Parthenolide Cooperates with NS398 to Inhibit Growth of Human Hepatocellular Carcinoma Cells through Effects on Apoptosis and G0-G1 Cell Cycle Arrest

Ralstin, Matthew; Gage, Earl A.; Yip-Schneider, Michele; Klein, Patrick; Wiebke, Eric A.; Schmidt, C. Max

doi:10.1158/1541-7786.mcr-05-0157

Cited by 40 publications

(20 citation statements)

References 67 publications

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“…Previous studies have verified that parthenolide can inhibit activation of IKK in pancreatic and hepatocellular carcinoma cells lines (25,27). Here, we examined whether parthenolide has the same effect in human NSCLC lines.…”

Section: Ikk Kinase Complexmentioning

confidence: 90%

Nuclear Factor-κB Inhibition by Parthenolide Potentiates the Efficacy of Taxol in Non–Small Cell Lung Cancer In vitro and In vivo

Zhang

Qiu²,

Jin³

et al. 2009

Molecular Cancer Research

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In this study, we have examined the molecular events induced by parthenolide, a sesquiterpene lactone, and explored possible mechanisms of resistance and sensitization of tumor cells to Taxol. We showed that parthenolide could antagonize Taxol-mediated nuclear factor-κB (NF-κB) nuclear translocation and activation and Bcl-xl up-regulation by selectively targeting I-κB kinase activity. In A549 cells, inhibition of nuclear factor-κB by parthenolide resulted in activation of the mitochondrial death pathway to promote cytochrome c release and caspase 3 and 9 activation. In contrast, Taxol alone induced apoptosis via a pathway independent of mitochondria cytochrome c cascade. In addition, depletion of Bcl-xl rescued the apoptotic response to Taxol. Moreover, treatment with parthenolide increased the efficacy of the Taxol-induced inhibition of A549 tumor xenografts in mice. This study elucidated the cellular responses induced by parthenolide that decrease the threshold of mitochodriadependent apoptosis in the treatment of non-small cell lung cancer cells.

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Section: Ikk Kinase Complexmentioning

confidence: 90%

Nuclear Factor-κB Inhibition by Parthenolide Potentiates the Efficacy of Taxol in Non–Small Cell Lung Cancer In vitro and In vivo

Zhang

Qiu²,

Jin³

et al. 2009

Molecular Cancer Research

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“…The anticancer potential of parthenolide has been described both in vitro (43,(46)(47)(48)(49) and on animal models (44,50). Moreover, it has been shown that parthenolide could reduce metastasis (50).…”

Section: Discussionmentioning

confidence: 99%

Parthenolide Inhibits Tubulin Carboxypeptidase Activity

et al. 2007

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Microtubules are centrally involved in cell division, being the principal components of mitotic spindle. Tubulin, the constituent of microtubules, can be cyclically modified on its A-subunit by enzymatic removal of the COOH-terminal tyrosine residue by an ill-defined tubulin carboxypeptidase (TCP) and its readdition by tubulin tyrosine ligase (TTL). We and others have previously shown that suppression of TTL and resulting accumulation of detyrosinated tubulin are frequent in human cancers of poor prognosis. Explanations for the involvement of TTL and detyrosinated tubulin in tumor progression arise from the recent discovery that tubulin detyrosination leads to CAP-Gly protein mislocalization, which correlates with defects in spindle positioning during mitosis. Impaired control of spindle positioning is one factor favoring tumor invasiveness. Thus, TCP could be a target for developing novel therapeutic strategies against advanced stages of cancers. Inhibitors of TCP, by reversing abnormal detyrosinated tubulin accumulation in tumor cells, could impair tumor progression. TCP has never been isolated and this has hampered search of specific inhibitors. In this article, we describe a cell-based assay of TCP activity and its use to screen a library of natural extracts for their inhibitory potency. This led to the isolation of two sesquiterpene lactones. We subsequently found that parthenolide, a structurally related compound, can efficiently inhibit TCP. This inhibitory activity is a new specific property of parthenolide independent of its action on the nuclear factor-KB pathway. Parthenolide is also known for its anticancer properties. Thus, TCP inhibition could be one of the underlying mechanisms of these anticancer properties.

