrimental consequences in non-malignant keratinocytes. We conclude, that the observed differential aftermath of CDDO-Me treatment in malignant OSCC and non-malignant skin cells may be utilized to broaden the therapeutic range of clinical radiotherapy.

Highlights

Malignancies of the oral cavity are among the most common cancers within the European Union
Cal-27 cells treated with CDDO-Me 6 h before receiving 2 Gy ionizing radiation (IR) were subsequently implanted on vascularized chick egg chorioallantoic membranes to test the inhibitory capacity of the triterpenoid on tumor growth
The unexpected absence of synergistic effects in the in ovo model prompted us to focus on the role of CDDO-Me itself first

Summary

Introduction

Malignancies of the oral cavity are among the most common cancers within the European Union. According to estimates of the European Cancer Information System (ECIS) over 45,000 cancer cases of the lip and oral cavity were diagnosed in 2018, representing a crude incidence rate of 8.9 per 100,000 (Likhtarev et al, 2006). The therapeutic window for radiotherapy is mainly narrowed by local side effects mainly due to damage of surrounding normal tissue when targeting cancer sites. Aside from the recent implementation and constant advancement of intensitymodulated radiotherapy (IMRT), a further strategy to restrict radiation doses for neighboring normal cells lies within the identification of small-molecule drugs allowing for the radiosensitization of cancer cells and ideally with a radio-protective effect on healthy tissue (Lindemann et al, 2018; Ho et al, 2019; Morra et al, 2019)

Methods

Results

Conclusion