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Oridonin induced A375-S2 cell apoptosis VIA BAX-regulated caspase pathway activation, dependent on the cytochrome C/CASPASE-9 apoptosome

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Two diterpenoids, oridonin (1) and ponicidin (2), were isolated from the 95% ethanol extract of Rabdosia rubescens and were evaluated for antiproliferative activity on cancer cells and human peripheral blood mononuclear cells (PBMC) in vitro. Oridonin has much more potent cytotoxic effects on four tumor cells (human melanoma A375-S2, human cervical cancer HeLa, human breast adenocarcinoma MCF-7, murine fibrosarcoma L929) than does ponicidin. The growth-inhibitory activity of oridonin for A375-S2 cells was more potent than that for the other cell lines, with an IC
50
of 15.1±1.2 μmol L-1. Treatment with oridonin (34.3 μmol L
-1
) for 12 h significantly inhibited A375-S2 cell growth, and showed weaker cytotoxicity against PBMC. By contrast, ponicidin markedly inhibited the growth of PBMC under the same conditions. When caspases-3 and -8 were activated at early stages after treatment of A375-S2 cells with oridonin (34.3 μmol L
-1
), apoptotic bodies were formed, nuclear damage was observed by Hoechst 33258 staining and DNA fragmentation was exhibited. In addition, oridonin increased the expression of the apoptosis inducer, Bax, promoted the release of cytochrome c without affecting Bcl-2 expression, and activated down-stream caspase-9 in the mitochondrial pathway. These observations indicated that an appropriate dose of oridonin gave an initial premitochondrial phase that involved the Bcl-2 family of the pro-apoptotic protein Bax that required the participation of caspase-9 and caspase-3. However, on treatment with oridonin (137.4 μmol L
-1
) for 12 h, the majority of A375-S2 cells underwent necrosis as measured by an LDH activity-based assay. Our results suggest that oridonin induces A375-S2 cell death on the balance of apoptosis and necrosis.
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Keywords: A375-S2; Apoptosis; Bax; Caspase; Necrosis; Oridonin

Document Type: Research Article

Affiliations: 1: China-Japan Research Institute of Medical and Pharmaceutical Sciences Shenyang Pharmaceutical University 110016 Shenyang China 2: Department of Phytochemistry Shenyang Pharmaceutical University 110016 Shenyang China 3: Department of Clinical and Biomedical Sciences Showa Pharmaceutical University 194-8543 Tokyo Japan

Publication date: June 1, 2004

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