An<i>ent</i>-Kaurene Diterpene Enhances Apoptosis Induced by Tumor Necrosis Factor in Human Leukemia Cells

Suzuki, Itsuko S.; Kondoh, Masuo; Harada, Motoki; Koizumi, Naoya; Fujii, Makiko; Nagashima, Fumihiro; Asakawa, Yoshinori; Watanabe, Yoshihisa

doi:10.1055/s-2004-827202

Cited by 37 publications

(23 citation statements)

References 14 publications

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“…Certain previously studied kaurane diterpenes, all possessing an enone group, have been reported to have pro‐apoptotic activity through activation of caspase‐8 and ‐3 (Nagashima et al , 2003; Kondoh et al , 2004; Suzuki et al , 2004a, 2004b). By contrast, foliol and linearol lacking this chemical group have shown protective effects on apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Kaurane diterpenes protect against apoptosis and inhibition of phagocytosis in activated macrophages

Heras

Hortelano

Girón

et al. 2007

British J Pharmacology

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Background and purpose: The kaurane diterpenes foliol and linearol are inhibitors of the activation of nuclear factor kB, a transcription factor involved in the inflammatory response. Effects of these diterpenes on apoptosis and phagocytosis have been analysed in cultured peritoneal macrophages and in the mouse macrophage cell line, RAW 264.7. Experimental approach: Macrophages were maintained in culture and activated with pro-inflammatory stimuli in the absence or presence of diterpenes. Apoptosis and the phagocytosis in these cells under these conditions were determined. Key results: Incubation of macrophages with a mixture of bacterial lipopolysaccharide (LPS)/interferon-g (IFN-g) induced apoptosis through a NO-dependent pathway, an effect significantly inhibited by foliol and linearol in the low mM range, without cytotoxic effects. Apoptosis in macrophages induced by NO donors was also inhibited. The diterpenes prevented apoptosis through a mechanism compatible with the inhibition of caspase-3 activation, release of cytochrome c to the cytosol and p53 overexpression, as well as an alteration in the levels of proteins of the Bcl-2 family, in particular, the levels of Bax. Cleavage of poly(ADP-ribose) polymerase, a well-established caspase substrate, was reduced by these diterpenes. Treatment of cells with foliol and linearol decreased phagocytosis of zymosan bioparticles by RAW 264.7 cells and to a greater extent by peritoneal macrophages. Conclusions and implications: Both diterpenes protected macrophages from apoptosis and inhibited phagocytosis, resulting in a paradoxical control of macrophage function, as viability was prolonged but inflammatory and phagocytic functions were impaired.

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Section: Discussionmentioning

confidence: 99%

Kaurane diterpenes protect against apoptosis and inhibition of phagocytosis in activated macrophages

Heras

Hortelano

Girón

et al. 2007

British J Pharmacology

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“…IR-spectra with KBr plates were on an IFS-120H IR spectrometer. 1 H-, 13 C-and 2D-NMR spectra were recorded on an INOVA (Varian) spectrometer with TMS as internal standard. FABMS and ELMS spectra were recorded on an Autospec 3000 spectrometer.…”

Section: Instruments and Reagentsmentioning

confidence: 99%

“…According to the molecular skeleton, ent-kaurene diterpenoids are classified into four principal categories: C-20-non-oxygenated-ent-kaurenes, C-20-oxygenatedent-kaurenes, 6,7-seco-ent-kaurenes enmein type, and 6,7-seco-ent-kaurenes spirolactone type [8]. The literature shows that ent-kaurene diterpenoids possess varied biological activities, including anti-tumor [9,10], anti-bacterial [11,12], antiinflammatory [8], induction of apoptosis [13], antioxidant [14] and cytotoxicity [15][16][17][18]. The most extensive and predominant reports are about their in vitro cytotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Structure–activity relationships of eight ent-kaurene diterpenoids from three Isodon plants

