Inhibition of caspase-9 by oridonin, a diterpenoid isolated from Rabdosia rubescens, augments apoptosis in human laryngeal cancer cells

Kang,Ning; Cao,Shi-Jie; Zhou,Yan; He,Hao; Tashiro,Shin-Ichi; Onodera,Satoshi; Qiu,Feng; Ikejima,Takashi

doi:10.3892/ijo.2015.3186

Inhibition of caspase-9 by oridonin, a diterpenoid isolated from Rabdosia rubescens, augments apoptosis in human laryngeal cancer cells

Authors:
- Ning Kang
- Shi-Jie Cao
- Yan Zhou
- Hao He
- Shin-Ichi Tashiro
- Satoshi Onodera
- Feng Qiu
- Takashi Ikejima
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Affiliations: School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, P.R. China, Department of Natural Products Chemistry, Shenyang Pharmaceutical University, Shenyang 110016, P.R. China, China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang 110016, P.R. China, Institute for Clinical and Biomedical Sciences, Kyoto 603-8072, Japan, Department of Clinical and Biomedical Science, Showa Pharmaceutical University, Tokyo 194-8543, Japan, College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, P.R. China
Published online on: September 28, 2015 https://doi.org/10.3892/ijo.2015.3186
Pages: 2045-2056
Copyright: © Kang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Rabdosia rubescens, a commonly used traditional Chinese medicine, has increasingly gained attention for its use as an antitumor herb. Oridonin, a bioactive diterpenoid isolated from Rabdosia rubescens, has been reported to induce apoptosis in human laryngeal cancer HEp-2 cells by our group. Here, we made unexpected observations that the caspase-9 inhibitor (C9i) enhanced apoptosis in response to selected stimuli, and HEp-2 cells which were made deficient in caspase-9 using siRNA exhibited no resistance to apoptotic signals and actually demonstrated increased apoptotic sensitivity to oridonin. The results were reversed by the transfection of an exogenous caspase-9 expression vector. Caspase-9 reduced sensitivity to apoptotic stimuli through reactive oxygen species (ROS)-suppressing and autophagy-promoting methods. ROS triggered the progression of apoptosis through activation of both the caspase-9-independent mitochondrial pathway and death receptor pathways, and the autophagy had an anti-apoptotic function in oridonin-treated HEp-2 cells. These collective results suggest that oridonin targets caspase-9 to alter ROS production and autophagy situation to promote HEp-2 cell apoptosis. Therefore, oridonin has the potential to be developed as an anticancer agent, and the combination of oridonin with those agents leading to reduction of caspase-9 expression in tumor cells could represent a novel approach to human laryngeal cancer treatment.

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