A novel compound modified from tanshinone inhibits tumor growth in vivo via activation of the intrinsic apoptotic pathway

Tian, Hong-Lei; Yu, Ting; Xu, Nai-Ning; Feng, Chao; Zhou, Li-Ying; Luo, Hou-Wei; Chang, Donald C.; Le, Xiao-Feng; Luo, Kathy Qian

doi:10.1016/j.canlet.2010.04.020

« Previous Next »Cancer Letters
Volume 297, Issue 1 , Pages 18-30, 1 November 2010

A novel compound modified from tanshinone inhibits tumor growth in vivo via activation of the intrinsic apoptotic pathway

Hong-Lei Tian
- Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong
Ting Yu
- Division of Bioengineering, School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore 637457, Singapore
Nai-Ning Xu
- Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong
Chao Feng
- Department of Chemical and Biomolecular Engineering, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong
Li-Ying Zhou
- Department of Chemical and Biomolecular Engineering, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong
Hou-Wei Luo
- Department of Natural Medical Chemistry, China Pharmaceutical University, Nanjing, China
Donald C. Chang
- Department of Biology, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong
Xiao-Feng Le
- Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
Kathy Qian Luo
- Division of Bioengineering, School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore 637457, Singapore
- Corresponding author. Address: Division of Bioengineering, School of Chemical and Biomedical Engineering, Nanyang Technological University, 70 Nanyang Drive, Singapore 637457, Singapore. Tel.: +65 6790 4257; fax: +65 6791 1761.

Received 30 December 2009; received in revised form 12 April 2010; accepted 22 April 2010. published online 24 May 2010.

Abstract

A novel compound, acetyltanshinone IIA (ATA) was obtained from chemical modifications of tanshinone TIIA (TIIA) isolated from a medicinal plant, Salvia miltiorrhiza. ATA exhibited increased water solubility and stronger apoptotic activity on multiple cancer cell lines than TIIA. ATA displayed a higher growth inhibition ability on breast cancer especially HER2 positive cells than normal cells and it inhibited xenografted tumor growth in mice. Mechanistic studies showed that ATA could induce significant reactive oxygen species (ROS) generation, Bax translocation to mitochondria, resulting in mitochondria damage, cytochrome c release, caspase-3 activation and apoptotic cell death. ATA-mediated ROS production and its downstream apoptotic events could be blocked by an antioxidant agent, propyl gallate, indicating the prominent role of ROS in ATA-induced apoptosis. Overexpression of Bcl-2 protein reduced ATA-induced cell death. In conclusion, ATA is a novel anticancer agent with potent in vitro and in vivo anticancer ability. ROS-mediated Bax activation should be the mechanism by which ATA induces apoptosis and inhibits tumor growth.

Keywords: Breast cancer, Anticancer drug, Apoptosis, Reactive oxygen species, Tanshinone IIA