et al. 2010

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Eight ent-kaurene diterpenoids were isolated from three Isodon plants, Isodon excisoides (Sun ex C. H. Hu) C. Y. Wu et H. W. Li, Isodon weisiensis C. Y. Wu, and Isodon racemosa (Hemsl.) Hara. Their cytotoxicities were tested by SRB assay against four human tumor cell lines, HepG2, Tb, HO-8910 and SGC-7901. The DNA damage degrees on their Hep G2 cells were evaluated by Comet assay. The results showed that ent-kaurene diterpenoids were selectively toxic against these four tumor cell lines. Weisiensic C had the lowest cytotoxicity against four cell lines and degree of DNA damage on the Hep G2 cell line. Leukamenin E and Glaucocalyxin A had similar IC 50 values and also induced a similar degree of DNA damage. The cytotoxicity and degree of DNA damage of eight entkaurene diterpenoids on Hep G2 was in the order Leukamenin E [ Glaucocalyxin A [ Wangzaozin A [ Kamebanin [ Macrocalyxin D [ Weisiensin B [ Excisanin K [ Weisiensic C. The structure-activity relationships indicated that there was some correlation between the substituents and their structures of ent-kaurene diterpenoids and their activities on Hep G2 cells.

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“…We previously found that both Bcl-2 mRNA and protein levels in the MCF-7 cancer cell line lowered after exposure to the natural compound ent-16b-17a-dihydroxykaurane (DHK) in a way which was not directly associated to NFjB molecule inactivation [24], as other kaurenoid diterpenes have been reported [25][26][27]. In this work we showed that DHK affected Rb and E2F1 protein levels in opposite ways to favor the apoptosis onset in MCF-7 cells.…”

Section: Introductionmentioning

confidence: 77%

The natural diterpene ent-16β-17α-dihydroxykaurane down-regulates Bcl-2 by disruption of the Ap-2α/Rb transcription activating complex and induces E2F1 up-regulation in MCF-7 cells

Morales¹,

Álvarez²,

Arvelo

et al. 2011

Apoptosis

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ent-Kauranes are diterpene-type compounds commonly found in most plant species, especially from the Euphorbiaceae family. These compounds have been studied due to their anti-inflammatory and anti-tumor properties. Regulation of apoptosis, or programmed cell death, is commonly bypassed by tumoral cells, giving rise to uncontrolled proliferating cells, which eventually become carcinogenic. In a previous work, we showed that both mRNA and protein expression levels of the antiapoptotic gene Bcl-2 are reduced in MCF-7 cancer cells by the effect of the natural diterpene ent-16β-17α-dihydroxykaurane (DHK). This effect was not directly associated with the inactivation of NF-κB, as has been shown with other diterpenes compounds. Herein, we report that DHK is dissociating the Ap2α-Rb activating complex, affecting its binding ability for the Bcl-2 gene promoter. These events down-regulate Bcl-2 and is temporally accompanied by the induction of E2F1 and its target pro-apoptotic gene Puma. Disruption of the Rb-Ap2α activation complex was corroborated by chromatin immunoprecipitation and protein immunolocalization, which also revealed that Ap2α sorts out from the nucleus and relocalizes in the cell periphery. Taken together, our study confirms the regulation of Bcl-2 gene transcription by the Ap2α-Rb complex and describes a singular protein relocalization for Ap2α induced by DHK, implicating a new potential therapeutic target to differentially onset apoptosis in tumor cells.

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Anent-Kaurene Diterpene Enhances Apoptosis Induced by Tumor Necrosis Factor in Human Leukemia Cells

Cited by 37 publications

References 14 publications

Kaurane diterpenes protect against apoptosis and inhibition of phagocytosis in activated macrophages

Kaurane diterpenes protect against apoptosis and inhibition of phagocytosis in activated macrophages

Structure–activity relationships of eight ent-kaurene diterpenoids from three Isodon plants

The natural diterpene ent-16β-17α-dihydroxykaurane down-regulates Bcl-2 by disruption of the Ap-2α/Rb transcription activating complex and induces E2F1 up-regulation in MCF-7 cells

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