Shikonin induces ROS-based mitochondria-mediated apoptosis in colon cancer

// Wenquan Liang 1, 2, * , Jianxin Cui 1, 2, * , Kecheng Zhang 1, 2, * , Hongqing Xi 1, 2 , Aizhen Cai 1 , Jiyang Li 1, 2 , Yunhe Gao 1, 2 , Chong Hu 1, 2 , Yi Liu 1, 2 , Yixun Lu 1, 2 , Ning Wang 1 , Xiaosong Wu 1 , Bo Wei 1, 2 and Lin Chen 1, 2 1 Department of General Surgery, Chinese People’s Liberation Army General Hospital, Beijing 100853, China 2 Institute of General Surgery, Chinese People’s Liberation Army General Hospital, Beijing 100853, China * These authors have contributed equally to this work Correspondence to: Lin Chen, email: chenlinbj@sina.com Bo Wei, email: weibo@vip.163.com Xiaosong Wu, email: wuxs216@163.com Keywords: colon cancer; shikonin; ROS; mitochondria; apoptosis Received: January 10, 2017      Accepted: August 26, 2017      Published: November 17, 2017 ABSTRACT Colon cancer is the third most common malignancy worldwide, and chemotherapy is a widely used strategy in clinical therapy. Chemotherapy-resistant of colon cancer is the main cause of recurrence and progression. Novel drugs with efficacy and safety in treating colon cancer are urgently needed. Shikonin, a naphthoquinone derived from the roots of the herbal plant Lithospermum erythrorhizon , has been determined to be a potent anti-tumor agent. The aim of the present study was to detect the underlying anti-tumor mechanism of shikonin in colon cancer. We found that shikonin suppressed the growth of colon cancer cells in a dose-dependent manner in vitro and in vivo . Shikonin induced mitochondria-mediated apoptosis, which was regulated by Bcl-2 family proteins. Shikonin increased the generation of intracellular ROS, which played an upstream role in shikonin-induced apoptosis. Our data indicated that generation of ROS, down-regulated expression of Bcl-2 and Bcl-xL, depolarization of the mitochondrial membrane potential and activation of the caspase cascade were components of the programmed event of shikonin-induced apoptosis in colon cancer cells. In addition, shikonin presented minimal toxicity to non-neoplastic colon cells and no liver injury in xenograft models, showing safety in the control of colon cancer cell growth in vitro and in vivo . Taken together, our findings suggest that shikonin might serve as a potential novel therapeutic drug in the treatment of human colon cancer.