Down-regulation of c-FLIP, XIAP and Mcl-1 protein as well as depletion of reduced glutathione contribute to the apoptosis induction of glycyrrhenitic acid derivatives in leukemia cells

Song, Dandan; Gao, Yuan; Wang, Rui; Liú, Dan; Zhao, Liang; Jing, Yongkui

doi:10.4161/cbt.9.2.10287

Cited by 33 publications

(23 citation statements)

References 37 publications

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“…There are precedents that NAC protects drug-induced apoptosis through its thiol-disulfide exchange activity independent of its antioxidant activity [26,38,39]. In our study, we found that perifosine decreased the levels of intracellular GSH, as did DEM.…”

Section: Discussionsupporting

confidence: 69%

c-Jun NH2-terminal kinase-dependent upregulation of DR5 mediates cooperative induction of apoptosis by perifosine and TRAIL

Elrod

et al. 2010

Mol Cancer

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BackgroundPerifosine, an alkylphospholipid tested in phase II clinical trials, modulates the extrinsic apoptotic pathway and cooperates with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to augment apoptosis. The current study focuses on revealing the mechanisms by which perifosine enhances TRAIL-induced apoptosis.ResultsThe combination of perifosine and TRAIL was more active than each single agent alone in inducing apoptosis of head and neck squamous cell carcinoma cells and inhibiting the growth of xenografts. Interestingly, perifosine primarily increased cell surface levels of DR5 although it elevated the expression of both DR4 and DR5. Blockade of DR5, but not DR4 upregulation, via small interfering RNA (siRNA) inhibited perifosine/TRAIL-induced apoptosis. Perifosine increased phosphorylated c-Jun NH2-terminal kinase (JNK) and c-Jun levels, which were paralleled with DR4 and DR5 induction. However, only DR5 upregulaiton induced by perifosine could be abrogated by both the JNK inhibitor SP600125 and JNK siRNA. The antioxidants, N-acetylcysteine and glutathione, but not vitamin C or tiron, inhibited perifosine-induced elevation of p-c-Jun, DR4 and DR5. Moreover, no increased production of reactive oxygen species was detected in perifosine-treated cells although reduced levels of intracellular GSH were measured.ConclusionsDR5 induction plays a critical role in mediating perifosine/TRAIL-induced apoptosis. Perifosine induces DR5 expression through a JNK-dependent mechanism independent of reactive oxygen species.

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Section: Discussionsupporting

confidence: 69%

c-Jun NH2-terminal kinase-dependent upregulation of DR5 mediates cooperative induction of apoptosis by perifosine and TRAIL

Elrod

et al. 2010

Mol Cancer

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“…The results also showed that the esterification at C-30 (compound 3 , Scheme 1 ) could improve the antitumor efficacy compared with compound 2 . The same result could be found from previous findings and parallel results [ 28 , 29 , 30 , 31 , 32 ]. Besides, the introduction of nitrogen-containing substituents to the ring-A seemed to improve the anti-proliferative effect of GA derivatives.…”

Section: Four Aspects Of the Structural Modifications Of Glycyrrhesupporting

confidence: 92%

An Overview of Structurally Modified Glycyrrhetinic Acid Derivatives as Antitumor Agents

Zhang

et al. 2017

Molecules

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Glycyrrhetinic Acid (GA), a triterpenoid aglycone component of the natural product glycyrrhizinic acid, was found to possess remarkable anti-proliferative and apoptosis-inducing activity in various cancer cell lines. Though GA was not as active as other triterpenes, such as betulinic acid and oleanolic acid, it could trigger apoptosis in tumor cells and it can be obtained easily and cheaply, which has stimulated scientific interest in using GA as a scaffold to synthesize new antitumor agents. The structural modifications of GA reported in recent decades can be divided into four groups, which include structural modifications on ring-A, ring-C, ring-E and multiple ring modifications. The lack of a comprehensive and recent review on this topic prompted us to gather more new information. This overview is dedicated to summarizing and updating the structural modification of GA to improve its antitumor activity published between 2005 and 2016. We reviewed a total of 210 GA derivatives that we encountered and compiled the most active GA derivatives along with their activity profile in different series. Furthermore, the structure activity relationships of these derivatives are briefly discussed. The included information is expected to be of benefit to further studies of structural modifications of GA to enhance its antitumor activity.

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“…Compound 19 was determined to be the most selective substance of this study. The cytotoxicity of these compounds is comparable to that of well-known anti-tumor substances like CDODO-Me-11 (1.48 µ M on HL-60 cells) or CDODO-Me-12 (0.36 µ M on HL-60 cells) [29].…”

Section: Resultsmentioning

confidence: 60%

Synthesis and Cytotoxic Activity of Methyl Glycyrrhetinate Esterified with Amino Acids

Csuk

Schwarz

Siewert

et al. 2012

Zeitschrift Für Naturforschung B

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Methyl glycyrrhetinate was esterified at position C3 of ring A using different amino acids. A short, unbranched chain of four carbon atoms with two amino groups in positions 2 and 4 was shown to be the most active compound of this series (IC 50 = 0.8 M on liposarcoma Lipo cells). These compounds trigger apoptosis as shown by an acridine orange/ethidium bromide assay, trypan blue tests and DNAladdering experiments.

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Down-regulation of c-FLIP, XIAP and Mcl-1 protein as well as depletion of reduced glutathione contribute to the apoptosis induction of glycyrrhenitic acid derivatives in leukemia cells

Cited by 33 publications

References 37 publications

c-Jun NH2-terminal kinase-dependent upregulation of DR5 mediates cooperative induction of apoptosis by perifosine and TRAIL

c-Jun NH2-terminal kinase-dependent upregulation of DR5 mediates cooperative induction of apoptosis by perifosine and TRAIL

An Overview of Structurally Modified Glycyrrhetinic Acid Derivatives as Antitumor Agents

Synthesis and Cytotoxic Activity of Methyl Glycyrrhetinate Esterified with Amino Acids

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