title: Inhibition of caspase-9 by oridonin, a diterpenoid isolated from Rabdosia rubescens, augments apoptosis in human laryngeal cancer cells.
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.
authors.affiliation: School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, P.R. China.
authors.forename: Ning
authors.initials: N
authors.lastname: Kang
authors.affiliation: Department of Natural Products Chemistry, Shenyang Pharmaceutical University, Shenyang 110016, P.R. China.
authors.forename: Shi-Jie
authors.initials: SJ
authors.lastname: Cao
authors.affiliation: Department of Natural Products Chemistry, Shenyang Pharmaceutical University, Shenyang 110016, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang 110016, P.R. China.
authors.forename: Hao
authors.initials: H
authors.lastname: He
authors.affiliation: Institute for Clinical and Biomedical Sciences, Kyoto 603-8072, Japan.
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Tashiro
authors.affiliation: Department of Clinical and Biomedical Science, Showa Pharmaceutical University, Tokyo 194-8543, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Onodera
authors.affiliation: College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, P.R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Qiu
authors.affiliation: China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang 110016, P.R. China.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ikejima
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D015153:Blotting, Western; D053453:Caspase 9 / Q000378:metabolism*; D045744:Cell Line, Tumor; D045786:Diterpenes, Kaurane / Q000494:pharmacology*; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D006801:Humans; D037602:Isodon / Q000737:chemistry; D007822:Laryngeal Neoplasms / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D046529:Microscopy, Electron, Transmission; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D014162:Transfection
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D045786:Diterpenes, Kaurane; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C011959:oridonin; C506433:CASP9 protein, human; D053453:Caspase 9