Novel effects of glycyrrhetinic acid on the central nervous system tumorigenic progenitor cells: Induction of actin disruption and tumor cell-selective toxicity

Yamaguchi, Hideaki; Noshita, Toshiro; Tang, Yu; Kidachi, Yumi; Kamiie, Katsuyoshi; Umetsu, Hironori; Ryoyama, Kazuo

doi:10.1016/j.ejmech.2010.03.021

Cited by 52 publications

(26 citation statements)

References 27 publications

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“…Furthermore, GA also down-regulates H-Ras activity in cancer cells [34]. Lastly, GA disrupts F-actin extensions and down-regulates -actin protein in cancer cells, inducing significant cytostatic (antiproliferative) and anti-migratory effects in these cancer cells through the disruption of the actin cytoskeleton [35].…”

Section: Historical Overview Of the Anticancer Potential Of Glycyrrhementioning

confidence: 99%

Structure-Activity Relationship Analyses of Glycyrrhetinic Acid Derivatives as Anticancer Agents

Lallemand¹,

Gelbcke²,

Dubois³

et al. 2011

MRMC

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Cancer cell resistance to kinase inhibitors and targeted agents, acquisition of a multidrug-resistant (MDR) phenotype and/or intrinsic resistance to apoptosis prevent effective treatment in about 50% of solid cancers in adults, and the percentage is even higher in children. Glycyrrhetinic acid (GA) and some of its derivatives may offer hope in combating cancer types associated with poor prognoses. Some GA derivatives are indeed able to target both the proteasome and peroxisome proliferator-activated receptors (PPARs), two proteins that play major roles in cancer cell biology but are not related to MDR and/or apoptosis-related resistance phenotypes.

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Section: Historical Overview Of the Anticancer Potential Of Glycyrrhementioning

confidence: 99%

Structure-Activity Relationship Analyses of Glycyrrhetinic Acid Derivatives as Anticancer Agents

Lallemand¹,

Gelbcke²,

Dubois³

et al. 2011

MRMC

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“…Ras pathways have been targeted for the development of chemotherapeutic interventions against tumor cells by interfering with cytoskeletal proteins such as actin (31) and tubulin (43). Furthermore, in our previous (44,45) and current studies, we found that GA disrupted F-actin and ␤III-tubulin, which could lead to loss of functionality for cell growth or proliferation and result in apoptosis of the cells. These findings indicate that disturbances in cytoskeletal proteins may be the factors involved in the toxic effects of GA against the tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Ligand-receptor Interaction between Triterpenoids and the 11β-Hydroxysteroid dehydrogenase type 2 (11βHSD2) Enzyme Predicts Their Toxic Effects against Tumorigenic r/m HM-SFME-1 Cells

