Cytochrome c Release From Oridonin-Treated Apoptotic A375-S2 Cells Is Dependent on p53 and Extracellular Signal-Regulated Kinase Activation

Zhang, Chunyu; Li-jun, WU; Zuo, Hai-Jun; Tashiro, Shin‐ichi; Onodera, Satoshi; Ikejima, Takashi

doi:10.1254/jphs.fpj04008x

Cited by 56 publications

(35 citation statements)

References 32 publications

(35 reference statements)

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“…[4][5][6][7][8] Inhibition of PI3K, PKC, MAPK, NFkB and activation of p53 have been suggested to underlie the effects of oridonin. [5][6][7][8][9]22,23 Our results in this study demonstrated that oridonin decreased cell viability in all the 3 tested cell lines in concentration-and time-dependent manner. The predominant mode of cell death in these cells was apoptosis, as determined by characteristic changes in cell morphology with Hochest 33258 staining and by the presence of sub-G 1 peak with flow cytometry measurement.…”

Section: Discussionsupporting

confidence: 55%

“…46 There are very limited studies on the regulation and function of MAPKs in oridonin-induced cell death. Oridonin has been demonstrated to induce the activation of ERK1/2 and inactivation of p38 MAPK in human macrophage-like U937 cells, murine fibrosarcoma cell line L929 and A375-S2 cell line 9,22,47,48 whereas, the activities of JNK was not affected by oridonin. 47 Inconsistent with these reports, our study demonstrated that oridonin treatment induced marked inactivation of ERK and activation of p38 MAPK and JNK.…”

Section: Discussionmentioning

confidence: 97%

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Oridonin induced apoptosis through Akt and MAPKs signaling pathways in human osteosarcoma cells

Jin¹,

Shen²,

Wang³

et al. 2007

Cancer Biology & Therapy

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Previous studies have shown that oridonin, a diterpenoid isolated from Rabdosia rubescens, was able to inhibit proliferation and induce apoptosis in several cell types. But the mechanisms remain poorly understood. In this study, we investigated the apoptosis-inducing effect and mechanisms of action of oridonin in human osteosarcoma cells. Our results demonstrated that oridonin induced concentration-and time-dependent suppression of proliferation and activation of apoptosis in U2OS, MG63 and SaOS-2 osteosarcoma cell lines. Oridonin induced the release of cytochrome c accompanied by activation of caspase-9, caspase-3 and cleavage of poly(ADP-ribose) polymerase (PARP). These events were all inhibited by z-VAD-fmk, a universal inhibitor of caspases. Oridonin treatment dephosphorylated constitutively active AKT, FOXO transcription factor, and glycogen synthase kinase 3 (GSK3). In addition, oridonin decreased the phosphorylation of ERK and increased the phosphorylation of p38 MAPK and JNK. Furthermore, oridonin treatment down-regulated the expression of the inhibitor of apoptosis protein(IAP) in osteosarcoma cells. All together, our results suggested that oridonin is able to inactivate Akt and ERK and activate p38 MAPK and JNK signalling pathways in osteosarcoma cells causing the suppression of proliferation and induction of mitochondria-and caspasedependent apoptosis.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 97%

Oridonin induced apoptosis through Akt and MAPKs signaling pathways in human osteosarcoma cells

Jin¹,

Shen²,

Wang³

et al. 2007

Cancer Biology & Therapy

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“…Previous reports have demonstrated that oridonin exerted inhibitory effects on various cancers such as human prostate carcinoma, non-small cell lung cancer, acute promyelocytic leukemia, and glioblastoma multiforme (5). In our previous study, we found that oridonin induced A375-S2 cell apoptosis via the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathway (6). In addition, we have shown that oridonin enhances 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated U937 cells to phagocytose UVirradiated apoptotic U937 cells by a mechanism involving tumor necrosis factor (TNF) α and interleukin (IL)-1β release (7).…”

Section: Introductionmentioning

confidence: 93%

Activation of Phosphoinositide 3-Kinase, Protein Kinase C, and Extracellular Signal-Regulated Kinase Is Required for Oridonin-Enhanced Phagocytosis of Apoptotic Bodies in Human Macrophage-Like U937 Cells

