Senolytics (DQ) Mitigates Radiation Ulcers by Removing Senescent Cells.

Huilan Wang,Qingzhi Jiang,Min Luo,Xiaowu Sheng,Ziwen Wang,Yawei Wang,Yu Huang,Peng Luo,Yue Zhou,Chunmeng Shi

doi:10.3389/fonc.2019.01576

Abstract

Radiation ulcers are a prevalent toxic side effect in patients receiving radiation therapy. At present, there is still no effective treatment for the complication. Senescent cells accumulate after radiation exposure, which can induce cell and tissue dysfunction. Here we demonstrate increased expression of p16 (a senescence biomarker) in human radiation ulcers after radiotherapy and radiation-induced persistent cell senescence in animal ulcer models. Furthermore, senescent cells secreted the senescence-associated secretory phenotype (SASP) and induced cell senescence in adjacent cells, which was alleviated by JAK inhibition. In addition, the clearance of senescent cells following treatment with a senolytics cocktail, Dasatinib plus Quercetin (DQ), mitigated radiation ulcers. Finally, DQ induced tumor cell apoptosis and enhanced radiosensitivity in representative CAL-27 and MCF-7 cell lines. Our results demonstrate that cell senescence is involved in the development of radiation ulcers and that elimination of senescent cells might be a viable strategy for patients with this condition.

Highlights

Radiation therapy is a common and efficacious treatment for patients with solid cancers
Senescence can be induced by multiple mechanisms such as DNA damage, reactive oxygen species (ROS) production, and oxidative stress [21], and DNA damage is a critical mediator of cellular alterations caused by radiation exposure [22]
To explore the hypothesis that cell senescence and senescence-associated secretory phenotype (SASP) are related to human radiation ulcers after radiotherapy, we first analyzed established senescence genes in the GSE103412 dataset [23] corresponding to mucositis in patients with tonsil squamous cell carcinoma and control human cohorts

Summary

Introduction

Radiation therapy is a common and efficacious treatment for patients with solid cancers. About 50% of cancer patients receive radiation therapy, alone or in combination with other treatment methods such as surgery [1]. Radiotherapy is the main treatment method for patients with head and neck tumors and has varying success [2], but oral mucositis is a crucial dose-limiting toxic effect [3]. Palifermin, a recombinant human form of keratinocyte growth factor (KGF), is the only U.S Food & Drug Administration–approved agent that is used to prevent oral mucositis in patients with bone marrow transplantation, but fibroblast growth factor receptor 2b (FGFR2b) is often overexpressed in cancer cells and increases the risk of tumor growth [6].

Methods

Results

Conclusion