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“…A previous study reported that the cytostatic effects of low concentrations of PTL inhibit the growth of tumor lines by labeling the S-phase of BrdU cells, a mouse fibrosarcoma cell line, though the results were unclear (15). Ralstin et al found that PTL functions in cooperation with NS398 to inhibit the growth of human hepatocellular carcinoma cells by effects on apoptosis and G 0 /G 1 cell cycle arrest (16). In the present study, we investigated the kinetics of apoptosis induction and cell cycle distribution after 0, 6, 12, and 24 h of incubation with PTL, treatment with hyperthermia and combination treatment using flow cytometric analysis.…”

Section: Introductionmentioning

confidence: 89%

“…3). PTL may also be effective in combination with COX-2 inhibitors for the treatment of hepatocellular carcinoma, for example, combination treatment with PTL and NS398 altered the cell cycle distribution resulting in greater G 0 /G 1 accumulation, which increased apoptosis only in PLC cells, 1 of 3 human hepatocellular carcinoma lines, which may decrease the apoptotic threshold in cells (16). As for the cell cycle distribution of HL-60 and Jurkat cells with inactive NF-κB, it was demonstrated that PTL induced transient cell arrest in the G 2 and M phases followed by apoptosis (46).…”

Section: Assessment Of Sub-g 1 Fraction With Flow Cytometric Distribumentioning

confidence: 99%

Inhibition of NF-κB by combination therapy with parthenolide and hyperthermia and kinetics of apoptosis induction and cell cycle arrest in human lung adenocarcinoma cells

Hayashi

Sakurai²,

Hayashi³

et al. 2009

Int J Mol Med

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Abstract. We investigated the mechanisms of thermosensitization related to combination therapy with sesquiterpene lactone parthenolide (PTL), a nuclear factor-κB (NF-κB) inhibitor, and hyperthermia using human lung adenocarcinoma cells A549. The kinetics of apoptosis induction and cell cycle of cells treated with PTL, heating, and combined treatment were examined by flow cytometric analysis. The flow cytometric distribution was calculated and expressed as a percentage. The ratios of the sub-G 1 division, used to determine the induction of apoptosis, increased significantly with the combination therapy. Furthermore, the ratios of G 2 /M division increased and the ratios of G 0 /G 1 division decreased, indicating cell cycle arrest in G 2 /M. The cell phase response to PTL by A549 cells synchronized in the G 1 /S border with hydroxyurea was also analyzed. PTL showed remarkable cytotoxicity at the S phase of the cell cycle in A549 cells at all concentrations as well as with hyperthermia, thus PTL reduced the number of cells in the proliferation phase. Inhibition of intracellular transcription factor NF-κB activation in A549 cells with various incubation periods after treatments with PTL, heating and combined treatment was examined by Western blot analysis. Unexpectedly, PTL alone did not inhibit NF-κB activation in cells stimulated with TNF-·, while heating alone inhibited NF-κB early after treatment and that effect faded over time. In contrast, PTL combined with heating completely inhibited NF-κB activation. Our results demonstrated that PTL and heating in combination cause significant thermosensitization of A549 cells via induction of apoptosis or cell cycle arrest in G 2 /M by inhibiting NF-κB activation in a synergistic manner.

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Parthenolide Cooperates with NS398 to Inhibit Growth of Human Hepatocellular Carcinoma Cells through Effects on Apoptosis and G0-G1 Cell Cycle Arrest

Cited by 40 publications

References 67 publications

Nuclear Factor-κB Inhibition by Parthenolide Potentiates the Efficacy of Taxol in Non–Small Cell Lung Cancer In vitro and In vivo

Nuclear Factor-κB Inhibition by Parthenolide Potentiates the Efficacy of Taxol in Non–Small Cell Lung Cancer In vitro and In vivo

Parthenolide Inhibits Tubulin Carboxypeptidase Activity

Inhibition of NF-κB by combination therapy with parthenolide and hyperthermia and kinetics of apoptosis induction and cell cycle arrest in human lung adenocarcinoma cells

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