Ajoene-induced cell death in human promyeloleukemic cells does not require JNK but is amplified by the inhibition of ERK

Antlsperger, Dorothee; Dirsch, Verena M.; Ferreira, David; Su, Jen Liang; Kuo, Min Liang; Vollmar, Angelika M.

doi:10.1038/sj.onc.1206161

Cited by 32 publications

(28 citation statements)

References 44 publications

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“…Activation of JNK (late and sustained), p38 (fast and sustained), and ERK1/2 as well as the survival kinase Akt (fast and transient) has also been observed in HL-60 cells treated with ajoene [Antlsperger et al, 2003]. However, ajoene-induced mitochondrial membrane permeabilization and subsequent caspase activation in this model was shown to be independent of JNK activation [Antlsperger et al, 2003].…”

Section: Modulation Of Bcl-2 Familymentioning

confidence: 91%

Apoptosis induction by sulfur‐containing compounds in malignant and nonmalignant human cells

Fimognari

Lenzi

Hrelia

2009

Environ and Mol Mutagen

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Plants have traditionally represented a main source for the discovery of many biologically active substances with therapeutic values. Sulfur-containing compounds exhibit pleiotropic biological effects supporting their potential use in multitargeted cancer prevention and treatment. As potential anti-cancer agents, they have been shown to inhibit or retard the growth of various cancer cells in culture and implanted tumors in vivo. The compounds significantly inhibit experimental tumorigenesis in a wide range of animal models. A critical and well-elucidated cellular mechanism involved in the anticancer activities of sulfur-containing compounds is the induction of apoptosis through the fine-tuning of orchestrated intracellular signal transduction. This review summarizes the established proapoptotic activities of sulfur-containing compounds in malignant and nonmalignant cells with a special focus on their molecular mechanisms. The potential toxicological implications of proapoptotic effects on normal cells will also be discussed.

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Section: Modulation Of Bcl-2 Familymentioning

confidence: 91%

Apoptosis induction by sulfur‐containing compounds in malignant and nonmalignant human cells

Fimognari

Lenzi

Hrelia

2009

Environ and Mol Mutagen

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“…Altogether, active JNK seems to be a contributor rather than the sole required factor for ASC-triggered cell death. The requirement of JNK in stress-induced cell death appears to be highly dependent on the cell type and the signaling context: transient activation of JNK when also accompanied by survival pathways, including Akt kinase and ERK1/2 MAPK, may not be associated with cell death (Barr and Bogoyevitch, 2001;Antlsperger et al, 2003). ASC-induced JNK activation occurs transiently: phospho-JNK was visible at 4 and 8 h only (Figure 5a).…”

Section: Discussionmentioning

confidence: 99%

Apoptosis signaling triggered by the marine alkaloid ascididemin is routed via caspase-2 and JNK to mitochondria

Dirsch

Kirschke

Estermeier³

et al. 2003

Oncogene

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The marine alkaloid ascididemin (ASC) was shown to exert cytotoxicity even against multidrug-resistant cancer cells. Here, we address the signaling pathways utilized by ASC to trigger apoptosis in Jurkat leukemia T cells. We show that ASC (0.5-20 lM) induces a mitochondrial pathway that requires the activation of the initiator caspase-2 upstream of mitochondria. ASC-triggered apoptosis occurred independent of CD95, but required mitochondrial dysfunction. The activation of caspase-2 was shown to precede the processing of caspase-8, -9 and -3. The specific caspase-2 inhibitor zVDVADfmk abrogated ASC-induced DNA fragmentation almost completely. Overexpression of Bcl-x L blocked caspase-8 but not caspase-2 processing. Conversely, caspase-2 inhibition strongly reduced caspase-9 activation. As a possible link between caspase-2 and mitochondrial dysfunction, Bid was found to be cleaved by ASC. In addition, JNK was activated by ASC upstream of mitochondria via reactive oxygen species. The specific JNK inhibitor SP600125 partially inhibited caspase-2 and -9 processing as well as cytochrome c release and DNA fragmentation indicating that JNK contributes to, but is not necessary for ASCmediated apoptosis. Thus, ASC triggers a pathway in which early activation of caspase-2 provides a possible link between its DNA-damaging activity and the induction of mitochondrial dysfunction. The activation of JNK contributes to this signaling upstream of mitochondria.

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“…These effects were due to cell cycle arrest in G 2 and mitosis and apoptosis. It is shown that ajoene, an organosulphur compound originating from garlic, activated signal pathways that may have anti-and proapoptotic effects, respectively (Antlsperger et al, 2003). Importantly inhibition of extracellular signal-regulated kinases (ERK) 1/2 amplified the ajoene-induced cell death and this combination could therefore be interesting in cancer treatment.…”

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confidence: 99%

Garlic arrests MDA-MB-435 cancer cells in mitosis, phosphorylates the proapoptotic BH3-only protein BimEL and induces apoptosis

et al. 2005

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Components of garlic (Allium sativum) can cause disruption of microtubules, cell cycle arrest, and apoptosis in cancer cells. We show here that a water-soluble extract of garlic arrested MDA-MB-435 cancer cells in mitosis and caused apoptosis. The proapoptotic BH3-only, bcl-2 family protein Bim EL , which in healthy cells can be tightly sequestered to the microtubule-associated dynein motor complex, was modified after garlic treatment. The main effect of garlic on Bim EL was a considerable increase in a phosphorylated form of the protein. This phosphorylation(s), probably partly dependent on c-jun N-terminal kinase activity, promoted mitochondrial localisation of Bim EL . Furthermore, inhibition of extracellular signal-regulated kinases 1/2 increased the amount of another form of Bim EL present in the mitochondrial cellular fraction. Treatment of cells with the garlic compound diallyl disulphide had similar effects on Bim EL . The results indicate that the apoptotic effect of garlic and a combination of garlic and the inhibitor of extracellular signalregulated kinases 1/2 in MDA-MB-435 cells partly is due to modifications that are necessary for translocation of the proapoptotic protein Bim EL to mitochondria where it executes its proapoptotic function.

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Ajoene-induced cell death in human promyeloleukemic cells does not require JNK but is amplified by the inhibition of ERK

Cited by 32 publications

References 44 publications

Apoptosis induction by sulfur‐containing compounds in malignant and nonmalignant human cells

Apoptosis induction by sulfur‐containing compounds in malignant and nonmalignant human cells

Apoptosis signaling triggered by the marine alkaloid ascididemin is routed via caspase-2 and JNK to mitochondria

Garlic arrests MDA-MB-435 cancer cells in mitosis, phosphorylates the proapoptotic BH3-only protein BimEL and induces apoptosis

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