Biomol Ther  
Cis-3-O-p-hydroxycinnamoyl Ursolic Acid Induced ROS-Dependent p53-Mediated Mitochondrial Apoptosis in Oral Cancer Cells
Ching-Ying Wang1,†, Chen-Sheng Lin2,†, Chun-Hung Hua3,†, Yu-Jen Jou1, Chi-Ren Liao4, Yuan-Shiun Chang4, Lei Wan5, Su-Hua Huang6, Mann-Jen Hour7,* and Cheng-Wen Lin1,6,*
1Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 40402, Taiwan
2Division of Gastroenterology, Kuang Tien General Hospital, Taichung 43303, Taiwan
3Department of Otolaryngology, China Medical University Hospital, Taichung 40447, Taiwan
4Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung 40402, Taiwan
5Department of Medical Genetics and Medical Research, China Medical University Hospital, Taichung 40447, Taiwan
6Department of Biotechnology, Asia University, Wufeng, Taichung 41357, Taiwan
7School of Pharmacy, China Medical University, Taichung 40402, Taiwan
E-mail: (Lin CW), (Hour MJ)
Tel: +886-4-22053366 (Lin CW), +886-4-22053366 (Hour MJ)
Fax: +886-4-22057414 (Lin CW), +886-4-22078083 (Hour MJ)
The first three authors contributed equally to this work.
Received: December 4, 2017; Revised: July 5, 2018; Accepted: August 8, 2018; Published online: September 27, 2018.
© The Korean Society of Applied Pharmacology. All rights reserved.

Cis-3-O-p-hydroxycinnamoyl ursolic acid (HCUA), a triterpenoid compound, was purified from Elaeagnus oldhamii Maxim. This traditional medicinal plant has been used for treating rheumatoid arthritis and lung disorders as well as for its anti-inflammation and anticancer activities. This study aimed to investigate the anti-proliferative and apoptotic-inducing activities of HCUA in oral cancer cells. HCUA exhibited anti-proliferative activity in oral cancer cell lines (Ca9-22 and SAS cells), but not in normal oral fibroblasts. The inhibitory concentration of HCUA that resulted in 50% viability was 24.0 μM and 17.8 μM for Ca9-22 and SAS cells, respectively. Moreover, HCUA increased the number of cells in the sub-G1 arrest phase and apoptosis in a concentration-dependent manner in both oral cancer cell lines, but not in normal oral fibroblasts. Importantly, HCUA induced p53-mediated transcriptional regulation of pro-apoptotic proteins (Bax, Bak, Bim, Noxa, and PUMA), which are associated with mitochondrial apoptosis in oral cancer cells via the loss of mitochondrial membrane potential. HCUA triggered the production of intracellular reactive oxygen species (ROS) that was ascertained to be involved in HCUA-induced apoptosis by the ROS inhibitors YCG063 and N-acetyl-L-cysteine. As a result, HCUA had potential antitumor activity to oral cancer cells through eliciting ROS-dependent and p53-mediated mitochondrial apoptosis. Overall, HCUA could be applicable for the development of anticancer agents against human oral cancer.
Keywords: Cis-3-O-p-hydroxycinnamoyl ursolic acid, Oral cancer cells, ROS, Mitochondrial apoptosis

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