Jaridonin, a Novel Ent-Kaurene Diterpenoid from Isodon rubescens, Inducing Apoptosis via Production of Reactive Oxygen Species in Esophageal Cancer Cells

Yong-Cheng      Ma; Yu      Ke; Xiaolin      Zi; Wen      Zhao; Xiao-Jing      Shi; Hong-Min      Liu

doi:10.2174/15680096113139990030

Abstract

Isodon rubescens, a Chinese herb, has been used as a folk, botanical medicine in China for inflammatory diseases and cancer treatment for many years. Recently, we isolated a new ent-kaurene diterpenoid, named Jaridonin, from Isodon rubescens. The chemical structure of Jaridonin was verified by Infrared (IR), Nuclear magnetic resonance (NMR), and Mass spectrum (MS) data as well as X-ray spectra. Jaridonin potently reduced viabilities of several esophageal cancer cell lines, including EC109, EC9706 and EC1. Jaridonin treatment resulted in typical apoptotic morphological characteristics, increased the number of annexin V-positive staining cells, as well as caused a G2/M arrest in cell cycle progression. Furthermore, Jaridonin resulted in a significant loss of mitochondrial membrane potential, release of cytochrome c into the cytosol, and then activation of Caspase-9 and -3, leading to activation of the mitochondria mediated apoptosis. Furthermore, these effects of Jaridonin were accompanied by marked reactive oxygen species (ROS) production and increased expression of p53, p21waf1/Cip1 and Bax, whereas two ROS scavengers, N-acetyl-L-cysteine (LNAC) and Vitamin C, significantly attenuated the effects of Jaridonin on the mitochondrial membrane potential, DNA damage, expression of p53 and p21waf1/Cip1 and reduction of cell viabilities. Taken together, our results suggest that a natural ent-kaurenoid diterpenoid, Jaridonin, is a novel apoptosis inducer and deserves further investigation as a new chemotherapeutic strategy for patients with esophageal cancer.

Keywords: Apoptosis, ent-kaurene diterpenoid, esophageal cancer, mitochondria pathway, rabdosia rubescens, reactive oxygen species.