You

Tashiro

et al. 2005

J Pharmacol Sci

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Abstract. Our previous study showed that oridonin isolated from Rabdosia rubescens enhanced phagocytosis of apoptotic cells by macrophage-like U937 cells through tumor necrosis factor (TNF) α and interleukin (IL)-1β release. In this study, we further investigated signaling events involved in oridonin-augmented phagocytosis. Phagocytic stimulation was significantly suppressed by inhibitors, including a phosphoinositide 3-kinases (PI3K) inhibitor (wortmannin), a protein kinase C (PKC) inhibitor (stauroporine), and a phospholipase C (PLC) inhibitor (U73122). Exposure of U937 cells to oridonin caused an increase in PKC activity timedependently, which was prevented by pretreatment with inhibitors of PI3K and PLC. Simultaneously, the activation of protein kinase B (PKB / Akt) and the increased expression of PLCγ2 were also blocked by wortmannin. In addition, an extracellular signal-regulated kinase (ERK) MAPK inhibitor, PD98059, suppressed oridonin-augmented phagocytosis, whereas the p38 MAPK inhibitor (SB203580) and c-Jun N-terminal kinase (JNK) MAPK inhibitor (SP98059) had no inhibitory effect. Furthermore, pretreatment of U937 cells with anti-TNFα and anti-IL-1β antibodies blocked oridonin-induced phagocytic stimulation as well as phosphorylation of ERK, but did not block the activation of PKC, indicating that these signaling events are triggered by oridonin, whereas secreted TNFα or IL-1β only activate the ERK-dependent pathway. Taken together, oridonin is suggested to enhance phagocytosis of apoptotic bodies by activating PI3K, PKC, and ERK-dependent pathways.

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“…In the aggressive HT1080 fibrosarcoma cell line, oridonin has been shown to induce apoptosis through a p53-mediated mechanism that is regulated by nF-κB (20). another study with the human melanoma a375-S2 cell line also demonstrated that oridonin acts via a p53-mediated mechanism inhibited by blocking pi3-K pathway activation (21).…”

Section: Discussionmentioning

confidence: 98%

Genomic and in vivo evidence of synergy of a herbal extract compared to its most active ingredient: Rabdosia rubescens vs. oridonin

Wong

Zhang

Kesler

et al. 2010

Experimental and Therapeutic Medicine

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Abstract. Rabdosia rubescens is a herbal root extract of traditional Chinese medicine (TCM) used to treat inflammatory diseases and oral cancers. a key principle of tcm is that multiple ingredients in a plant extract are more effective and less toxic than a single purified active ingredient or a purified drug derived from a plant product. Rabdosia rubescens extract (RRE) contains terpenoids and flavonoids, but the most active ingredient within the extract attributed to the inhibition of cancer is the kaurene diterpene, oridonin. in order to research synergy with a complete plant extract, the effects of rrE on the inhibition of prostate cancer cell proliferation were compared to the effects of pure oridonin alone in vitro. three groups of 8 Scid mice bearing human prostate cancer xenografts (lapc-4) were administered either rrE containing 0.02 mg/g oridonin, pure oridonin at a dose of 0.02 mg/g, or pure oridonin at a dose of 0.1 mg/g, by gavage for 5 days/week for 4 weeks. rrE and pure oridonin at 0.1 mg/g inhibited tumor growth to a similar extent, while oridonin at a dose of 0.02 mg/g did not. Therefore, in comparison to RRE, five times more pure oridonin was required to obtain equivalent prostate xenograft growth inhibition. Since the nuclear factor-κB signaling pathway and inflammation are implicated in prostate carcinogenesis, gene microarray analysis was conducted and demonstrated activation of genes by rrE that was not evident with oridonin treatment alone. this study demonstrated that genomic methods and xenograft studies are capable of demonstrating the benefits of the synergy of whole plant extracts rather than active ingredients isolated and purified as drugs. IntroductionBotanical extracts are used for the prevention and treatment of common conditions by 80% of the world's population according to estimates made by the World health Organization (1). drugs are produced from botanical sources by isolation and purification of the most active ingredients, while other substances in the raw fraction are separated. Synergistic interactions of mixtures of bioactive constituents and related substances or analogs in plant extracts have been proposed to occur with the most active ingredient. these interactions help explain the improved effectiveness of extracts containing multiple ingredients compared to drugs developed from single constituents.We previously studied the action and metabolism of chinese red yeast rice (Monascus purpureus Went) (crYr), a dietary supplement containing monacolins, one of which (monacolin K) is identical in structure to the statin drug lovastatin, and to unsaturated fatty acids and phytosterols capable of lowering low-density lipoprotein (ldl) cholesterol in humans (2-5). the apparent bioactivity of crYr containing 6 mg of Monacolin K was equivalent to 20 mg of purified lovastatin. moreover, crYr is well tolerated in patients who are intolerant to statin drugs (6), suggesting that the lower amounts of active substances, enhanced action and more complete metabolism in comparison to a d...

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Cytochrome c Release From Oridonin-Treated Apoptotic A375-S2 Cells Is Dependent on p53 and Extracellular Signal-Regulated Kinase Activation

Cited by 56 publications

References 32 publications

Oridonin induced apoptosis through Akt and MAPKs signaling pathways in human osteosarcoma cells

Oridonin induced apoptosis through Akt and MAPKs signaling pathways in human osteosarcoma cells

Activation of Phosphoinositide 3-Kinase, Protein Kinase C, and Extracellular Signal-Regulated Kinase Is Required for Oridonin-Enhanced Phagocytosis of Apoptotic Bodies in Human Macrophage-Like U937 Cells

Genomic and in vivo evidence of synergy of a herbal extract compared to its most active ingredient: Rabdosia rubescens vs. oridonin

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