Apigenin inhibits renal cell carcinoma cell proliferation.

Shuai Meng,Li-Ping Xie,Zhen Liang,Yi Zhu,Hong Chen,Xiao Wang,Jiang-Feng Li,Shi-Qi Li,Xin Xu,Ben Liu,Xiang-Yi Zheng

doi:10.18632/oncotarget.15771

Abstract

Apigenin, a natural flavonoid found in vegetables and fruits, has antitumor activity in several cancer types. The present study evaluated the effects and mechanism of action of apigenin in renal cell carcinoma (RCC) cells. We found that apigenin suppressed ACHN, 786-0, and Caki-1 RCC cell proliferation in a dose- and time-dependent manner. A comet assay suggested that apigenin caused DNA damage in ACHN cells, especially at higher doses, and induced G2/M phase cell cycle arrest through ATM signal modulation. Small interfering RNA (siRNA)-mediated p53 knockdown showed that apigenin-induced apoptosis was likely p53 dependent. Apigenin anti-proliferative effects were confirmed in an ACHN cell xenograft mouse model. Apigenin treatment reduced tumor growth and volume in vivo, and immunohistochemical staining revealed lower Ki-67 indices in tumors derived from apigenin-treated mice. These findings suggest that apigenin exposure induces DNA damage, G2/M phase cell cycle arrest, p53 accumulation and apoptosis, which collectively suppress ACHN RCC cell proliferation in vitro and in vivo. Given its antitumor effects and low in vivo toxicity, apigenin is a highly promising agent for treatment of RCC.

Highlights

As a natural phytoestrogen flavonoid widely distributed in vegetables and fruits [1], apigenin (4’,5,7-trihydroxyflavone) effectively inhibits proliferation in multiple cancer cell types, including colon, lung, breast, prostate, melanoma, and leukemia [2,3,4,5,6,7] and DNA damage mechanisms were comprised in lots of studies [8]
These findings suggest that apigenin exposure induces DNA damage, G2/M phase cell cycle arrest, p53 accumulation and apoptosis, which collectively suppress ACHN renal cell carcinoma (RCC) cell proliferation in vitro and in vivo
Cell Counting Kit-8 (CCK-8) analysis indicated that treatment with apigenin at varying concentrations (5–80 μM) inhibited proliferation of ACHN, 786-0, and Caki-1 RCC cells, and of the normal renal proximal tubule epithelial cell line, HK-2, in a dose- and time-dependent manner (Figure 1A)

Summary

Introduction

As a natural phytoestrogen flavonoid widely distributed in vegetables and fruits [1], apigenin (4’,5,7-trihydroxyflavone) effectively inhibits proliferation in multiple cancer cell types, including colon, lung, breast, prostate, melanoma, and leukemia [2,3,4,5,6,7] and DNA damage mechanisms were comprised in lots of studies [8]. Renal cell carcinoma (RCC) is the most common type of adult malignant kidney tumor. RCC is the most lethal of the common urological cancers; despite diagnostic advances, 25–30% of patients present with metastasis. Suitable therapeutic agents must reduce RCC proliferation, but should have low toxicity in healthy tissues. We designed the present study to investigate whether apigenin had anti-proliferation activity in RCC cell lines in vitro and in vivo. We observed for the first time that apigenin exposure induced DNA damage, G2/M phase cell cycle arrest, and apoptosis in ACHN RCC cells via ATM serine/threonine kinase signaling modulation and the p53 pathway

Methods

Results

Conclusion