12-O-tetradecanoylphorbol-13-acetate (TPA) increases murine intestinal crypt stem cell survival following radiation injury.

Yaojie Liang,Kun Qian,Lei Zhou,Ailing Deng,Yonghui Li,Wanping Deng,Li Wang,Lili Wang,Anqi Liu,Lanlan Qiu,Hongwei Zhou,Bianhong Wang,Zhihong Wang,Yu Cui,Zhengtao Han,Boning Gao,Xi Zheng,Yuanrong Yao ,Min‐Hang Zhou ,Ye-Jian Lu ,Jian Sun

doi:10.18632/oncotarget.17269

Abstract

Radiation enteropathy is a common complication in cancer patients following radiation therapy. Thus, there is a need for agents that can protect the intestinal epithelium against radiation. 12-O-tetradecanoylphorbol-13-acetate (TPA) has been shown to induce differentiation and/or apoptosis in multiple cell lines and primary cells. In the current report, we studied the function of TPA in radiation induced enteropathy in cultured rat intestinal epithelial cell line IEC-6 after ionizing radiation (IR) and in mice after high dose total-body gamma-IR (TBI). In IEC-6 cells, there were reduced apoptosis and cell cycle arrest in TPA treated cells after IR. We detected a four-fold increase in crypt cell survival and a two-fold increase in animal survival post TBI in TPA treated mice. The beneficial effects of TPA were accompanied by upregulation of stem cells markers and higher level of proteins that are involved in PKC signaling pathway. In addition, TPA also decreased the TBI-augmented levels of the DNA damage indicators. The effects were only observed when TPA was given before irradiation. These results suggest that TPA has the ability to modulate intestinal crypt stem cells survival and this may represent a promising countermeasure against radiation induced enteropathy.

Highlights

Radiotherapy is one of the major treatment modalities used to control or eradicate malignant solid tumors, which is used in at least 50% of patients with cancer and plays a crucial role in 25% of cancer cures [1]
We studied the function of TPA in radiation induced enteropathy in cultured rat intestinal epithelial cell line IEC-6 after ionizing radiation (IR) and in mice after high dose total-body gamma-IR (TBI)
These results suggest that TPA has the ability to modulate intestinal crypt stem cells survival and this may represent a promising countermeasure against radiation induced enteropathy

Summary

Introduction

Radiotherapy is one of the major treatment modalities used to control or eradicate malignant solid tumors, which is used in at least 50% of patients with cancer and plays a crucial role in 25% of cancer cures [1]. The intestinal epithelium is very sensitive to ionizing radiation (IR) injury [2, 3], and is one of the organs most vulnerable to radiation toxicity [4]. Radiation enteropathy is a common complication in cancer patients following radiotherapy, especially in those treated for abdominal and pelvic tumors who experience more pronounced side effects than others. Effective therapeutic remedies are urgently needed, and identifying effective and useful substances for the prevention or treatment of intestinal and others injuries due to radiation exposure is of utmost importance

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Results

Conclusion