Yamaguchi

Tang

Noshita

et al. 2011

Journal of Biological Chemistry

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The present study deals with in silico prediction and in vitro evaluation of the selective cytotoxic effects of triterpenoids on tumorigenic human c-Ha-ras and mouse c-myc cotransfected highly metastatic serum-free mouse embryo-1 (r/m HM-SFME-1) cells. Ligand fitting of five different triterpenoids to 11␤-hydroxysteroid dehydrogenase type 2 (11␤HSD2) was analyzed with a molecular modeling method, and glycyrrhetinic acid (GA) was the best-fitted triterpenoid to the ligand binding site in 11␤HSD2. Analysis of antiproliferative effects revealed that GA, oleanolic acid, and ursolic acid had selective toxicity against the tumor cells and that GA was the most potent triterpenoid in its selectivity. The toxic activity of the tested triterpenoids against the tumor cells showed good correlations with the partition coefficient (logP) and polar surface area values. Time-lapse microscopy, fluorescence staining, and confocal laser scanning microscopic observation revealed that GA induced morphologic changes typical of apoptosis such as cell shrinkage and blebbing and also disrupted the cytoskeletal proteins. Furthermore, GA exhibited a strong inhibitory effect on 11␤HSD2 activity in the tumor cells. Our current results suggest that analysis of the ligand-receptor interaction between triterpenoids and 11␤HSD2 can be utilized to predict their antitumor effects and that GA can be used as a possible chemopreventive and therapeutic antitumor agent. To the best of our knowledge, this is the first report on in silico prediction of the toxic effects of triterpenoids on tumor cells by 11␤HSD2 inhibition.Triterpenoids, which are biosynthesized in plants by cyclization of squalene, are widely distributed throughout the vegetable kingdom, utilized in many food products and the major components of medicinal plants used in Asian countries (1). There is a growing interest in elucidating the biological and pharmacological roles of triterpenoids in analgesic, anti-inflammatory, anti-tumor, hepatoprotective, and immunomodulatory effects (1), and we have been focusing our attention on certain triterpenoids as multifunctional agents for the prevention and treatment of cancer. Recently, we found that ursolic acid (UA) 2 from apples was selectively toxic to tumorigenic human c-Ha-ras and mouse c-myc cotransfected highly metastatic serum-free mouse embryo-1 (r/m HM-SFME-1) cells (2). We further found that glycyrrhetinic acid (GA), a licorice component, was not only selectively toxic to the tumor cells but also more potent than some clinically available antitumor agents in its selectivity (3). SFME cells, which were established by Loo et al. (4), were originally derived from a 16-day-old whole Balb/c mouse embryo and are maintained in a serum-free culture medium. These cells do not undergo growth crisis, maintain their diploid karyotype for extended passages, and are non-tumorigenic in vivo. Consequently, they are non-transformed, behave as primary cultures, have a finite lifespan, and display the characteristics of the CNS progenitor cells (5, 6)....

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“…There have been several reports suggesting the association of 11β-HSD type 2 (11βHSD2) with cancers, such as colonic and pituitary adenomas3,4 and breast and colorectal cancers 5–7. Our previous studies showed that glycyrrhetinic acid (GA), a specific 11βHSD2 inhibitor, was selectively toxic toward central nervous system-derived tumor cells 8,9. These studies exhibited that 11βHSD2 could play an important role in tumor regulation and that targeting 11βHSD2 for tumor prevention and therapy could be an effective strategy with highly selective 11βHSD2 inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Mouse 11β-Hydroxysteroid Dehydrogenase Type 2 for Human Application: Homology Modeling, Structural Analysis and Ligand-Receptor Interaction

et al. 2011

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Mouse (m) 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) was homology-modeled, and its structure and ligand-receptor interaction were analyzed. The modeled m11βHSD2 showed significant 3D similarities to the human (h) 11βHSD1 and 2 structures. The contact energy profiles of the m11βHSD2 model were in good agreement with those of the h11βHSD1 and 2 structures. The secondary structure of the m11βHSD2 model exhibited a central 6-stranded all-parallel β-sheet sandwich-like structure, flanked on both sides by 3-helices. Ramachandran plots revealed that only 1.1% of the amino acid residues were in the disfavored region for m11βHSD2. Further, the molecular surfaces and electrostatic analyses of the m11βHSD2 model at the ligand-binding site exhibited that the model was almost identical to the h11βHSD2 model. Furthermore, docking simulation and ligand-receptor interaction analyses revealed the similarity of the ligand-receptor bound conformation between the m11βHSD2 and h11βHSD2 models. These results indicate that the m11βHSD2 model was successfully evaluated and analyzed. To the best of our knowledge, this is the first report of a m11βHSD2 model with detailed analyses, and our data verify that the mouse model can be utilized for application to the human model to target 11βHSD2 for the development of anticancer drugs.

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Novel effects of glycyrrhetinic acid on the central nervous system tumorigenic progenitor cells: Induction of actin disruption and tumor cell-selective toxicity

Cited by 52 publications

References 27 publications

Structure-Activity Relationship Analyses of Glycyrrhetinic Acid Derivatives as Anticancer Agents

Structure-Activity Relationship Analyses of Glycyrrhetinic Acid Derivatives as Anticancer Agents

Ligand-receptor Interaction between Triterpenoids and the 11β-Hydroxysteroid dehydrogenase type 2 (11βHSD2) Enzyme Predicts Their Toxic Effects against Tumorigenic r/m HM-SFME-1 Cells

Mouse 11β-Hydroxysteroid Dehydrogenase Type 2 for Human Application: Homology Modeling, Structural Analysis and Ligand-Receptor Interaction

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